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Sample records for metastatic breast tumor

  1. Serum-derived exosomes from mice with highly metastatic breast cancer transfer increased metastatic capacity to a poorly metastatic tumor.

    PubMed

    Gorczynski, Reginald M; Erin, Nuray; Zhu, Fang

    2016-02-01

    Altered interaction between CD200 and CD200R represents an example of "checkpoint blockade" disrupting an effective, tumor-directed, host response in murine breast cancer cells. In CD200R1KO mice, long-term cure of EMT6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB/c mice. The reverse was observed with 4THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD200R1KO. We explored possible explanations for this difference. We measured the frequency of circulating tumor cells (CTCs) in peripheral blood of tumor bearers, as well as lung/liver and draining lymph nodes. In some cases mice received infusions of exosomes from nontumor controls, or tumor bearers, with/without additional infusions of anticytokine antibodies. The measured frequency of circulating tumor cells (CTCs) in peripheral blood was equivalent in the two models in WT and CD200R1KO mice. Increased metastasis in EMT6 tumor bearers was seen in vivo following adoptive transfer of serum, or serum-derived exosomes, from 4THM tumor bearers, an effect which was attenuated by anti-IL-6, and anti-IL-17, but not anti-TNFα, antibody. Anti-IL-6 also attenuated enhanced migration of EMT6 cells in vitro induced by 4THM serum or exosomes, or recombinant IL-6. Exosome cytokine proteomic profiles responses in 4THM and EMT6 tumor-bearing mice were regulated by CD200:CD200R interactions, with attenuation of both IL-6 and IL-17 in 4THM CD200(tg) mice, and enhanced levels in 4THM CD200R1KO mice. We suggest these cytokines act on the microenvironment at sites within the host, and/or directly on tumor cells themselves, to increase metastatic potential. PMID:26725371

  2. Serum-derived exosomes from mice with highly metastatic breast cancer transfer increased metastatic capacity to a poorly metastatic tumor.

    PubMed

    Gorczynski, Reginald M; Erin, Nuray; Zhu, Fang

    2016-02-01

    Altered interaction between CD200 and CD200R represents an example of "checkpoint blockade" disrupting an effective, tumor-directed, host response in murine breast cancer cells. In CD200R1KO mice, long-term cure of EMT6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB/c mice. The reverse was observed with 4THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD200R1KO. We explored possible explanations for this difference. We measured the frequency of circulating tumor cells (CTCs) in peripheral blood of tumor bearers, as well as lung/liver and draining lymph nodes. In some cases mice received infusions of exosomes from nontumor controls, or tumor bearers, with/without additional infusions of anticytokine antibodies. The measured frequency of circulating tumor cells (CTCs) in peripheral blood was equivalent in the two models in WT and CD200R1KO mice. Increased metastasis in EMT6 tumor bearers was seen in vivo following adoptive transfer of serum, or serum-derived exosomes, from 4THM tumor bearers, an effect which was attenuated by anti-IL-6, and anti-IL-17, but not anti-TNFα, antibody. Anti-IL-6 also attenuated enhanced migration of EMT6 cells in vitro induced by 4THM serum or exosomes, or recombinant IL-6. Exosome cytokine proteomic profiles responses in 4THM and EMT6 tumor-bearing mice were regulated by CD200:CD200R interactions, with attenuation of both IL-6 and IL-17 in 4THM CD200(tg) mice, and enhanced levels in 4THM CD200R1KO mice. We suggest these cytokines act on the microenvironment at sites within the host, and/or directly on tumor cells themselves, to increase metastatic potential.

  3. Inhibition of metastatic tumor growth and metastasis via targeting metastatic breast cancer by chlorotoxin-modified liposomes.

    PubMed

    Qin, Chao; He, Bing; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Wang, Guangji; Yin, Lifang; Zhang, Qiang

    2014-10-01

    A liposome system modified with chlorotoxin (ClTx), a scorpion venom peptide previously utilized for targeting brain tumors, was established. Its targeting efficiency and antimetastasis behavior against metastatic breast cancer highly expressed MMP-2, the receptor of ClTx, were investigated. 4T1, a metastatic breast cancer cell line derived from a murine breast tumor, was selected as the cell model. As results, the ClTx-modified liposomes displayed specific binding to 4T1 as determined by flow cytometry and confocal imaging. The cytotoxicity assay revealed that the ClTx modification increased the toxicity compared with nonmodified liposomes. In addition, the modified liposomes also exhibited high in vivo targeting efficiency in the BALB/c mice bearing 4T1 tumors. Importantly, this system inhibited the growth of metastatic tumor and prevented the incidence of lung metastasis in mice bearing 4T1 tumors with only low systemic toxicity. The data obtained from the in vitro and in vivo studies confirmed that the ClTx-modified liposomes increased the drug delivery to metastatic breast cancers. This study proved that the ClTx-modified liposomes had targeting ability to metastatic breast cancer in addition to brain cancer, and displayed an obvious antimetastasis effect. Generally, it may provide a promising strategy for metastatic breast cancer therapy.

  4. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor.

    PubMed

    Velez-Cubian, Frank O; Gabordi, Robert C; Smith, Prudence V; Toloza, Eric M

    2016-06-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SFT containing metastatic invasive ductal breast carcinoma as well as a synchronous contralateral primary adenocarcinoma of the lung. The literature on tumor-to-tumor metastasis is then reviewed.

  5. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor.

    PubMed

    Velez-Cubian, Frank O; Gabordi, Robert C; Smith, Prudence V; Toloza, Eric M

    2016-06-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SFT containing metastatic invasive ductal breast carcinoma as well as a synchronous contralateral primary adenocarcinoma of the lung. The literature on tumor-to-tumor metastasis is then reviewed. PMID:27293861

  6. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor

    PubMed Central

    Velez-Cubian, Frank O.; Gabordi, Robert C.; Smith, Prudence V.

    2016-01-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SFT containing metastatic invasive ductal breast carcinoma as well as a synchronous contralateral primary adenocarcinoma of the lung. The literature on tumor-to-tumor metastasis is then reviewed. PMID:27293861

  7. Tumor Therapeutic Response and Vessel Tortuosity: Preliminary Report in Metastatic Breast Cancer

    PubMed Central

    Bullitt, Elizabeth; Lin, Nancy U.; Ewend, Matthew G.; Zeng, Donglin; Winer, Eric P.; Carey, Lisa A.; Smith, J. Keith

    2008-01-01

    No current non-invasive method is capable of assessing the efficacy of brain tumor therapy early during treatment. We outline an approach that evaluates tumor activity via statistical analysis of vessel shape using vessels segmented from MRA. This report is the first to describe the changes in vessel shape that occur during treatment of metastatic brain tumors as assessed by sequential MRA. In this preliminary study of 16 patients undergoing treatment for metastatic breast cancer we conclude that vessel shape may predict tumor response several months in advance of traditional methods. PMID:17354817

  8. Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients.

    PubMed

    Madic, Jordan; Kiialainen, Anna; Bidard, Francois-Clement; Birzele, Fabian; Ramey, Guillemette; Leroy, Quentin; Rio Frio, Thomas; Vaucher, Isabelle; Raynal, Virginie; Bernard, Virginie; Lermine, Alban; Clausen, Inga; Giroud, Nicolas; Schmucki, Roland; Milder, Maud; Horn, Carsten; Spleiss, Olivia; Lantz, Olivier; Stern, Marc-Henri; Pierga, Jean-Yves; Weisser, Martin; Lebofsky, Ronald

    2015-05-01

    Circulating tumor DNA (ctDNA) is a new circulating tumor biomarker which might be used as a prognostic biomarker in a way similar to circulating tumor cells (CTCs). Here, we used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTC detection rates and prognostic value in metastatic TNBC patients. Forty patients were enrolled before starting a new line of treatment. TP53 mutations were characterized in archived tumor tissues and in plasma DNA using two next generation sequencing (NGS) platforms in parallel. Archived tumor tissue was sequenced successfully for 31/40 patients. TP53 mutations were found in 26/31 (84%) of tumor samples. The same mutation was detected in the matched plasma of 21/26 (81%) patients with an additional mutation found only in the plasma for one patient. Mutated allele fractions ranged from 2 to 70% (median 5%). The observed correlation between the two NGS approaches (R(2) = 0.903) suggested that ctDNA levels data were quantitative. Among the 27 patients with TP53 mutations, CTC count was ≥1 in 19 patients (70%) and ≥5 in 14 patients (52%). ctDNA levels had no prognostic impact on time to progression (TTP) or overall survival (OS), whereas CTC numbers were correlated with OS (p = 0.04) and marginally with TTP (p = 0.06). Performance status and elevated LDH also had significant prognostic impact. Here, absence of prognostic impact of baseline ctDNA level suggests that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumor burden, biological features that do not dramatically affect patient outcome.

  9. Identification of Molecular Determinants of Primary and Metastatic Tumor Re-Initiation in Breast Cancer

    PubMed Central

    Ross, Jason B.; Huh, Doowon; Noble, Lisa B.; Tavazoie, Sohail F.

    2015-01-01

    Through in vivo selection of multiple ER-negative human breast cancer populations for enhanced tumor-forming capacity, we have derived sub-populations that generate tumors more efficiently than their parental populations at low cell numbers. Tumorigenic-enriched (TE) sub-populations displayed increased expression of LAMA4, FOXQ1 and NAP1L3—genes that are also expressed at greater levels by independently derived metastatic sub-populations. These genes promote metastatic efficiency. FOXQ1 promotes LAMA4 expression, while LAMA4 enhances clonal expansion upon substratum-detachment in vitro, tumor re-initiation in multiple organs, and disseminated metastatic cell proliferation and colonization. LAMA4’s promotion of cancer cell proliferation and tumor re-initiation requires β1-integrin. Increased LAMA4 expression marks the transition of human pre-malignant breast lesions to malignant carcinomas, while tumoral LAMA4 over-expression predicts reduced relapse-free survival in ER-negative patients. Our findings reveal common features that govern primary and metastatic tumor re-initiation and identify a key molecular determinant of these processes. PMID:25866923

  10. Protective effects of dendrosomal curcumin on an animal metastatic breast tumor.

    PubMed

    Farhangi, Baharak; Alizadeh, Ali Mohammad; Khodayari, Hamid; Khodayari, Saeed; Dehghan, Mohammad Javad; Khori, Vahid; Heidarzadeh, Alemeh; Khaniki, Mahmood; Sadeghiezadeh, Majid; Najafi, Farhood

    2015-07-01

    Curcumin has been shown to inhibit migration and invasion of cancer angiogenesis via interacting with key regulatory molecules like NF-κB. Rapidly metabolized and conjugated in the liver, curcumin has the limited systemic bioavailability. Previous results have shown a new light of potential biocompatibility, biodegradability, as well as anti-cancer effects of dendrosomal curcumin (DNC) in biological systems. The present study aims to deliberate the protective effects of DNC on metastatic breast tumor in vitro and in vivo. After the dosing procedure, twenty-seven female mice were divided into 40 and 80mg/kg groups of DNC, along with a control group to investigate the anti-metastatic effects of DNC on mammary tumor-bearing mice. In vitro results showed that the different concentrations of DNC reduced the migration and the adhesion of 4T1 cells after 24h (P<0.05). Under the dosing procedure, DNC was safe at 80mg/kg and lower doses. The treated DNC animals had a higher survival rate and lower metastatic signs (14%) compared to control (100%) (P<0.05). The metastatic tumors were more common in control mice than the treated groups in the lung, the liver and the sternum tissues. Animals treated with DNC had smaller tumor volume in comparison with control group (P<0.05). Final mean tumor volume reached to approximately 1.11, 0.31 and 0.27cm(3) in the control, and 40 and 80mg/kg DNC groups, respectively (P<0.05). Furthermore, suppression of NF-κB expression by DNC led to down-regulation of VEGF, COX-2, and MMP-9 expressions in the breast tumor, the lung, the brain, the spleen and the liver tissues (P<0.05). These outcomes indicate that dendrosomal curcumin has a chemoprotective effect on the breast cancer metastasis through suppression of NF-κB and its regulated gene products. PMID:25863259

  11. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo.

    PubMed

    Nelson, Michaela; Yang, Ming; Millican-Slater, Rebecca; Brackenbury, William J

    2015-10-20

    Voltage-gated Na+ channels (VGSCs) mediate action potential firing and regulate adhesion and migration in excitable cells. VGSCs are also expressed in cancer cells. In metastatic breast cancer (BCa) cells, the Nav1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Nav1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Nav1.5 is up-regulated at the protein level in BCa compared with matched normal breast tissue. Na+ current, reversibly blocked by tetrodotoxin, was retained in cancer cells in tumor tissue slices, thus directly confirming functional VGSC activity in vivo. Stable down-regulation of Nav1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Nav1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro, Nav1.5 down-regulation altered cell morphology and reduced CD44 expression, suggesting that VGSC activity may regulate cellular invasion via the CD44-src-cortactin signaling axis. We conclude that Nav1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Nav1.5 may be useful for reducing metastasis. PMID:26452220

  12. Mutational analysis of single circulating tumor cells by next generation sequencing in metastatic breast cancer

    PubMed Central

    Galardi, Francesca; Pestrin, Marta; Gabellini, Stefano; Simi, Lisa; Mancini, Irene; Vannucchi, Alessandro Maria; Pazzagli, Mario; Di Leo, Angelo; Pinzani, Pamela

    2016-01-01

    Circulating Tumor Cells (CTCs) represent a “liquid biopsy” of the tumor potentially allowing real-time monitoring of cancer biology and therapies in individual patients. The purpose of the study was to explore the applicability of a protocol for the molecular characterization of single CTCs by Next Generation Sequencing (NGS) in order to investigate cell heterogeneity and provide a tool for a personalized medicine approach. CTCs were enriched and enumerated by CellSearch in blood from four metastatic breast cancer patients and singularly isolated by DEPArray. Upon whole genome amplification 3–5 single CTCs per patient were analyzed by NGS for 50 cancer-related genes. We found 51 sequence variants in 25 genes. We observed inter- and intra-patient heterogeneity in the mutational status of CTCs. The highest number of somatic deleterious mutations was found in the gene TP53, whose mutation is associated with adverse prognosis in breast cancer. The discordance between the mutational status of the primary tumor and CTCs observed in 3 patients suggests that, in advanced stages of cancer, CTC characteristics are more closely linked to the dynamic modifications of the disease status. In one patient the mutational profiles of CTCs before and during treatment shared only few sequence variants. This study supports the applicability of a non-invasive approach based on the liquid biopsy in metastatic breast cancer patients which, in perspective, should allow investigating the clonal evolution of the tumor for the development of new therapeutic strategies in precision medicine. PMID:27034166

  13. Management of non metastatic phyllodes tumors of the breast: review of the literature.

    PubMed

    Khosravi-Shahi, Parham

    2011-12-01

    Phyllodes tumors of the breast are rare tumors, accounting for less than 0.5% of all breast tumors. These tumors are comprised of both stromal and epithelial elements; and traditionally they are graded by the use of a set of histologic features into benign, borderline, and malignant subtypes. Unfortunately, the histologic classification of phyllodes tumors does not reliably predict clinical behavior. The mainstay of treatment of non metastatic phyllodes tumors of the breast is complete surgical resection with wide resection margins. Lumpectomy or partial mastectomy is the preferred surgical therapy. However, despite the complete surgical resection, local failure rate may be high; and 22% of malignant tumors may give rise to haematogenous metastases. The most frequent site of distant metastases is the lungs. Several predictive factors of recurrence and metastases have been described in the literature, such as positive surgical margins, increased stromal cellularity, stromal overgrowth, stromal atypia and increased mitotic activity. Nevertheless, the role of adjuvant therapies (radiotherapy and chemotherapy) is presently undefined and should be tested in multicenter, prospective, randomized trials.

  14. Preemptive tumor profiling for biomarker-stratified early clinical drug development in metastatic breast cancer patients.

    PubMed

    Welt, Anja; Tewes, Mitra; Aktas, Bahriye; O Hoffmann, Oliver; Wiesweg, Marcel; Ting, Saskia; Reis, Henning; Worm, Karl; Richly, Heike; Hense, Jörg; Palmer, Michael R; Lee, Benjamin H; Wendling, Johanna; Kossow, Josef; Scheulen, Max E; Lehnerdt, Cathrin; Kohl, Marzena; Derks, Cordula; Skottky, Silke; Haus, Ulrike; Schmid, Kurt W; Kimmig, Rainer; Schuler, Martin; Kasper, Stefan

    2013-11-01

    Biomarker-stratified cancer pharmacotherapy was pioneered in the care of breast cancer patients. The utility of agents modulating hormone receptors, synthesis of steroid hormones, or HER2-targeting agents has been greatly enhanced by the detection of predictive biomarkers in diagnostic tumor samples. Based on deeper understanding of breast cancer biology multiple drug candidates have been developed to modulate additional molecular targets which may associate with specific biomarker profiles. Accordingly, exploratory biomarkers are increasingly incorporated in early clinical trials, thus demanding a new process of patient selection. Here, we describe the implementation of preemptive, multiplexed biomarker profiling linked to standard diagnostic algorithms for metastatic breast cancer patients treated at the West German Cancer Center. Profiling for experimental biomarkers was prospectively offered to patients with metastatic breast cancer who met generic clinical trial inclusion criteria. Formalin-fixed, paraffin-embedded tumor samples were retrieved and studied for potentially “actionable” biomarkers related to active clinical trials by immunohistochemistry, amplicon sequencing, and in situ hybridization. The clinical course of those “profiled” patients was closely monitored to offer trial participation whenever applicable. Here, we report results from the first 131 patients enrolled in this program. PIK3CA mutations (23 %) and amplifications (2 %), loss of PTEN expression (13 %), and FGFR1 amplifications (8 %) were detected next to established biomarkers such as estrogen (67 %) and progesterone receptor expression (52 %), and HER2 overexpression or amplification (23 %). So far 16 “profiled” patients (12 %) have been enrolled in biomarker-stratified early clinical trials. Preemptive profiling of investigational biomarkers can be integrated into the diagnostic algorithm of a large Comprehensive Cancer Center. Extensive administrative efforts are required

  15. Function of immunoadjuvants in laser immunotherapy for treatment of metastatic breast tumors in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Liu, Hong; Wolf, Roman F.; Lucroy, Michael D.; Nordquist, Robert E.

    2002-06-01

    Tumor cell destruction usually induces host immune responses, such as local inflammation and increased activities of macrophages and neutrophils. Use of immunoadjuvant can usually enhance such immune activities. Laser immunotherapy is designed to use the combination of laser photothermal and immunological interactions to induce long-term antitumor immunity with the help of immunoadjuvant. It uses a selective hyperthermia for acute tumor destruction through an intratumor administration of indocyanine green and a noninvasive irradiation by an 805-nm laser. The concurrent in situ administration of immunoadjuvant helped achieve the desired effect: tumor eradication and antitumor immunity. The current study further explores the function of immunoadjuvants in laser immunotherapy by testing four different adjuvants: glycated chitosan, complete Freund's adjuvant, incomplete Freund's adjuvant, and c-parvum. Each adjuvant provided long-term tumor cure in the treatment of a metastatic mammary tumor model in rats. However, glycated chitosan and complete Freund's adjuvant were most effective with 25% and 18% long- term cure rates, respectively. Different concentrations of glycated chitosan were also used in treatment of rats bearing metastatic breast tumors.

  16. Peptide-based method for detection of metastatic transformation in primary tumors of breast cancer.

    PubMed

    Li, Hao; Huang, Yue; Yu, Yue; Li, Weiwei; Yin, Yongmei; Li, Genxi

    2015-09-15

    Detection of metastatic activity before the onset of the actual metastasis can be a promising method to combat metastasis, the foremost cause of death in cancer. Therefore, in this work, we have developed an assay method for the detection of metastatic tumor cells in primary tumor, by using a protein of the metastatic cell signaling as the biomarker. In this assay, a peptide-based probe targeting the marker protein and a sensitive nanoparticle doped graphene nanolabel are combined to enable the detection of metastatic cells. Consequently, the metastatic cells can be specifically detected and discriminated from primary tumor cells. By applying this assay method to clinical samples of primary tumor, a low amount of metastatic activity can be detected in the tumor sites, which may suggest the activity of local metastatic transformation. So, these results may point to the prospect of using the proposed method for controlling metastatic cancer.

  17. Tumor lysis syndrome in metastatic breast cancer after a single dose of paclitaxel.

    PubMed

    Vaidya, Gaurang Nandkishor; Acevedo, Russell

    2015-02-01

    Tumor lysis syndrome (TLS) is an oncologic emergency characterized by spillage of intracellular material into the blood caused by disruption of massive load of tumor cells. It is more commonly reported in hematological cancers and can have fatal consequences due to renal and multi-organ failure and arrhythmias due to electrolyte imbalance. We describe a case with metastatic breast cancer who presented with TLS after a single dose of paclitaxel, second such case in literature. The development of a risk stratification score to assess the need for hospitalization or close observation of these patients and the documentation of appropriate preventive strategies could help prevent such fatal occurrences. TLS should be included in the differential when cancer patients on treatment present with acute decompensation. PMID:25178848

  18. Diagnostic dilemma involving a mass in the parapharyngeal space: A metastatic breast carcinoma masquerading as a malignant salivary gland tumor.

    PubMed

    Murhekar, Kanchan; Majhi, Urmila; Krishnamurthy, Arvind; Ramshankar, Vijayalakshmi

    2015-01-01

    Parapharyngeal space (PPS) tumors are rare and account for about 0.5% of all head and neck neoplasms. Most PPS tumors are benign (up to 80%) while the remaining 20% are malignant. These tumors are either primaries; most commonly arising from salivary glands or metastatic tumors or due to direct extension of tumors from the adjacent sites. Distant metastasis from breast cancers more commonly involves the lungs, bones, brain and liver. Metastasis to the PPS from a primary breast carcinoma is rare, with only one case reported in literature. We, to the best of our knowledge report the second case of a carcinoma breast metastasizing to the PPS and further discuss the diagnostic and therapeutic challenges involved in its management. A fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography scan apart from explicitly defining the extent of the PPS tumor, majorly influenced the therapeutic decision making process by ruling out other sites of metastasis.

  19. Palbociclib in Combination With Tamoxifen as First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer

    ClinicalTrials.gov

    2016-10-04

    Hormone Receptor Positive Malignant Neoplasm of Breast; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Estrogen Receptor Positive Breast Cancer; Progesterone Receptor Positive Tumor; Metastatic Breast Cancer

  20. Metastatic pleural tumor

    MedlinePlus

    ... persons. Alternative Names Tumor - metastatic pleural Images Pleural space References Arenberg D, Pickens A. Metastatic malignant tumors. In: Mason RJ, Murray JF, Broaddus VC, et al., eds. Murray and Nadel's Textbook of Respiratory Medicine . 5th ed. Philadelphia, PA: Elsevier Saunders; 2010:chap ...

  1. Detection and Characterization of Circulating Tumor Associated Cells in Metastatic Breast Cancer

    PubMed Central

    Mu, Zhaomei; Benali-Furet, Naoual; Uzan, Georges; Znaty, Anaëlle; Ye, Zhong; Paolillo, Carmela; Wang, Chun; Austin, Laura; Rossi, Giovanna; Fortina, Paolo; Yang, Hushan; Cristofanilli, Massimo

    2016-01-01

    The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs. In this pilot study, we evaluated circulating tumor associated cells in one blood draw by size exclusion technology and cytological analysis. Among 30 prospectively enrolled MBC patients, CTCs, circulating tumor cell clusters (CTC clusters), CTCs of epithelial–mesenchymal transition (EMT) and cancer associated macrophage-like cells (CAMLs) were detected and analyzed. For molecular characterization of CTCs, size-exclusion method for CTC enrichment was tested in combination with DEPArray™ technology, which allows the recovery of single CTCs or pools of CTCs as a pure CTC sample for mutation analysis. Genomic mutations of TP53 and ESR1 were analyzed by targeted sequencing on isolated 7 CTCs from a patient with MBC. The results of genomic analysis showed heterozygous TP53 R248W mutation from one single CTC and pools of three CTCs, and homozygous TP53 R248W mutation from one single CTC and pools of two CTCs. Wild-type ESR1 was detected in the same isolated CTCs. The results of this study reveal that size-exclusion method can be used to enrich and identify circulating tumor associated cells, and enriched CTCs were characterized for genetic alterations in MBC patients, respectively. PMID:27706044

  2. Identifying metastatic breast tumors using textural kinetic features of a contrast based habitat in DCE-MRI

    NASA Astrophysics Data System (ADS)

    Chaudhury, Baishali; Zhou, Mu; Goldgof, Dmitry B.; Hall, Lawrence O.; Gatenby, Robert A.; Gillies, Robert J.; Drukteinis, Jennifer S.

    2015-03-01

    The ability to identify aggressive tumors from indolent tumors using quantitative analysis on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) would dramatically change the breast cancer treatment paradigm. With this prognostic information, patients with aggressive tumors that have the ability to spread to distant sites outside of the breast could be selected for more aggressive treatment and surveillance regimens. Conversely, patients with tumors that do not have the propensity to metastasize could be treated less aggressively, avoiding some of the morbidity associated with surgery, radiation and chemotherapy. We propose a computer aided detection framework to determine which breast cancers will metastasize to the loco-regional lymph nodes as well as which tumors will eventually go on to develop distant metastses using quantitative image analysis and radiomics. We defined a new contrast based tumor habitat and analyzed textural kinetic features from this habitat for classification purposes. The proposed tumor habitat, which we call combined-habitat, is derived from the intersection of two individual tumor sub-regions: one that exhibits rapid initial contrast uptake and the other that exhibits rapid delayed contrast washout. Hence the combined-habitat represents the tumor sub-region within which the pixels undergo both rapid initial uptake and rapid delayed washout. We analyzed a dataset of twenty-seven representative two dimensional (2D) images from volumetric DCE-MRI of breast tumors, for classification of tumors with no lymph nodes from tumors with positive number of axillary lymph nodes. For this classification an accuracy of 88.9% was achieved. Twenty of the twenty-seven patients were analyzed for classification of distant metastatic tumors from indolent cancers (tumors with no lymph nodes), for which the accuracy was 84.3%.

  3. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial.

    PubMed

    Fehm, Tanja; Müller, Volkmar; Aktas, Bahriye; Janni, Wolfgang; Schneeweiss, Andreas; Stickeler, Elmar; Lattrich, Claus; Löhberg, Christian R; Solomayer, Erich; Rack, Brigitte; Riethdorf, Sabine; Klein, Christoph; Schindlbeck, Christian; Brocker, Kerstin; Kasimir-Bauer, Sabine; Wallwiener, Diethelm; Pantel, Klaus

    2010-11-01

    There is a growing body of evidence that HER2 status can change during disease recurrence or progression in breast cancer patients. In this context, re-evaluation of HER2 status by assessment of HER2 expression on circulating tumor cells (CTCs) is a strategy with potential clinical application. The aim of this trial was to determine the HER2 status of CTCs in metastatic breast cancer patients comparing two CTC assays. A total of 254 patients with metastatic breast cancer from nine German university breast cancer centers were enrolled in this prospective study. HER2 status of CTCs was assessed using both the FDA-approved CellSearch® assay and AdnaTest BreastCancer™. Using the CellSearch assay, 122 of 245 (50%) patients had ≥5 CTCs, and HER2-positive CTCs were observed in 50 (41%) of these patients. Ninety of 229 (39%) patients were CTC positive using AdnaTest BreastCancer, and HER2 positivity rate was 47% (42 of 90). The rate of breast cancer patients with HER2-negative primary tumors but HER2-positive CTCs was 32% (25 of 78) and 49% (28 of 57) using the CellSearch assay and AdnaTest BreastCancer, respectively. Considering only those patients who had CTCs on both tests (n = 62), concordant results regarding HER2 positivity were obtained in 50% of the patients (31/62) (P = 0.96, κ = -0.006). HER2-positive CTCs can be detected in a relevant number of patients with HER2 negative primary tumors. Therefore, it will be mandatory to correlate the assay-dependent HER2 status of CTCs to the clinical response on HER2-targeted therapies.

  4. Curing Metastatic Breast Cancer.

    PubMed

    Sledge, George W

    2016-01-01

    Metastatic breast cancer is generally considered incurable, and this colors doctor-patient interactions for patients with metastatic disease. Although true for most patients, there appear to be important exceptions, instances where long-term disease-free survival occurs. Although these instances are few in number, they suggest the possibility of cure. How will we move toward cure for a much larger population of patients with metastatic disease? This article outlines a potential research agenda that might move us toward that distant goal. PMID:26759458

  5. EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer

    PubMed Central

    Schneck, Helen; Gierke, Berthold; Uppenkamp, Frauke; Behrens, Bianca; Niederacher, Dieter; Stoecklein, Nikolas H.; Templin, Markus F.; Pawlak, Michael; Fehm, Tanja; Neubauer, Hans

    2015-01-01

    Circulating tumor cells (CTCs) are the potential precursors of metastatic disease. Most assays established for the enumeration of CTCs so far–including the gold standard CellSearch—rely on the expression of the cell surface marker epithelial cell adhesion molecule (EpCAM). But, these approaches may not detect CTCs that express no/low levels of EpCAM, e.g. by undergoing epithelial-to-mesenchymal transition (EMT). Here we present an enrichment strategy combining different antibodies specific for surface proteins and extracellular matrix (ECM) components to capture an EpCAMlow/neg cell line and EpCAMneg CTCs from blood samples of breast cancer patients depleted for EpCAM-positive cells. The expression of respective proteins (Trop2, CD49f, c-Met, CK8, CD44, ADAM8, CD146, TEM8, CD47) was verified by immunofluorescence on EpCAMpos (e.g. MCF7, SKBR3) and EpCAMlow/neg (MDA-MB-231) breast cancer cell lines. To test antibodies and ECM proteins (e.g. hyaluronic acid (HA), collagen I, laminin) for capturing EpCAMneg cells, the capture molecules were first spotted in a single- and multi-array format onto aldehyde-coated glass slides. Tumor cell adhesion of EpCAMpos/neg cell lines was then determined and visualized by Coomassie/MitoTracker staining. In consequence, marginal binding of EpCAMlow/neg MDA-MB-231 cells to EpCAM-antibodies could be observed. However, efficient adhesion/capturing of EpCAMlow/neg cells could be achieved via HA and immobilized antibodies against CD49f and Trop2. Optimal capture conditions were then applied to immunomagnetic beads to detect EpCAMneg CTCs from clinical samples. Captured CTCs were verified/quantified by immunofluorescence staining for anti-pan-Cytokeratin (CK)-FITC/anti-CD45 AF647/DAPI. In total, in 20 out of 29 EpCAM-depleted fractions (69%) from 25 metastatic breast cancer patients additional EpCAMneg CTCs could be identified [range of 1–24 CTCs per sample] applying Trop2, CD49f, c-Met, CK8 and/or HA magnetic enrichment. Ep

  6. Circulating Tumor Cells and Response to Chemotherapy in Metastatic Breast Cancer: SWOG S0500

    PubMed Central

    Smerage, Jeffrey B.; Barlow, William E.; Hortobagyi, Gabriel N.; Winer, Eric P.; Leyland-Jones, Brian; Srkalovic, Gordan; Tejwani, Sheela; Schott, Anne F.; O'Rourke, Mark A.; Lew, Danika L.; Doyle, Gerald V.; Gralow, Julie R.; Livingston, Robert B.; Hayes, Daniel F.

    2014-01-01

    Purpose Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS). Patients and Methods Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). Results Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001). Conclusion This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy. PMID:24888818

  7. Unbiased quantitative assessment of Her-2 expression of circulating tumor cells in patients with metastatic and non-metastatic breast cancer.

    PubMed

    Ligthart, S T; Bidard, F-C; Decraene, C; Bachelot, T; Delaloge, S; Brain, E; Campone, M; Viens, P; Pierga, J-Y; Terstappen, L W M M

    2013-05-01

    Background Circulating tumor cells (CTCs) can provide the basis for a liquid biopsy and may guide the use of targeted therapies. We report on unbiased quantification of Her-2 protein expression of CTCs. Patients and methods Her-2 assessment of CTCs was carried out using the CellSearch(®) system in 103 metastatic (M1) and 88 non-metastatic (M0) breast-cancer patients. Expression of Her-2 on CTCs was determined by a manual review and an automated algorithm using Her-2- fluorescein isothiocyanate (FITC) fluorescence of leukocytes to determine the Her-2-expression threshold in each sample. Results Her-2 expression of CTCs varied greatly within and among patients compared with Her-2 expression of leukocytes. In M1 patients, a threshold of 75% of Her-2 positive CTCs in patients with ≥5 CTCs was set. Applying this threshold, 9% of M1 patients with Her-2-negative primary tumors had Her-2-positive CTC status and 29% of M1 patients with Her-2-positive primary tumors had Her-2-negative CTC status. No Her-2 discrepancy was observed between CTCs and primary tumors in M0 patients. Conclusions Our findings demonstrate that Her-2 expression is heterogeneous among CTCs within each patient. We show the feasibility of unbiased quantitative and reproducible assessment of treatment targets on CTCs, opening a path towards personalized treatment.

  8. Specific expression of the human voltage-gated proton channel Hv1 in highly metastatic breast cancer cells, promotes tumor progression and metastasis

    SciTech Connect

    Wang, Yifan; Li, Shu Jie; Pan, Juncheng; Che, Yongzhe; Yin, Jian; Zhao, Qing

    2011-08-26

    Highlights: {yields} Hv1 is specifically expressed in highly metastatic human breast tumor tissues. {yields} Hv1 regulates breast cancer cytosolic pH. {yields} Hv1 acidifies extracellular milieu. {yields} Hv1 exacerbates the migratory ability of metastatic cells. -- Abstract: The newly discovered human voltage-gated proton channel Hv1 is essential for proton transfer, which contains a voltage sensor domain (VSD) without a pore domain. We report here for the first time that Hv1 is specifically expressed in the highly metastatic human breast tumor tissues, but not in poorly metastatic breast cancer tissues, detected by immunohistochemistry. Meanwhile, real-time RT-PCR and immunocytochemistry showed that the expression levels of Hv1 have significant differences among breast cancer cell lines, MCF-7, MDA-MB-231, MDA-MB-468, MDA-MB-453, T-47D and SK-BR-3, in which Hv1 is expressed at a high level in highly metastatic human breast cancer cell line MDA-MB-231, but at a very low level in poorly metastatic human breast cancer cell line MCF-7. Inhibition of Hv1 expression in the highly metastatic MDA-MB-231 cells by small interfering RNA (siRNA) significantly decreases the invasion and migration of the cells. The intracellular pH of MDA-MB-231 cells down-regulated Hv1 expression by siRNA is obviously decreased compared with MDA-MB-231 with the scrambled siRNA. The expression of matrix metalloproteinase-2 and gelatinase activity in MDA-MB-231 cells suppressed Hv1 by siRNA were reduced. Our results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells.

  9. Comparative analysis of innate immune system function in metastatic breast, colorectal, and prostate cancer patients with circulating tumor cells.

    PubMed

    Santos, Mark F; Mannam, Venkat K R; Craft, Barbara S; Puneky, Louis V; Sheehan, Natale T; Lewis, Robert E; Cruse, Julius M

    2014-06-01

    In recent years, circulating tumor cells (CTCs) in metastatic cancer patients have been found to be a promising biomarker to predict overall survival and tumor progression in these patients. A relatively high number of CTCs has been correlated with disease progression and poorer prognosis. This study was designed to assess innate immune system function, known to be responsible for the immune defense against developing neoplasms, in metastatic cancer patients with CTCs. Our aim is to provide a link between indication of poorer prognosis, represented by the number of CTCs to the cytotoxic activity of natural killer cells, an important component of the innate immune system, and to represent a promising expanded approach to management of metastatic cancer patients with CTCs. Seventy-four patients, with metastatic breast, colorectal, or prostate cancer, were recruited for this study. Using a flow cytometric assay, we measured natural killer (NK) cell cytotoxicity against K562 target cells; and CTCs were enumerated using the CellSearch System. Toll-like receptors 2 and 4 expression was also determined by flow cytometry. We found that within each of our three metastatic cancer patient groups, NK cell cytotoxic activity was decreased in patients with a relatively high number of CTCs in peripheral blood compared to patients with a relatively low number of CTCs. In the breast and prostate cancer group, patients with CTCs greater than 5 had decreased NK cell cytotoxicity when compared to patients with less than 5 CTCs. In the colorectal cancer group, we found that 3 or more CTCs in the blood was the level at which NK cell cytotoxicity is diminished. Additionally, we found that the toll-like receptors 2 and 4 expression was decreased in intensity in all the metastatic cancer patients when compared to the healthy controls. Furthermore, within each cancer group, the expression of both toll-like receptors was decreased in the patients with relatively high number of CTCs, i

  10. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients

    PubMed Central

    Aktas, Bahriye; Tewes, Mitra; Fehm, Tanja; Hauch, Siegfried; Kimmig, Rainer; Kasimir-Bauer, Sabine

    2009-01-01

    Introduction The persistence of circulating tumor cells (CTC) in breast cancer patients might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, these cells also may undergo phenotypic changes, known as epithelial-mesenchymal transition (EMT), which allows them to travel to the site of metastasis formation without getting affected by conventional treatment. Here we evaluated 226 blood samples of 39 metastatic breast cancer patients during a follow-up of palliative chemo-, antibody – or hormonal therapy for the expression of the stem cell marker ALDH1 and markers for EMT and correlated these findings with the presence of CTC and response to therapy. Methods 2 × 5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1 and HER2 transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [Twist1, Akt2, PI3Kα] and separately for the tumor stem-cell markers ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample. Results 97% of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts. CTC were detected in 69/226 (31%) cancer samples. In the CTC (+) group, 62% were positive for at least one of the EMT markers and 69% for ALDH1, respectively. In the CTC (-) group the percentages were 7% and 14%, respectively. In non-responders, EMT and ALDH1 expression was found in 62% and 44% of patients, in responders the rates were 10% and 5%, respectively. Conclusions Our data indicate that a major proportion of CTC of metastatic breast cancer patients shows EMT and tumor stem cell characteristics. Further studies are needed to prove whether these markers might serve as an indicator for therapy resistant tumor cell populations and, therefore, an inferior prognosis. PMID:19589136

  11. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease

    PubMed Central

    Olsson, Eleonor; Winter, Christof; George, Anthony; Chen, Yilun; Howlin, Jillian; Tang, Man-Hung Eric; Dahlgren, Malin; Schulz, Ralph; Grabau, Dorthe; van Westen, Danielle; Fernö, Mårten; Ingvar, Christian; Rose, Carsten; Bendahl, Pär-Ola; Rydén, Lisa; Borg, Åke; Gruvberger-Saal, Sofia K; Jernström, Helena; Saal, Lao H

    2015-01-01

    Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0–37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment. PMID:25987569

  12. Near-infrared pH-activatable fluorescent probes for imaging primary and metastatic breast tumors.

    PubMed

    Lee, Hyeran; Akers, Walter; Bhushan, Kumar; Bloch, Sharon; Sudlow, Gail; Tang, Rui; Achilefu, Samuel

    2011-04-20

    Highly tumor selective near-infrared (NIR) pH-activatable probe was developed by conjugating pH-sensitive cyanine dye to a cyclic arginine-glycine-aspartic acid (cRGD) peptide targeting α(v)β(3) integrin (ABIR), a protein that is highly overexpressed in endothelial cells during tumor angiogenesis. The NIR pH-sensitive dye used to construct the probe exhibits high spectral sensitivity with pH changes. It has negligible fluorescence above pH 6 but becomes highly fluorescent below pH 5, with a pK(a) of 4.7. This probe is ideal for imaging acidic cell organelles such as tumor lysosomes or late endosomes. Cell microscopy data demonstrate that binding of the cRGD probe to ABIR facilitated the endocytosis-mediated lysosomal accumulation and subsequent fluorescence enhancement of the NIR pH-activatable dye in tumor cells (MDA-MB-435 and 4T1/luc). A similar fluorescence enhancement mechanism was observed in vivo, where the tumors were evident within 4 h post injection. Moreover, lung metastases were also visualized in an orthotopic tumor mouse model using this probe, which was further confirmed by histologic analysis. These results demonstrate the potential of using the new integrin-targeted pH-sensitive probe for the detection of primary and metastatic cancer.

  13. Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)

    ClinicalTrials.gov

    2016-10-25

    Breast Tumor; Breast Cancer; Cancer of the Breast; Estrogen Receptor- Negative Breast Cancer; HER2- Negative Breast Cancer; Progesterone Receptor- Negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer; Triple-negative Metastatic Breast Cancer; Metastatic Breast Cancer

  14. In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide.

    PubMed

    Yang, Dongzhi; Feng, Liangzhu; Dougherty, Casey A; Luker, Kathryn E; Chen, Daiqin; Cauble, Meagan A; Banaszak Holl, Mark M; Luker, Gary D; Ross, Brian D; Liu, Zhuang; Hong, Hao

    2016-10-01

    Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. (64)Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of (64)Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ((64)Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers

  15. In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide.

    PubMed

    Yang, Dongzhi; Feng, Liangzhu; Dougherty, Casey A; Luker, Kathryn E; Chen, Daiqin; Cauble, Meagan A; Banaszak Holl, Mark M; Luker, Gary D; Ross, Brian D; Liu, Zhuang; Hong, Hao

    2016-10-01

    Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. (64)Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of (64)Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ((64)Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers

  16. Efficacy of bisphosphonates and other bone-targeted agents in metastatic bone disease from solid tumors other than breast and prostate cancers.

    PubMed

    Karim, Syed Mustafa; Brown, Janet; Zekri, Jamal

    2013-05-01

    Metastatic bone disease complicates the course of malignancy in a substantial proportion of patients with advanced cancer. Bisphosphonates are now widely used to improve skeleton-related outcomes of patients with metastatic cancer to the bone. Most studies evaluating the efficacy of bisphosphonates and other bone-targeted agents have been performed in patients with metastatic breast and prostate cancer. Only a few studies have evaluated the role of bisphosphonates in other tumor types involving the skeletal system. We present a review of the clinical literature focusing on the current and potential roles of bisphosphonates (particularly zoledronic acid) and newer bone-targeted therapies in patients with metastasis to bone arising from solid tumors other than breast and prostate cancer.

  17. A Cross-Sectional Comparison of Druggable Mutations in Primary Tumors, Metastatic Tissue, Circulating Tumor Cells, and Cell-Free Circulating DNA in Patients with Metastatic Breast Cancer: The MIRROR Study Protocol

    PubMed Central

    Picornell, Antoni C; Alvarez, Enrique L; Martin, Miguel

    2016-01-01

    Background Characterization of the driver mutations in an individual metastatic breast cancer (MBC) patient is critical to selecting effective targeted therapies. Currently, it is believed that the limited efficacy of many targeted drugs may be due to the expansion of drug resistant clones with different genotypes that were already present in the primary tumor. Identifying the genomic alterations of these clones, and introducing combined or sequential targeted drug regimens, could lead to a significant increase in the efficacy of currently available targeted therapies. Objective The primary objective of this study is to assess the concordance/discordance of mutations between the primary tumor and metastatic tissue in MBC patients. Secondary objectives include comparing the genomic profiles of circulating tumor cells (CTCs) and circulating free DNA (cfDNA) from peripheral blood with those of the primary tumor and metastatic tissue for each patient, evaluating these mutations in the signaling pathways that are relevant to the disease, and testing the feasibility of introducing liquid biopsy as a translational laboratory tool in clinical practice. Methods The multicenter, transversal, observational MIRROR study is currently ongoing in three participating hospitals. All consecutive patients with MBC confirmed by radiologic findings will be screened for eligibility, either at first relapse or if tumor regrowth occurs while on treatment for metastatic disease. Results Patient recruitment is currently ongoing. To date, 41 patients have a complete set of tissue samples available (plasma, CTCs, and formalin-fixed, paraffin-embedded primary tumor and metastatic tumor). However, none of these samples have undergone nucleic acids extraction or targeted deep sequencing. Conclusions The results of this study may have a significant influence on the practical management of patients with MBC, and may provide clues to clinicians that lead towards a better stratification of patients

  18. Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack

    PubMed Central

    Bulfoni, Michela; Turetta, Matteo; Del Ben, Fabio; Di Loreto, Carla; Beltrami, Antonio Paolo; Cesselli, Daniela

    2016-01-01

    Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM+/CK+) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a “surrogate” of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug-resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well. PMID:27783057

  19. Treatment of metastatic breast cancer.

    PubMed

    Gradishar, William J

    2014-05-01

    Many newer agents in combination are being studied in the front-line treatment of women with HER2-positive metastatic breast cancer (MBC), but the story in the endocrine arena is more about the wise use of new strategies to overcome endocrine resistance, because no new antihormonal agents have been approved in the past decade. During his presentation at the NCCN 19th Annual Conference, Dr. William Gradishar explored what's new in the treatment of MBC, focusing primarily on enhancing the effect of endocrine therapy to overcome resistance with newer targeted agents such as everolimus, reevaluating the role of rebiopsy on disease progression and measuring circulating tumor cells as a surrogate of response to treatment, and reviewing the effective treatment regimens for HER2-positive disease.

  20. The accuracy of preoperative axillary nodal staging in primary breast cancer by ultrasound is modified by nodal metastatic load and tumor biology

    PubMed Central

    Dihge, Looket; Grabau, Dorthe A.; Rasmussen, Rogvi W.; Bendahl, Pär-Ola; Rydén, Lisa

    2016-01-01

    Abstract Background The outcome of axillary ultrasound (AUS) with fine-needle aspiration biopsy (FNAB) in the diagnostic work-up of primary breast cancer has an impact on therapy decisions. We hypothesize that the accuracy of AUS is modified by nodal metastatic burden and clinico-pathological characteristics. Material and methods The performance of AUS and AUS-guided FNAB for predicting nodal metastases was assessed in a prospective breast cancer cohort subjected for surgery during 2009–2012. Predictors of accuracy were included in multivariate analysis. Results AUS had a sensitivity of 23% and a specificity of 95%, while AUS-guided FNAB obtained 73% and 100%, respectively. AUS-FNAB exclusively detected macro-metastases (median four metastases) and identified patients with more extensive nodal metastatic burden in comparison with sentinel node biopsy. The accuracy of AUS was affected by metastatic size (OR 1.11), obesity (OR 2.46), histological grade (OR 4.43), and HER2-status (OR 3.66); metastatic size and histological grade were significant in the multivariate analysis. Conclusions The clinical utility of AUS in low-risk breast cancer deserves further evaluation as the accuracy decreased with a low nodal metastatic burden. The diagnostic performance is modified by tumor and clinical characteristics. Patients with nodal disease detected by AUS-FNAB represent a group for whom neoadjuvant therapy should be considered. PMID:27050668

  1. Breast cancer metastatic to the kidney with renal vein involvement.

    PubMed

    Nasu, Hatsuko; Miura, Katsutoshi; Baba, Megumi; Nagata, Masao; Yoshida, Masayuki; Ogura, Hiroyuki; Takehara, Yasuo; Sakahara, Harumi

    2015-02-01

    The common sites of breast cancer metastases include bones, lung, brain, and liver. Renal metastasis from the breast is rare. We report a case of breast cancer metastatic to the kidney with extension into the renal vein. A 40-year-old woman had undergone left mastectomy for breast cancer at the age of 38. A gastric tumor, which was later proved to be metastasis from breast cancer, was detected by endoscopy. Computed tomography performed for further examination of the gastric tumor revealed a large left renal tumor with extension into the left renal vein. It mimicked a primary renal tumor. Percutaneous biopsy of the renal tumor confirmed metastasis from breast cancer. Surgical intervention of the stomach and the kidney was avoided, and she was treated with systemic chemotherapy. Breast cancer metastatic to the kidney may present a solitary renal mass with extension into the renal vein, which mimics a primary renal tumor.

  2. Metastatic gastrinoma in the breast mimicking primary solid papillary carcinoma.

    PubMed

    Burt, Michael; Madan, Rashna; Fan, Fang

    2016-10-01

    We report a case of metastatic gastrinoma to the breast morphologically mimicking solid papillary carcinoma of the breast. A 59-year-old woman presented with a hypoechoic right breast mass that histologically revealed solid nests of small monotonous tumor cells, fibrovascular cores, and round to oval nuclei with fine chromatin and small nucleoli. Immunohistochemistry demonstrated chromogranin and synaptophysin positivity. Tumor prognostic markers showed weak positivity for estrogen receptor and negativity for progesterone receptor. Although an initial diagnosis of solid papillary carcinoma was rendered, subsequent identification of the patient's clinical history of pancreatic gastrinoma and an additional immunohistochemical stain for gastrin supported a diagnosis of metastatic gastrinoma. We report this rare case to increase awareness of metastatic neuroendocrine tumors in the breast. Multiple breast lesions and lack of expression of estrogen/progesterone hormone receptors should prompt careful review of the patient's clinical history to rule out metastatic neuroendocrine disease. PMID:27342908

  3. Circulating Tumor Cells Following First Chemotherapy Cycle: An Early and Strong Predictor of Outcome in Patients With Metastatic Breast Cancer

    PubMed Central

    Custodio, Sara; de las Casas, Maria-Luisa Maestro; García-Sáenz, José-Ángel; de la Torre, Julio-César; Bellón-Cano, Jose-María; López-Tarruella, Sara; Vidaurreta-Lazaro, Marta; de la Orden, Virginia; Jerez, Yolanda; Márquez-Rodas, Iván; Casado, Antonio; Sastre, Javier; Díaz-Rubio, Eduardo

    2013-01-01

    We investigated the prognostic significance of circulating tumor cells (CTCs) determined immediately before the second cycle of chemotherapy in patients with metastatic breast cancer (MBC). The CTC counts were taken at baseline, before the first cycle of chemotherapy (CTC-0), and on day 21 before commencing the second cycle of chemotherapy (CTC-21) in consecutive MBC patients. The study's primary objectives were to analyze relationships between CTC-21 count and overall survival (OS). Based on the current literature, the CTC measurements were dichotomized as 0–4 versus ≥5 CTCs. Of 117 patients recruited, 99 were evaluable. Patients with 0–4 CTCs on day 21 had a significantly better OS than those with ≥5 CTCs (median OS: 38.5 months vs. 8.7 months). They also had a significantly better progression-free survival (PFS; median: 9.4 months vs. 3.0 months) and clinical benefit rate (77% vs. 44%). The OS of patients whose baseline CTCs were ≥5 but dropped to <5 on day 21 was apparently similar to those who had <5 CTCs at baseline. In a Cox regression analysis, CTC-21 was the only independent variable significantly predicting OS and PFS. Our data indicate that CTCs determined immediately before the second cycle of chemotherapy is an early and strong predictor of treatment outcome in MBC patients. PMID:23873719

  4. Dual targeting for metastatic breast cancer and tumor neovasculature by EphA2-mediated nanocarriers.

    PubMed

    Guo, Zhaoming; He, Bing; Yuan, Lan; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Zhang, Qiang

    2015-09-30

    EphA2 is a transmembrane receptor tyrosine kinase that is highly expressed on both tumor neovasculature and some kinds of tumor cells. Here, a homing peptide with a sequence of YSAYPDSVPMMSK (YSA) that binds specifically with EphA2 was utilized to modify the stealth liposomes (YSA-LP). With a particle size of about 85 nm, this functionalized nanocarrier was loaded with fluorescent probe or doxorubicin (DOX) and investigated in vitro and in vivo. In the cellular endocytosis studies in vitro, coumarin-6 loaded YSA-LP exhibited significant specificity to both EphA2-overexpressing tumor cells (MDA-MB-231) and human umbilical vein endothelial cells (HUVEC) via a YSA mediated interaction. In a MDA-MB-231 xenograft tumor mouse model, DiR-loaded YSA-LP showed more lasting accumulation in tumor tissue by small animal imaging compared to unmodified liposomes (LP). Further, YSA-LP greatly facilitated the efficacy of DOX loaded against both tumor cells and tumor angiogenesis in the same mouse model, evidenced by inhibiting tumor growth, metastasis and CD31 expression as well as inducing cancer cell apoptosis. Additionally, YSA-LP (DOX) showed relatively low systemic and cardiac toxicity compared with control groups. In conclusion, YSA might be a promising targeting motif for EphA2-overexpressing tumor cells and tumor neovasculature, which could be used to mediate drug delivery for chemotherapy agents. PMID:26004003

  5. Cutaneous metastatic pigmented breast carcinoma.

    PubMed

    Gaitan-Gaona, Francisco; Said, Mirra C; Valdes-Rodriguez, Rodrigo

    2016-01-01

    A 66-year-old woman presented with a 3 cm black, ulcerated nodule located on the skin of the upper abdomen, just below the breast. The lesion was painful to the touch, but the patient reported no other associated symptoms and was otherwise healthy. A 4-mm punch biopsy of the affected skin was obtained and the histological diagnosis was cutaneous metastatic pigmented breast carcinoma. PMID:27136637

  6. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer.

    PubMed

    Miller, M Craig; Doyle, Gerald V; Terstappen, Leon W M M

    2010-01-01

    The increasing number of treatment options for patients with metastatic carcinomas has created a concomitant need for new methods to monitor their use. Ideally, these modalities would be noninvasive, be independent of treatment, and provide quantitative real-time analysis of tumor activity in a variety of carcinomas. Assessment of circulating tumor cells (CTCs) shed into the blood during metastasis may satisfy this need. We developed the CellSearch System to enumerate CTC from 7.5 mL of venous blood. In this review we compare the outcomes from three prospective multicenter studies investigating the use of CTC to monitor patients undergoing treatment for metastatic breast (MBC), colorectal (MCRC), or prostate cancer (MPC) and review the CTC definition used in these studies. Evaluation of CTC at anytime during the course of disease allows assessment of patient prognosis and is predictive of overall survival.

  7. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer

    PubMed Central

    Miller, M. Craig; Doyle, Gerald V.; Terstappen, Leon W. M. M

    2010-01-01

    The increasing number of treatment options for patients with metastatic carcinomas has created a concomitant need for new methods to monitor their use. Ideally, these modalities would be noninvasive, be independent of treatment, and provide quantitative real-time analysis of tumor activity in a variety of carcinomas. Assessment of circulating tumor cells (CTCs) shed into the blood during metastasis may satisfy this need. We developed the CellSearch System to enumerate CTC from 7.5 mL of venous blood. In this review we compare the outcomes from three prospective multicenter studies investigating the use of CTC to monitor patients undergoing treatment for metastatic breast (MBC), colorectal (MCRC), or prostate cancer (MPC) and review the CTC definition used in these studies. Evaluation of CTC at anytime during the course of disease allows assessment of patient prognosis and is predictive of overall survival. PMID:20016752

  8. Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital

    PubMed Central

    Iafrate, John A.; Sundaresan, Tilak; Younger, Jerry; Nardi, Valentina

    2016-01-01

    The last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the “right drug” for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues. In this article, we review the key considerations involved in clinical decision making while reviewing a molecular genotyping report. We present the case of a 67-year-old postmenopausal female with metastatic estrogen receptor-positive (ER+) breast cancer, whose tumor progressed on multiple endocrine therapies. Molecular genotyping of the metastatic lesion revealed the presence of an ESR1 mutation (encoding p.Tyr537Asn), which was absent in the primary tumor. The same ESR1 mutation was also detected in circulating tumor DNA (ctDNA) extracted from her blood. The general approach for interpretation of genotyping results, the clinical significance of the specific mutation in the particular cancer, potential strategies to target the pathway, and implications for clinical practice are reviewed in this article. Key Points ER+ breast tumors are known to undergo genomic evolution during treatment with the acquisition of new mutations that confer resistance to treatment. ESR1 mutations in the ligand-binding domain of ER can lead to a ligand-independent, constitutively active form of ER

  9. Phase II Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer

    ClinicalTrials.gov

    2016-04-18

    Extensive Stage Small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Tumors Metastatic to Brain; Metastatic Breast Cancer

  10. miR-16-5p Is a Stably-Expressed Housekeeping MicroRNA in Breast Cancer Tissues from Primary Tumors and from Metastatic Sites

    PubMed Central

    Rinnerthaler, Gabriel; Hackl, Hubert; Gampenrieder, Simon Peter; Hamacher, Frank; Hufnagl, Clemens; Hauser-Kronberger, Cornelia; Zehentmayr, Franz; Fastner, Gerd; Sedlmayer, Felix; Mlineritsch, Brigitte; Greil, Richard

    2016-01-01

    For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA profiling using TaqMan® Array Human MicroRNA Cards, enabling quantification of 754 unique human miRNAs, was performed in FFPE specimens from 58 patients with metastatic breast cancer. Forty-two (72%) samples were collected from primary tumors and 16 (28%) from metastases. In a cross-platform analysis of a validation cohort of 32 FFPE samples from patients with early breast cancer genome-wide microRNA expression analysis using SurePrintG3 miRNA (8 × 60 K)® microarrays from Agilent® was performed. Eleven microRNAs could be detected in all samples analyzed. Based on NormFinder and geNorm stability values and the high correlation (rho ≥ 0.8) with the median of all measured microRNAs, miR-16-5p, miR-29a-3p, miR-126-3p, and miR-222-3p are suitable single gene housekeeper candidates. In the cross-platform validation, 29 human microRNAs were strongly expressed (mean log2-intensity > 10) and 21 of these microRNAs including miR-16-5p and miR-29a-3p were also stably expressed (CV < 5%). Thus, miR-16-5p and miR-29a-3p are both strong housekeeper candidates. Their Normfinder stability values calculated across the primary tumor and metastases subgroup indicate that miR-29a-3p can be considered as the strongest housekeeper in a cohort with mainly samples from primary tumors, whereas miR-16-5p might perform better in a metastatic sample enriched cohort. PMID:26821018

  11. Quantitative mitochondrial redox imaging of breast cancer metastatic potential

    NASA Astrophysics Data System (ADS)

    Xu, He N.; Nioka, Shoko; Glickson, Jerry D.; Chance, Britton; Li, Lin Z.

    2010-05-01

    Predicting tumor metastatic potential remains a challenge in cancer research and clinical practice. Our goal was to identify novel biomarkers for differentiating human breast tumors with different metastatic potentials by imaging the in vivo mitochondrial redox states of tumor tissues. The more metastatic (aggressive) MDA-MB-231 and less metastatic (indolent) MCF-7 human breast cancer mouse xenografts were imaged with the low-temperature redox scanner to obtain multi-slice fluorescence images of reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp). The nominal concentrations of NADH and Fp in tissue were measured using reference standards and used to calculate the Fp redox ratio, Fp/(NADH+Fp). We observed significant core-rim differences, with the core being more oxidized than the rim in all aggressive tumors but not in the indolent tumors. These results are consistent with our previous observations on human melanoma mouse xenografts, indicating that mitochondrial redox imaging potentially provides sensitive markers for distinguishing aggressive from indolent breast tumor xenografts. Mitochondrial redox imaging can be clinically implemented utilizing cryogenic biopsy specimens and is useful for drug development and for clinical diagnosis of breast cancer.

  12. Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells.

    PubMed

    Wang, Wendan; Belosay, Aashvini; Yang, Xujuan; Hartman, James A; Song, Huaxin; Iwaniec, Urszula T; Turner, Russell T; Churchwell, Mona I; Doerge, Daniel R; Helferich, William G

    2016-06-01

    Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Here we evaluate the effects of the aromatase inhibitor letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER-) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX + Letrozole, Intact, and Intact + Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 µg/g body weight. Tumor progression was monitored by bioluminescence imaging (BLI). Following necropsy, inoculated tibiae were scanned via µCT and bone response to tumor was scored from 0 (no ectopic mineralization/osteolysis) to 5 (extensive ectopic mineralization/osteolysis). OVX mice had higher tibial pathology scores indicative of more extensive bone destruction than intact mice, irrespective of letrozole treatment. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Furthermore, mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&E and Ki-67 staining, respectively. In conclusion, BC-inoculated OVX animals had higher tibia pathology scores than BC-inoculated intact animals and letrozole reduced BC metastases to lungs. These findings suggest that, by lowering systemic estrogen level and/or by interacting with the host organ, the aromatase inhibitor letrozole has the potential to reduce ER- BC metastasis to lung. PMID:27209469

  13. Ixabepilone: a new chemotherapeutic option for refractory metastatic breast cancer

    PubMed Central

    Puhalla, Shannon; Brufsky, Adam

    2008-01-01

    Taxane therapy is commonly used in the treatment of metastatic breast cancer. However, most patients will eventually become refractory to these agents. Ixabepilone is a newly approved chemotherapeutic agent for the treatment of metastatic breast cancer. Although it targets microtubules similarly to docetaxel and paclitaxel, ixabepilone has activity in patients that are refractory to taxanes. This review summarizes the pharmacology of ixapebilone and clinical trials with the drug both as a single agent and in combination. Data were obtained using searches of PubMed and abstracts of the annual meetings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium from 1995 to 2008. Ixapebilone is a semi-synthetic analog of epothilone B that acts to induce apoptosis of cancer cells via the stabilization of microtubules. Phase I clinical trials have employed various dosing schedules ranging from daily to weekly to 3-weekly. Dose-limiting toxicites included neuropathy and neutropenia. Responses were seen in a variety of tumor types. Phase II studies verified activity in taxane-refractory metastatic breast cancer. The FDA has approved ixabepilone for use as monotherapy and in combination with capecitabine for the treatment of metastatic breast cancer. Ixabepilone is an efficacious option for patients with refractory metastatic breast cancer. The safety profile is similar to that of taxanes, with neuropathy and neutropenia being dose-limiting. Studies are ongoing with the use of both iv and oral formulations and in combination with other chemotherapeutic and biologic agents. PMID:19707381

  14. Metastatic Hip Tumor in a Middle-Aged Woman.

    PubMed

    Callan, Brad

    2016-05-01

    A 44-year-old woman was referred to physical therapy by a podiatrist for "iliotibial band syndrome." No imaging had been done, and she denied all constitutional symptoms, but reported having breast cancer 5 years earlier. Following an increase in pain, radiographs and magnetic resonance imaging were performed, and biopsy confirmed a metastatic breast cancer tumor. J Orthop Sports Phys Ther 2016;46(5):400. doi:10.2519/jospt.2016.0407. PMID:27133943

  15. Neighborhood socioeconomic deprivation, tumor subtypes, and causes of death after non-metastatic invasive breast cancer diagnosis: a multilevel competing-risk analysis.

    PubMed

    Lian, Min; Pérez, Maria; Liu, Ying; Schootman, Mario; Frisse, Ann; Foldes, Ellen; Jeffe, Donna B

    2014-10-01

    The purpose of this study is to examine the associations of neighborhood socioeconomic deprivation and triple-negative breast cancer (TNBC) subtype with causes of death [breast cancer (BC)-specific and non-BC-specific] among non-metastatic invasive BC patients. We identified 3,312 patients younger than 75 years (mean age 53.5 years; 621 [18.8 %] TNBC) with first primary BC treated at an academic medical center from 1999 to 2010. We constructed a census-tract-level socioeconomic deprivation index using the 2000 U.S. Census data and performed a multilevel competing-risk analysis to estimate the hazard ratios (HR) and 95 % confidence intervals (CI) of BC-specific and non-BC-specific mortality associated with neighborhood socioeconomic deprivation and TNBC subtype. The adjusted models controlled for patient sociodemographics, health behaviors, tumor characteristics, comorbidity, and cancer treatment. With a median 62-month follow-up, 349 (10.5 %) patients died; 233 died from BC. In the multivariate models, neighborhood socioeconomic deprivation was independently associated with non-BC-specific mortality (the most- vs. the least-deprived quartile: HR = 2.98, 95 % CI = 1.33-6.66); in contrast, its association with BC-specific mortality was explained by the aforementioned patient-level covariates, particularly sociodemographic factors (HR = 1.15, 95 % CI = 0.71-1.87). TNBC subtype was independently associated with non-BC-specific mortality (HR = 2.15; 95 % CI = 1.20-3.84), while the association between TNBC and BC-specific mortality approached significance (HR = 1.42; 95 % CI = 0.99-2.03, P = 0.057). Non-metastatic invasive BC patients who lived in more socioeconomically deprived neighborhoods were more likely to die as a result of causes other than BC compared with those living in the least socioeconomically deprived neighborhoods. TNBC was associated with non-BC-specific mortality but not BC-specific mortality.

  16. 7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)

    ClinicalTrials.gov

    2013-09-27

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; Gastrointestinal Stromal Tumor; HER2-negative Breast Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Endometrial Carcinoma; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral

  17. Cold atmospheric plasma for selectively ablating metastatic breast cancer cells.

    PubMed

    Wang, Mian; Holmes, Benjamin; Cheng, Xiaoqian; Zhu, Wei; Keidar, Michael; Zhang, Lijie Grace

    2013-01-01

    Traditional breast cancer treatments such as surgery and radiotherapy contain many inherent limitations with regards to incomplete and nonselective tumor ablation. Cold atmospheric plasma (CAP) is an ionized gas where the ion temperature is close to room temperature. It contains electrons, charged particles, radicals, various excited molecules, UV photons and transient electric fields. These various compositional elements have the potential to either enhance and promote cellular activity, or disrupt and destroy them. In particular, based on this unique composition, CAP could offer a minimally-invasive surgical approach allowing for specific cancer cell or tumor tissue removal without influencing healthy cells. Thus, the objective of this research is to investigate a novel CAP-based therapy for selectively bone metastatic breast cancer treatment. For this purpose, human metastatic breast cancer (BrCa) cells and bone marrow derived human mesenchymal stem cells (MSCs) were separately treated with CAP, and behavioral changes were evaluated after 1, 3, and 5 days of culture. With different treatment times, different BrCa and MSC cell responses were observed. Our results showed that BrCa cells were more sensitive to these CAP treatments than MSCs under plasma dose conditions tested. It demonstrated that CAP can selectively ablate metastatic BrCa cells in vitro without damaging healthy MSCs at the metastatic bone site. In addition, our study showed that CAP treatment can significantly inhibit the migration and invasion of BrCa cells. The results suggest the great potential of CAP for breast cancer therapy.

  18. A Case of Choroidal Melanoma Metastatic to the Breast

    PubMed Central

    Taran-Munteanu, L.; Hartkopf, A.; Eigentler, T. K.; Vogel, U.; Brucker, S.; Taran, F. A.

    2016-01-01

    A 61-year-old woman developed blurred vision in her left eye in December 2006. A clinical diagnosis of choroidal melanoma was made. The patient underwent excision of the left lens, followed by vitrectomy and stereotactic radiotherapy. She remained systemically healthy until 50 months later when, during a CT scan done for staging purposes, a newly visible lump was noted in the lower quadrant of her left breast. Core needle biopsy of the lesion in the left breast was performed, and histologic examination revealed metastasis from the choroidal melanoma. The patient underwent breast-conserving surgery of the left breast. Definitive histological examination showed clear tumor margins in the resected specimen and one sentinel lymph node without evidence of metastatic cells. Twenty-nine months after surgery, a similar nodule was detected in the upper quadrant of the left breast. Core biopsy again showed metastatic melanoma, and similar breast-conserving surgery was performed. Systemic examination, including magnetic resonance imaging of the head and computed tomography of the pelvis, abdomen, and chest, was done regularly and revealed no significant findings. Solitary breast metastases from choroidal melanoma are extremely rare. Nevertheless, clinicians should be aware of this rare form of metastasis when treating patients with suspicious breast lesions and a history of choroidal melanoma. If solitary metastasis is confirmed, then breast-conserving surgery may be recommended. PMID:27239068

  19. Targeting Angiogenesis in Metastatic Breast Cancer

    PubMed Central

    Reddy, Sangeetha; Raffin, Michael

    2012-01-01

    Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC. PMID:22843553

  20. Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC) Uncovers Potential Novel Drivers of Hormonal Resistance

    PubMed Central

    Manso, Luis; Mourón, Silvana; Tress, Michael; Gómez-López, Gonzalo; Morente, Manuel; Ciruelos, Eva; Rubio-Camarillo, Miriam; Rodriguez-Peralto, Jose Luis; Pujana, Miguel A.; Pisano, David G.; Quintela-Fandino, Miguel

    2016-01-01

    We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC). We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001). Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001), and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC. PMID:27195705

  1. Sorafenib Tosylate in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2014-11-14

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Neuroendocrine Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  2. Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2015-08-29

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma

  3. Serial enumeration of circulating tumor cells predicts treatment response and prognosis in metastatic breast cancer: a prospective study in 393 patients

    PubMed Central

    2014-01-01

    Background To prospectively assess circulating tumor cell (CTC) status at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C), and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for their utility in predicting response, progression-free (PFS) and overall survival (OS) in metastatic breast cancer (MBC). Methods CTCBL and CTC1C status was determined as negative (-) or positive (+) for < 5 or ≥ 5 CTCs/7.5 ml blood using CellSearch™ (Veridex). CTCKIN was categorized as favorable (CTC1C-) or unfavorable (CTC1C+). Tumor response was to be assessed every 2–3 months using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Statistical analysis focused on the relation between CTC status and CTCKIN, and response, PFS, and OS. Results 133/393 (34%) patients enrolled were CTCBL+. CTC1C status after one cycle and radiological tumor response were assessed after median (range) periods of 1.2 (0.5–3.2) and 2.9 (0.5–4.8) months, respectively. 57/201 (28%) were CTC1C+. Median [95% confidence interval] PFS and OS (months) were significantly reduced in CTCBL+ vs. CTCBL- patients (PFS 4.7 [3.7–6.1] vs. 7.8 [6.4–9.2]; OS 10.4 [7.9–15.0] vs. 27.2 [22.3–29.9]), and for CTC1C+ vs. CTC1C- patients (PFS 4.3 [3.6–6.0] vs. 8.5 [6.6–10.4]; OS 7.7 [6.4–13.9] vs. 30.6 [22.6–not available]). Unfavorable CTCKIN was significantly associated with progressive disease. Multivariate Cox regression analysis revealed prognostic factors for shorter PFS (CTCBL+, persistent CTCs after one cycle, ≥ 3rd-line therapy, and triple-negative receptor status) and shorter OS (CTCBL+, persistent CTCs after one cycle, bone-and-visceral/local metastases, ≥ 3rd-line therapy, and triple-negative receptor status). Conclusions CTCBL, CTC1C, and CTCKIN are predictive of outcome in MBC. Serial CTC enumeration is useful in tailoring systemic treatment of MBC. Trial registration Not applicable. PMID:25015676

  4. Phyllodes tumor of the breast

    PubMed Central

    Herazo, Fernando; Gil, Monica; Echeverri, Carolina; Ángel, Gonzalo; Borrero, Mauricio; Madrid, Jorge; Jaramillo, Ricardo

    2015-01-01

    Introduction: Breast Phyllodes tumors are rare breast tumors present in less than 1% of new cases of breast cancer, usually occurring among middle-aged women (40-50 yrs). Objective: This study shows diagnostic experience, surgical management and follows up of patients with this disease during a period of ten years in a oncology referral center. Methods: Retrospectively, breast cancer registries at the institution were reviewed, identifying 77 patients with Phyllodes tumors between 2002 and 2012, who had been operated on at the Instituto de Cancerología - Clínica Las Américas, in Medellín (Colombia). Clinical and histopathological data belonging to these cases was captured and analyzed and descriptive statistics were used. Results: The follow up median was 22.5 months (IQR: 10.5-60.0), average age was 47.2 yrs (SD: 12.4), mean tumor size was 3.6 cm (SD: 4.6), 88.3% of the patients (68 cases) presented negative margins and none of them received adjuvant chemotherapy. Of the patients with Phyllodes tumors; 33.8% had benign, 31.2% had borderline and 35.0% had malignant tumor. Disease-free survival was 85.8% and overall survival was 94.5%. Discussion: Reported data in this article is in accordance with what has been reported in worldwide literature. In our cohort even the high mean size of the tumors, the risk of local relapse and metastatic disease is low than previously reported in literature. Trials with longer follow up and molecular trials in Phyllodes tumors are necessary to understand the behavior of these tumors in Hispanics population. PMID:26600624

  5. Talazoparib and HSP90 Inhibitor AT13387 in Treating Patients With Metastatic Advanced Solid Tumor or Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, or Triple Negative Breast Cancer

    ClinicalTrials.gov

    2016-07-22

    Adult Solid Neoplasm; Estrogen Receptor Negative; Fallopian Tube Serous Neoplasm; HER2/Neu Negative; Ovarian Serous Adenocarcinoma; Ovarian Serous Tumor; Primary Peritoneal Serous Adenocarcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Triple-Negative Breast Carcinoma

  6. Suppressive effects of a proton beam on tumor growth and lung metastasis through the inhibition of metastatic gene expression in 4T1 orthotopic breast cancer model.

    PubMed

    Kwon, Yun-Suk; Lee, Kyu-Shik; Chun, So-Young; Jang, Tae Jung; Nam, Kyung-Soo

    2016-07-01

    A proton beam is a next generation tool to treat intractable cancer. Although the therapeutic effects of a proton beam are well known, the effect on tumor metastasis is not fully described. Here, we investigated the effects of a proton beam on metastasis in highly invasive 4T1 murine breast cancer cells and their orthotopic breast cancer model. Cells were irradiated with 2, 4, 8 or 16 Gy proton beam, and changes in cell proliferation, survival, and migration were observed by MTT, colony forming and wound healing assays. 4T1 breast cancer cell-implanted BALB/c mice were established and the animals were randomly divided into 4 groups when tumor size reached 200 mm3. Breast tumors were selectively irradiated with 10, 20 or 30 Gy proton beam. Breast tumor sizes were measured twice a week, and breast tumor and lung tissues were pathologically observed. Metastasis-regulating gene expression was assessed with quantitative RT-PCR. A proton beam dose-dependently decreased cell proliferation, survival and migration in 4T1 murine breast cancer cells. Also, growth of breast tumors in the 4T1 orthotopic breast cancer model was significantly suppressed by proton beam irradiation without significant change of body weight. Furthermore, fewer tumor nodules metastasized from breast tumor into lung in mice irradiated with 30 Gy proton beam, but not with 10 and 20 Gy, than in control. We observed correspondingly lower expression levels of urokinase plasminogen activator (uPA), uPA receptor, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF), which are important factors in cancer metastasis, in breast tumor irradiated with 30 Gy proton beam. Proton beam irradiation did not affect expressions of matrix metalloproteinase (MMP)-9 and MMP-2. Taken together, the data suggest that, although proton beam therapy is an effective tool for breast cancer treatment, a suitable dose is necessary to prevent metastasis-linked relapse and poor prognosis. PMID:27176787

  7. Treatment of metastatic breast cancer with aminoglutethimide.

    PubMed

    Asbury, R F; Bakemeier, R F; Fölsch, E; McCune, C S; Savlov, E; Bennett, J M

    1981-04-15

    Seventy-three women with metastatic breast cancer were treated with aminoglutethimide and dexamethasone. No complete responses occurred. Ten patients (16%) achieved partial responses (mean duration, 12 months). The proportions of patients responding by disease site were breast (50%), nodes (33%), skin (23%), bone (16%), lung (11%), and liver (7%). Response did not correlate with age, menopausal status, performance status, or cortisol suppression. Ninety percent of responders had had previous responses to hormonal manipulations. No responses occurred in estrogen receptor negative patients. An additional 20% of patients had disease stabilization of eight or more months (mean, 17 months). Severe bone pain was present in 47 patients and was relieved in 19. Side effects occurred in 75% but caused discontinuation of therapy in only four patients. Somnolence, nausea, rash, Cushings syndrome, and leukopenia were the most frequent side effects. Aminoglutethimide with dexamethasone is an effective hormonal treatment for metastatic breast cancer.

  8. Duodenal Adenocarcinoma Metastatic to the Breast

    PubMed Central

    Yu, Haibo; Song, Hongliang; Jiang, Yi

    2016-01-01

    Abstract Duodenal adenocarcinoma, a very rare malignant gastrointestinal tumor, mainly metastasizes via the lymphatic system. Metastases from duodenal adenocarcinomas to the breast are very uncommon. A 31-year-old woman presented at our department with a left breast tumor. She had a past medical history of duodenal adenocarcinoma. Physical examination on admission confirmed a 2.5-cm-diameter tumor in the outer lower quadrant of the left breast. Computed tomography (CT) examination showed a soft lesion with tissue-like density and enlarged axillary lymph nodes. Local excision was performed to remove the breast lesion. The findings of cytologic, histologic, and immunohistochemistry examination indicated a breast metastasis from the previous duodenal adenocarcinoma. The patient was treated with palliative chemotherapy. Metastases from duodenal adenocarcinoma to the breast are rare. The diagnosis depends on medical history, imaging, and pathologic examination including immunohistochemistry. An accurate diagnosis is important to avoid unnecessary surgery. PMID:26986146

  9. Immunohistochemical analysis of aromatase in metastatic lymph nodes of breast cancer.

    PubMed

    Shibahara, Yukiko; Miki, Yasuhiro; Ishida, Takanori; Nakamura, Yasuhiro; Suzuki, Takashi; Ohuchi, Noriaki; Sasano, Hironobu

    2013-01-01

    Aromatase is the key enzyme in intratumoral estrogen production in postmenopausal breast cancer and third generation aromatase inhibitors suppress this enzymatic reaction effectively. Aromatase inhibitor is administered to metastatic breast cancer patients customarily in which estrogen receptor had been demonstrated only in the primary tumor, not the metastatic sites. The status of aromatase in metastatic sites has not been well-characterized to date. We immunolocalized aromatase in 46 estrogen receptor positive primary breast cancers and paired metastatic lymph nodes, using immunohistochemistry. Immunoreactivity was detected in 44/46 primary tumors and 40/46 metastatic lymph nodes. A significant correlation was detected between the status of aromatase in primary and metastatic sites. Aromatase immunoreactivity was correlated with age, size of primary tumor and Ki-67 index. Aromatase immunoreactivity was also detected in adipose tissue surrounding the lymph nodes. In conclusion, aromatase status in primary tumors generally represents its status in metastatic lymph nodes. This indicates that the endocrine environment of estrogen receptor positive tumors remain stable during the metastatic process. PMID:23356222

  10. Gefitinib in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  11. Detection of circulating tumor cells in blood of metastatic breast cancer patients using a combination of cytokeratin and EpCAM antibodies

    PubMed Central

    2012-01-01

    Background Circulating tumor cells (CTCs) are detectable in peripheral blood of metastatic breast cancer patients (MBC). In this paper we evaluate a new CTC separation method based on a combination of anti-EpCAM- and anti-cytokeratin magnetic cell separation with the aim to improve CTC detection with low target antigen densities. Methods Blood samples of healthy donors spiked with breast cancer cell line HCC1937 were used to determine accuracy and precision of the method. 10 healthy subjects were examined to evaluate specificity. CTC counts in 59 patients with MBC were measured to evaluate the prognostic value on overall survival. Results Regression analysis of numbers of recovered vs. spiked HCC1937 cells yielded a coefficient of determination of R2 = 0.957. The average percentage of cell recovery was 84%. The average within-run coefficient of variation for spiking of 185, 85 and 30 cells was 14%. For spiking of 10 cells the within-run CV was 30%. No CTCs were detected in blood of 10 healthy subjects examined. A standard threshold of 5 CTC/7.5 ml blood as a cut-off point between risk groups led to a highly significant prognostic marker (p < 0.001). To assess the prognostic value of medium CTC levels we additionally considered a low (CTC-L: 0 CTC), a medium (CTC-M: 1–4 CTC) and a high risk group (CTC-H: ≥5 CTC). The effect of this CTC-LMH marker on overall survival was significant as well (p < 0.001). A log-ratio test performed to compare the model with 3 vs. the model with 2 risk groups rejected the model with 2 risk groups (p = 0.026). For CTC as a count variable, we propose an offset reciprocal transformation 1/(1 + x) for overall survival prediction (p < 0.001). Conclusions We show that our CTC detection method is feasible and leads to accurate and reliable results. Our data suggest that a refined differentiation between patients with different CTC levels is reasonable. PMID:22646670

  12. Surgical Outcomes of Hemorrhagic Metastatic Brain Tumors

    PubMed Central

    Yoo, Heon; Jung, Eugene; Gwak, Ho Shin; Shin, Sang Hoon

    2011-01-01

    Purpose Hemorrhagic metastatic brain tumors are not rare, but little is known about the surgical outcome following treatment. We conducted this study to determine the result of the surgical outcome of hemorrhagic metastatic brain tumors. Materials and Methods From July 2001 to December 2008, 21 patients underwent surgery for hemorrhagic metastatic brain tumors at our institution. 15 patients had lung cancer, 3 had hepatocellular carcinoma, and the rest had rectal cancer, renal cell carcinoma, and sarcoma. 20 patients had macroscopic hemorrhage in the tumors, and one patient had intracerebral hemorrhage surrounding the tumor. A retrospective clinical review was conducted focusing on the patterns of presenting symptoms and signs, as well as local recurrence following surgery. Results Among 21 hemorrhagic brain metastases, local recurrence developed in two patients. The 12 month progression free survival rate was 86.1%. Mean time to progression was 20.8 months and median survival time after surgery was 11.7 months. Conclusion The results of our study showed that hemorrhagic metastatic brain tumors rarely recurred after surgery. Surgery should be considered as a good treatment option for hemorrhagic brain metastasis, especially in cases with increased intracranial pressure or severe neurologic deficits. PMID:21811426

  13. A Giant Phyllodes Tumor of the Breast

    PubMed Central

    Schillebeeckx, Charlotte; Verbeeck, Guy; Daenen, Geert; Servaes, Dirk; Bronckaers, Marc

    2016-01-01

    Phyllodes tumors of the breast are rare, accounting for less than 1% of the breast tumors. They are mostly seen in women between 45 and 49 years old. These are fast growing tumors with a large spectrum of behavior (from benign to metastatic) and can resemble fibroadenomas. Correct diagnosis mostly through core needle biopsy is important to decide whether a surgical excision has to be done. Here we report a case of a 57-year-old woman with a fast growing, ulcerated tumor in the left breast. Core needle biopsy suggested a malignant phyllodes tumor with heterologous liposarcomatous differentiation. Treatment with total mastectomy and adjuvant radiotherapy followed. Primary treatment is always surgery, whether radiotherapy or chemotherapy has to follow remains uncertain. There is a high-recurrence rate, especially when the surgical margins are narrow. PMID:27746880

  14. Metastatic breast cancer in patients with schizophrenia

    PubMed Central

    MEYER, AARON A.; HWANG, M.; FARASATPOUR, M.; JANARDHAN, R.; MARGENTHALER, J.A.; VIRGO, K.S.; JOHNSON, FRANK E.

    2013-01-01

    Breast cancer is a major health problem worldwide. The median survival duration for patients with metastatic breast cancer is two to three years. Approximately 1% of populations worldwide have schizophrenia. The manner in which schizophrenic patients fare when diagnosed with metastatic breast carcinoma (MBC) was evaluated. We queried the National Department of Veterans Affairs (DVA) datasets using computer codes for a pre-existing diagnosis of schizophrenia and a later diagnosis of breast carcinoma. Chart-based data concerning the identified subjects were then requested. Previously determined inclusion and exclusion criteria were applied to select evaluable patients from the medical records, prior to extracting demographic details and data concerning the treatment course in each subject. Ten patients had distant metastases at initial diagnosis, while seven developed MBC following prior curative-intent treatment. Two patients refused therapy. Ten did not comply with recommended management. Five harmed or threatened physicians, other caregivers or themselves. Schizophrenic patients with MBC often fail to understand the nature of their illnesses. Often they do not accept palliative treatment, while a number of them do not comply with therapy, once initiated. They often exhibit behaviors that are detrimental to themselves or others. Formal psychiatric consultation is therefore necessary in patients. Several detrimental behaviors may be predicted reliably by history alone. PMID:24649175

  15. Improvement of survival and prospect of cure in patients with metastatic breast cancer.

    PubMed

    Cheng, Yee Chung; Ueno, Naoto T

    2012-07-01

    Patients with metastatic breast cancer have traditionally been considered incurable with conventional treatment. However, 5-10% of those patients survive more than 5 years, and 2-5% survive more than 10 years. Recent studies suggest that the survival of patients with metastatic breast cancer has been slowly improving. In this review, we examine the possible curative approach for a certain group of patients with metastatic breast cancer. We identify that patients most likely to benefit from such an aggressive approach are young and have good performance status, adequate body functional reserve, long disease-free interval before recurrence, oligometastatic disease, and low systemic tumor load. An aggressive multidisciplinary approach including both local treatment of macroscopic disease and systemic treatment of microscopic disease can result in prolonged disease control in certain patients with metastatic breast cancer. Whether patients with prolonged disease control are "cured" remains controversial.

  16. Pre-Clinical Mouse Models of Primary and Metastatic Pleural Cancers of the Lung and Breast and the Use of Bioluminescent Imaging to Monitor Pleural Tumor Burden (ms#CP-10-0176)

    PubMed Central

    Servais, Elliot L.; Colovos, Christos; Kachala, Stefan S.; Adusumilli, Prasad S.

    2015-01-01

    Malignant pleural disease (MPD) results in an estimated 150,000 cases of malignant pleural effusions (MPE) annually. The most common malignancies associated with MPD are primary malignant pleural mesothelioma (MPM) and metastatic lung cancer, breast cancer and lymphoma. MPM is a rare, regionally aggressive, malignancy whose incidence is increasing secondary to the latency of disease progression. MPD is characteristic of advanced stage pleural disease and portends a grave clinical prognosis with a median survival between 3 to 12 months. Treatment for MPD is primarily palliative by thoracentesis to drain the effusion or surgical procedures to liberate trapped lung and obliterate cavities in order to limit subsequent collection of pleural effusions. Systemic chemotherapy is typically ineffective due to dose-limiting toxicities and poor intratumoral penetration. Preclinical investigations conducted in flank and intraperitoneal tumor models do not fully recapitulate the pleural tumor microenvironment and the results are not directly translational to the clinically setting. An orthotopic model of pleural malignancy allows investigators to evaluate the efficacy of therapies against novel molecular targets in a microenvironment that mimics the clinical tumor milieu. The protocol described herein provides a mouse model of MPM and MPD from non-hematogenous tumors resulting in reproducible tumor location, tumor progression, animal survival, and histopathology. Pleural tumor growth in this model resembles the regionally aggressive clinical course and tumor microenvironment of human pleural cancers and provides an optimal animal model to investigate MPD biology and therapies. PMID:21898334

  17. Malignant metastatic carcinoid presenting as brain tumor

    PubMed Central

    Sundar, I. Vijay; Jain, S. K.; Kurmi, Dhrubajyoti; Sharma, Rakesh; Chopra, Sanjeev; Singhvi, Shashi

    2016-01-01

    Carcinoid tumors are rarely known to metastasise to the brain. It is even more rare for such patients to present with symptoms related to metastases as the initial and only symptom. We present a case of a 60-year-old man who presented with hemiparesis and imaging features suggestive of brain tumor. He underwent surgery and the histopathology revealed metastatic malignant lesion of neuroendocrine origin. A subsequent work up for the primary was negative. Patient was treated with adjuvant radiotherapy. We present this case to highlight the pathophysiological features, workup and treatment options of this rare disease and discuss the methods of differentiating it from more common brain tumors. PMID:27366273

  18. Circulating Tumor Cells in Breast Cancer Patients.

    PubMed

    Hall, Carolyn; Valad, Lily; Lucci, Anthony

    2016-01-01

    Breast cancer is the most commonly diagnosed cancer among women, resulting in an estimated 40,000 deaths in 2014.1 Metastasis, a complex, multi-step process, remains the primary cause of death for these patients. Although the mechanisms involved in metastasis have not been fully elucidated, considerable evidence suggests that metastatic spread is mediated by rare cells within the heterogeneous primary tumor that acquire the ability to invade into the bloodstream. In the bloodstream, they can travel to distant sites, sometimes remaining undetected and in a quiescent state for an extended period of time before they establish distant metastases in the bone, lung, liver, or brain. These occult micrometastatic cells (circulating tumor cells, CTCs) are rare, yet their prognostic significance has been demonstrated in both metastatic and non-metastatic breast cancer patients. Because repeated tumor tissue collection is typically not feasible and peripheral blood draws are minimally invasive, serial CTC enumeration might provide "real-time liquid biopsy" snapshots that could be used to identify early-stage breast cancer patients with micrometastatic disease who are at risk for disease progression and monitor treatment response in patients with advanced disease. In addition, characterizing CTCs might aid in the development of novel, personalized therapies aimed at eliminating micrometastases. This review describes current CTC isolation, detection, and characterization strategies in operable breast cancer. PMID:27481009

  19. Targeting Mortalin by Embelin Causes Activation of Tumor Suppressor p53 and Deactivation of Metastatic Signaling in Human Breast Cancer Cells

    PubMed Central

    Nigam, Nupur; Grover, Abhinav; Goyal, Sukriti; Katiyar, Shashank P.; Bhargava, Priyanshu; Wang, Pi-Chao; Sundar, Durai; Kaul, Sunil C.; Wadhwa, Renu

    2015-01-01

    Embelin, a natural quinone found in the fruits of Embelia ribes, is commonly used in Ayurvedic home medicine for a variety of therapeutic potentials including anti-inflammation, anti-fever, anti-bacteria and anti-cancer. Molecular mechanisms of these activities and cellular targets have not been clarified to-date. We demonstrate that the embelin inhibits mortalin-p53 interactions, and activates p53 protein in tumor cells. We provide bioinformatics, molecular docking and experimental evidence to the binding affinity of embelin with mortalin and p53. Binding of embelin with mortalin/p53 abrogates their complex resulted in nuclear translocation and transcriptional activation function of p53 causing growth arrest in cancer cells. Furthermore, analyses of growth factors and metastatic signaling using antibody membrane array revealed their downregulation in embelin-treated cells. We also found that the embelin causes transcriptional attenuation of mortalin and several other proteins involved in metastatic signaling in cancer cells. Based on these molecular dynamics and experimental data, it is concluded that the anticancer activity of embelin involves targeting of mortalin, activation of p53 and inactivation of metastatic signaling. PMID:26376435

  20. Entinostat, Nivolumab, and Ipilimumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Locally Advanced or Metastatic HER2-Negative Breast Cancer

    ClinicalTrials.gov

    2016-09-26

    Breast Adenocarcinoma; HER2/Neu Negative; Invasive Breast Carcinoma; Recurrent Breast Carcinoma; Solid Neoplasm; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  1. Bone marrow endothelium-targeted therapeutics for metastatic breast cancer.

    PubMed

    Mai, Junhua; Huang, Yi; Mu, Chaofeng; Zhang, Guodong; Xu, Rong; Guo, Xiaojing; Xia, Xiaojun; Volk, David E; Lokesh, Ganesh L; Thiviyanathan, Varatharasa; Gorenstein, David G; Liu, Xuewu; Ferrari, Mauro; Shen, Haifa

    2014-08-10

    Effective treatment of cancer metastasis to the bone relies on bone marrow drug accumulation. The surface proteins in the bone marrow vascular endothelium provide docking sites for targeted drug delivery. We have developed a thioaptamer that specifically binds to E-selectin that is overexpressed in the vasculature of tumor and inflammatory tissues. In this study, we tested targeted delivery of therapeutic siRNA loaded in the E-selectin thioaptamer-conjugated multistage vector (ESTA-MSV) drug carrier to bone marrow for the treatment of breast cancer bone metastasis. We evaluated tumor type- and tumor growth stage-dependent targeting in mice bearing metastatic breast cancer in the bone, and carried out studies to identify factors that determine targeting efficiency. In a subsequent study, we delivered siRNA to knock down expression of the human STAT3 gene in murine xenograft models of human MDA-MB-231 breast tumor, and assessed therapeutic efficacy. Our studies revealed that the CD31(+)E-selectin(+) population accounted for 20.8%, 26.4% and 29.9% of total endothelial cells respectively inside the femur of mice bearing early, middle and late stage metastatic MDA-MB-231 tumors. In comparison, the double positive cells remained at a basal level in mice with early stage MCF-7 tumors, and jumped to 23.9% and 28.2% when tumor growth progressed to middle and late stages. Accumulation of ESTA-MSV inside the bone marrow correlated with the E-selectin expression pattern. There was up to 5-fold enrichment of the targeted MSV in the bone marrow of mice bearing early or late stage MDA-MB-231 tumors and of mice with late stage, but not early stage, MCF-7 tumors. Targeted delivery of STAT3 siRNA in ESTA-MSV resulted in knockdown of STAT3 expression in 48.7% of cancer cells inside the bone marrow. Weekly systemic administration of ESTA-MSV/STAT3 siRNA significantly extended survival of mice with MDA-MB-231 bone metastasis. In conclusion, targeting the overexpressed E

  2. Immune Stimulating Photoactive Hybrid Nanoparticles for Metastatic Breast Cancer†

    PubMed Central

    Marrache, Sean; Choi, Joshua H.; Tundup, Smanla; Zaver, Dillon; Harn, Donald A.; Dhar, Shanta

    2012-01-01

    A therapeutic technology that combines the phototoxic and immune-stimulating ability of photodynamic therapy (PDT) with the widespread effectiveness of the immune system can be very promising to treat metastatic breast cancer. We speculated that the knowledge of molecular mechanisms of existing multi-component therapies could provide clues to aid the discovery of new combinations of an immunostimulant with a photosensitizer (PS) using a nanoparticle (NP) delivery platform. Therapeutic challenges when administering therapeutic combinations include the choice of dosages to reduce side effects, the definitive delivery of the correct drug ratio, and exposure to the targets of interest. These factors are very difficult to achieve when drugs are individually administered. By combining controlled release polymer-based NP drug delivery approaches, we were able to differentially deliver zinc phthalocyanine (ZnPc) based PS to metastatic breast cancer cells along with CpG-ODN, a single-stranded DNA that is a known immunostimulant to manage the distant tumors in a temporally regulated manner resulting in more effective management of deadly metastatic breast cancer. We encapsulated ZnPc which is a long-wavelength absorbing PS within a polymeric NP core made up of poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG). After coating the outside of the polymeric core with gold NPs (AuNPs), we further modified the AuNP surface with CpG-ODN. In vitro cytotoxicity using 4T1 metastatic mouse breast carcinoma cells shows significant photocytotoxicity of the hybrid NPs containing both ZnPc and CpG-ODN after irradiation with a 660 nm LASER light and this activity was remarkably better than either treatment alone. Treatment of mouse bone marrow derived dendritic cells with the PDT-killed 4T1 cell lysate shows that the combination of PDT with a synergistic immunostimulant in a single NP system results in significant immune response, which can be used for the treatment of

  3. iTRAQ Quantitative Proteomic Comparison of Metastatic and Non-Metastatic Uveal Melanoma Tumors

    PubMed Central

    Crabb, John W.; Hu, Bo; Crabb, John S.; Triozzi, Pierre; Saunthararajah, Yogen; Singh, Arun D.

    2015-01-01

    Background Uveal melanoma is the most common malignancy of the adult eye. The overall mortality rate is high because this aggressive cancer often metastasizes before ophthalmic diagnosis. Quantitative proteomic analysis of primary metastasizing and non-metastasizing tumors was pursued for insights into mechanisms and biomarkers of uveal melanoma metastasis. Methods Eight metastatic and 7 non-metastatic human primary uveal melanoma tumors were analyzed by LC MS/MS iTRAQ technology with Bruch’s membrane/choroid complex from normal postmortem eyes as control tissue. Tryptic peptides from tumor and control proteins were labeled with iTRAQ tags, fractionated by cation exchange chromatography, and analyzed by LC MS/MS. Protein identification utilized the Mascot search engine and the human Uni-Prot/Swiss-Protein database with false discovery ≤ 1%; protein quantitation utilized the Mascot weighted average method. Proteins designated differentially expressed exhibited quantitative differences (p ≤ 0.05, t-test) in a training set of five metastatic and five non-metastatic tumors. Logistic regression models developed from the training set were used to classify the metastatic status of five independent tumors. Results Of 1644 proteins identified and quantified in 5 metastatic and 5 non-metastatic tumors, 12 proteins were found uniquely in ≥ 3 metastatic tumors, 28 were found significantly elevated and 30 significantly decreased only in metastatic tumors, and 31 were designated differentially expressed between metastatic and non-metastatic tumors. Logistic regression modeling of differentially expressed collagen alpha-3(VI) and heat shock protein beta-1 allowed correct prediction of metastasis status for each of five independent tumor specimens. Conclusions The present data provide new clues to molecular differences in metastatic and non-metastatic uveal melanoma tumors. While sample size is limited and validation required, the results support collagen alpha-3(VI) and

  4. Metastatic Breast Carcinoma to the Prostate Gland.

    PubMed

    Kapp, Meghan E; Giannico, Giovanna A; Desouki, Mohamed Mokhtar

    2016-01-01

    Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC) to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903) and no expression of P501S. The patient's previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors. PMID:27429817

  5. Stratification and therapeutic potential of PML in metastatic breast cancer.

    PubMed

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H; Scaltriti, Maurizio; Lawrie, Charles H; Aransay, Ana M; Iovanna, Juan L; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; Vivanco, Maria dM; Matheu, Ander; Gomis, Roger R; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  6. Stratification and therapeutic potential of PML in metastatic breast cancer

    PubMed Central

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D.; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R.; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M.; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H.; Scaltriti, Maurizio; Lawrie, Charles H.; Aransay, Ana M.; Iovanna, Juan L.; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; dM Vivanco, Maria; Matheu, Ander; Gomis, Roger R.; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  7. In Vitro Co-Culture Models of Breast Cancer Metastatic Progression towards Bone.

    PubMed

    Arrigoni, Chiara; Bersini, Simone; Gilardi, Mara; Moretti, Matteo

    2016-01-01

    Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing extensive bone lysis. In recent years, the crosstalk between tumor cells and secondary organs microenvironment is gaining much attention, being indicated as a crucial aspect in all metastatic steps. To investigate the complex interrelation between the tumor and the microenvironment, both in vitro and in vivo models have been exploited. In vitro models have some advantages over in vivo, mainly the possibility to thoroughly dissect in controlled conditions and with only human cells the cellular and molecular mechanisms underlying the metastatic progression. In this article we will review the main results deriving from in vitro co-culture models, describing mechanisms activated in the crosstalk between breast cancer and bone cells which drive the different metastatic steps. PMID:27571063

  8. In Vitro Co-Culture Models of Breast Cancer Metastatic Progression towards Bone

    PubMed Central

    Arrigoni, Chiara; Bersini, Simone; Gilardi, Mara; Moretti, Matteo

    2016-01-01

    Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing extensive bone lysis. In recent years, the crosstalk between tumor cells and secondary organs microenvironment is gaining much attention, being indicated as a crucial aspect in all metastatic steps. To investigate the complex interrelation between the tumor and the microenvironment, both in vitro and in vivo models have been exploited. In vitro models have some advantages over in vivo, mainly the possibility to thoroughly dissect in controlled conditions and with only human cells the cellular and molecular mechanisms underlying the metastatic progression. In this article we will review the main results deriving from in vitro co-culture models, describing mechanisms activated in the crosstalk between breast cancer and bone cells which drive the different metastatic steps. PMID:27571063

  9. Metastatic tumors to the pancreas: The role of surgery

    PubMed Central

    Sperti, Cosimo; Moletta, Lucia; Patanè, Giuseppe

    2014-01-01

    Pancreatic metastases from other primary malignancies are a rare entity. By far, the most common primary cancer site resulting in an isolated pancreatic metastasis is the kidney, followed by colorectal cancer, melanoma, breast cancer, lung carcinoma and sarcoma. Only few data on the surgical outcome of pancreatic resections performed for metastases from other primary tumor have been published, and there are no guidelines to address the surgical treatment for these patients. In this study, we performed a review of the published literature, focusing on the early and long-term results of surgery for the most frequent primary tumors metastasizing to the pancreas. Results for the Literature’s analysis show that in last years an increasing number of surgical resections have been performed in selected patients with limited pancreatic disease. Pancreatic resection for metastatic disease can be performed with acceptable mortality and morbidity rates. The usefulness of pancreatic resection is mainly linked to the biology of the primary tumor metastasizing to the pancreas. The benefit of metastasectomy in terms of patient survival has been observed for metastases from renal cell cancer, while for other primary tumors, such as lung and breast cancers, the role of surgery is mainly palliative. PMID:25320654

  10. Temsirolimus and Vinorelbine Ditartrate in Treating Patients With Unresectable or Metastatic Solid Tumors

    ClinicalTrials.gov

    2016-06-09

    Extensive Stage Small Cell Lung Cancer; Hereditary Paraganglioma; Male Breast Cancer; Malignant Paraganglioma; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Pheochromocytoma; Pancreatic Polypeptide Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Endometrial Carcinoma; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Neuroendocrine Carcinoma of the Skin; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pheochromocytoma; Recurrent Prostate Cancer; Recurrent Renal Cell Cancer; Recurrent Small Cell Lung Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Regional Pheochromocytoma; Stage III Cervical Cancer; Stage III Endometrial Carcinoma; Stage III Neuroendocrine Carcinoma of the Skin; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Prostate Cancer; Stage III Renal Cell Cancer; Stage III Uterine Sarcoma; Stage IIIA Breast Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Breast Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Endometrial Carcinoma; Stage IV Neuroendocrine Carcinoma of the Skin; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Uterine Sarcoma; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Thyroid Gland Medullary Carcinoma

  11. Olaparib and Hsp90 Inhibitor AT13387 in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, or Triple-Negative Breast Cancer

    ClinicalTrials.gov

    2016-09-12

    Estrogen Receptor Negative; HER2/Neu Negative; High Grade Fallopian Tube Serous Adenocarcinoma; High Grade Ovarian Serous Adenocarcinoma; Metastatic Solid Neoplasm; Primary Peritoneal High Grade Serous Adenocarcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Triple-Negative Breast Carcinoma; Unresectable Solid Neoplasm

  12. Eribulin Improves Survival of Women with Metastatic Breast Cancer

    Cancer.gov

    Treatment with eribulin (Halaven™) improved overall survival in women with metastatic breast cancer whose disease progressed despite multiple rounds of prior chemotherapy, according to the results of a phase III clinical trial called EMBRACE.

  13. Muscleblind-like 1 suppresses breast cancer metastatic colonization and stabilizes metastasis suppressor transcripts

    PubMed Central

    Fish, Lisa; Pencheva, Nora; Goodarzi, Hani; Tran, Hien; Yoshida, Mitsukuni; Tavazoie, Sohail F.

    2016-01-01

    Post-transcriptional deregulation is a defining feature of metastatic cancer. While many microRNAs have been implicated as regulators of metastatic progression, less is known about the roles and mechanisms of RNA-binding proteins in this process. We identified muscleblind-like 1 (MBNL1), a gene implicated in myotonic dystrophy, as a robust suppressor of multiorgan breast cancer metastasis. MBNL1 binds the 3′ untranslated regions (UTRs) of DBNL (drebrin-like protein) and TACC1 (transforming acidic coiled-coil containing protein 1)—two genes that we implicate as metastasis suppressors. By enhancing the stability of these genes’ transcripts, MBNL1 suppresses cell invasiveness. Consistent with these findings, elevated MBNL1 expression in human breast tumors is associated with reduced metastatic relapse likelihood. Our findings delineate a post-transcriptional network that governs breast cancer metastasis through RNA-binding protein-mediated transcript stabilization. PMID:26883358

  14. Muscleblind-like 1 suppresses breast cancer metastatic colonization and stabilizes metastasis suppressor transcripts.

    PubMed

    Fish, Lisa; Pencheva, Nora; Goodarzi, Hani; Tran, Hien; Yoshida, Mitsukuni; Tavazoie, Sohail F

    2016-02-15

    Post-transcriptional deregulation is a defining feature of metastatic cancer. While many microRNAs have been implicated as regulators of metastatic progression, less is known about the roles and mechanisms of RNA-binding proteins in this process. We identified muscleblind-like 1 (MBNL1), a gene implicated in myotonic dystrophy, as a robust suppressor of multiorgan breast cancer metastasis. MBNL1 binds the 3' untranslated regions (UTRs) of DBNL (drebrin-like protein) and TACC1 (transforming acidic coiled-coil containing protein 1)-two genes that we implicate as metastasis suppressors. By enhancing the stability of these genes' transcripts, MBNL1 suppresses cell invasiveness. Consistent with these findings, elevated MBNL1 expression in human breast tumors is associated with reduced metastatic relapse likelihood. Our findings delineate a post-transcriptional network that governs breast cancer metastasis through RNA-binding protein-mediated transcript stabilization.

  15. SEOM clinical guidelines in metastatic breast cancer 2015.

    PubMed

    Gavilá, J; Lopez-Tarruella, S; Saura, C; Muñoz, M; Oliveira, M; De la Cruz-Merino, L; Morales, S; Alvarez, I; Virizuela, J A; Martin, M

    2015-12-01

    Metastatic breast cancer is essentially an incurable disease. However, recent advances have resulted in a significant improvement of overall survival. The SEOM guidelines are intended to make evidence-based recommendations on how to manage patients with metastatic breast cancer to achieve the best patient outcomes based on a rational use of the currently available therapies. To assign a level of certainty and a grade of recommendation the United States Preventive Services Task Force guidelines methodology was selected as reference.

  16. Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer

    PubMed Central

    Han, Hyunju; Sohn, Joohyuk; Choi, Wonshik; Kim, Seung-Il; Jung, Hyo-Il; Kim, You-Sun

    2016-01-01

    The dissemination of circulating tumor cells (CTCs) requires the Epithelial-to-Mesenchymal transition (EMT), in which cells lose their epithelial characteristics and acquire more mesenchymal-like phenotypes. Current isolation of CTCs relies on affinity-based approaches reliant on the expression of Epithelial Cell Adhesion Molecule (EpCAM). Here we show EMT-induced breast cancer cells maintained in prolonged mammosphere culture conditions possess increased EMT markers and cancer stem cell markers, as well as reduced cell mass and size by quantitative phase microscopy; however, EpCAM expression is dramatically decreased in these cells. Moreover, CTCs isolated from breast cancer patients using a label-free microfluidic flow fractionation device had differing expression patterns of EpCAM, indicating that affinity approaches reliant on EpCAM expression may underestimate CTC number and potentially miss critical subpopulations. Further characterization of CTCs, including low-EpCAM populations, using this technology may improve detection techniques and cancer diagnosis, ultimately improving cancer treatment. PMID:27013581

  17. Romidepsin in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Regional Gastrointestinal Carcinoid Tumor; Somatostatinoma

  18. [Palliative radiotherapy for metastatic bone tumor].

    PubMed

    Yoshida, Kenji; Hiratsuka, Junichi

    2006-04-01

    Bone metastases are one of the most common conditions requiring radiation therapy today. Its main aim is relief of bone pain, prevention of pathological bone fractures as well as its healing, with anticipated effect upon improving mobility, function, and quality of life. For localized bone pain, external beam radiation therapy (EBRT) will be successful in reducing pain in some 80% of patients. However, optimal fraction dose and total doses of EBRT required for pain relief have been unknown. According to the recent reports, carbon ion radiotherapy seems to be a safe and effective modality in the management of metastatic bone tumor not eligible for conventional EBRT. For scattered painful metastases, the systemic administration of radioisotopes is thought to be effective. PMID:16582516

  19. Metastatic breast cancer and its complications.

    PubMed

    Rubens, R D

    1992-12-01

    Tamoxifen is now established for use in premenopausal as well as postmenopausal patients. Recent reports have not shown its activity to be enhanced by the addition of either prednisolone, progestogens, or interferon. Reversible ocular toxicity from tamoxifen appears to be more common than had been previously realized. Different schedules giving the same dose intensity of doxorubicin give markedly different pharmacokinetic profiles. Although this does not lead to differences in responses or physical toxicity, it seems to have important implications for quality of life. Taxol is showing impressive activity in advanced breast cancer, and significant response rates have also been reported for carboplatin and podophyllotoxin derivatives. To achieve maximum effectiveness from the cyclophosphamide, methotrexate, and fluorouracil combination, attention to schedule and dose intensity has been shown to be important. No new effective cytotoxic combinations have been described. High-dose chemotherapy requiring bone marrow support remains experimental. Further progress has been made in monitoring the response of metastatic bone disease to treatment. The precise significance for patients of the results in many of the papers reviewed is often uncertain because they lack quality-of-life measures; the importance of this approach is emphasized. PMID:1457519

  20. Mammaglobin, a Valuable Diagnostic Marker for Metastatic Breast Carcinoma

    PubMed Central

    Wang, Zhiqiang; Spaulding, Betsy; Sienko, Anna; Liang, Yiaoming; Li, Hongbao; Nielsen, Gitte; Yub Gong, Gyung; Ro, Jae Y.; “Jim” Zhai, Qihui

    2009-01-01

    Identification of metastasis and occult micrometastases of breast cancer demands sensitive and specific diagnostic markers. In this study, we assessed the utility of a mouse monoclonal antibody to human mammaglobin for one such purpose. Immunohistochemical stains were performed on paraffin-embedded sections from a total of 284 cases, which consisted of primary breast invasive carcinomas (41 cases) with matched metastases to ipsilateral axillary lymph nodes, metastatic breast carcinoma to liver (1 case) and kidney (1 case), non-breast neoplasms (161 cases), and normal human tissues (39 cases). The results showed 31 of the 41 cases of primary breast cancer with axillary lymph node metastases were positive for mammaglobin (76%). In the meantime, we documented expression of mammaglobin in occasional cases of endometrial carcinoma (17%). Our data further validated that mammaglobin is a valuable diagnostic marker for metastatic carcinoma of breast origin, although endometrial carcinoma should be considered as a major differential diagnosis. PMID:19158935

  1. Metastatic metaplastic breast carcinoma mimicking pulmonary squamous cell carcinoma on fine-needle aspiration.

    PubMed

    Nguyen, Doreen N; Kawamoto, Satomi; Cimino-Mathews, Ashley; Illei, Peter B; Rosenthal, Dorothy L; VandenBussche, Christopher J

    2015-10-01

    Metaplastic squamous cell carcinoma (SCC) of the breast is a rare type of breast cancer. Metastases to the lung, which can be a major site of second primary tumor development among breast cancer patients, are difficult to distinguish from primary SCC of the lung and present a unique challenge for pathologists. There are few available discriminating immunohistochemical markers as squamous differentiation typically leads to loss of expression of characteristic primary epithelial cell markers of both breast and lung origin. GATA protein binding 3 (GATA-3) is a useful marker of breast origin in metastatic ductal and lobular carcinomas including poorly differentiated triple-negative carcinomas and some metaplastic carcinomas. Here, we present a case of metastatic SCC presenting as a solitary lung mass with regional lymph node metastases and a single satellite lesion in a patient with a history of metaplastic SCC of the breast. In addition to the routine markers of squamous differentiation, the metastases were also positive for estrogen receptor (ER) and GATA-3 on cytologic material obtained by transbronchial FNA. This suggests that immunoreactivity for ER and GATA-3 may support a diagnosis of metastatic SCC in the context of a prior metaplastic SCC of the breast.

  2. Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis

    PubMed Central

    Lee, Esak; Fertig, Elana J.; Jin, Kideok; Sukumar, Saraswati; Pandey, Niranjan B.; Popel, Aleksander S.

    2014-01-01

    Breast cancer metastasis involves lymphatic dissemination in addition to hematogenous spreading. Although stromal lymphatic vessels (LVs) serve as initial metastatic routes, roles of organ-residing LVs are under-investigated. Here we show that lymphatic endothelial cells (LECs), a component of LVs within pre-metastatic niches, are conditioned by triple-negative breast cancer (TNBC) cells to accelerate metastasis. LECs within the lungs and lymph nodes, conditioned by tumor-secreted factors express CCL5 that is not expressed either in normal LECs or cancer cells, and direct tumor dissemination into these tissues. Moreover, tumor-conditioned LECs promote angiogenesis in these organs, allowing tumor extravasation and colonization. Mechanistically, tumor cell-secreted IL6 causes Stat3 phosphorylation in LECs. This pStat3 induces HIF-1α and VEGF, and a pStat3-pc-Jun-pATF-2 ternary complex induces CCL5 expression in LECs. This study demonstrates anti-metastatic activities of multiple repurposed drugs, blocking a self-reinforcing paracrine loop between breast cancer cells and LECs. PMID:25178650

  3. Local therapy in metastatic breast cancer is associated with improved survival.

    PubMed

    Sofi, Aijaz A; Mohamed, Iman; Koumaya, Meghan; Kamaluddin, Zarine

    2013-01-01

    Patients presenting with stage-IV breast cancer are usually offered systemic chemotherapy to control metastatic tumor burden and palliative radiation therapy to manage the symptomatic primary tumor. The aim of this study was to assess the result of local therapy on the overall outcome of patients with metastatic breast cancer. We reviewed medical records of all patients with metastatic breast cancer that presented to our institution between 2000 and 2009. Based on the treatment received, the patients were grouped as follows: group 1 included patients who underwent surgery and also received radiotherapy and chemotherapy/hormonal therapy, group 2 included patients who received radiotherapy and chemotherapy/hormonal therapy only, and group 3 included patients who received chemotherapy/hormonal therapy alone. Of the 37 patients included in the study, 10 patients were placed in group 1, 17 patients in group 2, and 10 patients in group 3. About 38% had high to anaplastic tumor grade, and 48% had ≥2 metastatic sites in the body. Overall, the average survival time was 3.13 years (range: 0-17 years). A significant difference in survival estimates was noted between groups 1, 2, and 3 with mean survival times of 8.83, 4.9, and 2.26 years, respectively (log rank χ = 10.44, P = 0.005). In age-adjusted multivariate Cox regression model (χ = 21.729, P= 0.001), high/anaplastic tumor grade (P = 0.036), African American race (P = 0.009), central nervous system metastasis (P = 0.003), group 2 (P = 0.006), and group 3 (P = 0.002) were associated with poor survival. Survival was not associated with estrogen and progesterone receptor and visceral or bone metastases. We conclude that aggressive local control of primary tumor in patients presenting with stage-IV breast cancer is associated with improved survival.

  4. Anti-metastatic outcome of isoform-specific prolactin receptor targeting in breast cancer.

    PubMed

    Yonezawa, Tomohiro; Chen, Kuan-Hui Ethan; Ghosh, Mrinal K; Rivera, Lorena; Dill, Riva; Ma, Lisa; Villa, Pedro A; Kawaminami, Mitsumori; Walker, Ameae M

    2015-09-28

    Controversy exists concerning the role of the long prolactin receptor (PRLR) in the progression of breast cancer. By targeting pre-mRNA splicing, we succeeded in knocking down only the long PRLR in vivo, leaving the short forms unaffected. Using two orthotopic and highly-metastatic models of breast cancer, one of which was syngeneic (mouse 4T1) to allow assessment of tumor-immune interactions and one of which was endocrinologically humanized (human BT-474) to activate human PRLRs, we examined the effect of long PRLR knockdown on disease progression. In both models, knockdown dramatically inhibited metastatic spread to the lungs and liver and resulted in increased central death in the primary tumor. In the syngeneic model, immune infiltrates in metastatic sites were changed from innate inflammatory cells to lymphocytes, with an increase in the incidence of tumor-specific cytotoxic T cells. Long PRLR knockdown in three-dimensional culture induced apoptosis of tumor-initiating/cancer stem cells (death of 95% of cells displaying stem cell markers in 15 days). We conclude that the long PRLR plays an important role in breast cancer metastasis. PMID:26095602

  5. A phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer

    PubMed Central

    Tolaney, S. M.; Najita, J.; Sperinde, J.; Huang, W.; Chen, W. Y.; Savoie, J.; Fornier, M.; Winer, E. P.; Bunnell, C.; Krop, I. E.

    2013-01-01

    Background A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. Patients and methods Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1–2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m2 as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored. Results Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatment-related toxic effects included neuropathy (grade ≥2, 56%), leukopenia (grade ≥2, 26%), myalgias (grade ≥2, 21%), neutropenia (grade ≥2, 23%), and anemia (grade ≥2, 18%). Conclusions This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer. PMID:23559151

  6. Trends in presentation, management and survival of patients with de novo metastatic breast cancer in a Southeast Asian setting.

    PubMed

    Bhoo-Pathy, Nirmala; Verkooijen, Helena Marieke; Tan, Ern-Yu; Miao, Hui; Taib, Nur Aishah Mohd; Brand, Judith S; Dent, Rebecca A; See, Mee-Hoong; Subramaniam, ShriDevi; Chan, Patrick; Lee, Soo-Chin; Hartman, Mikael; Yip, Cheng-Har

    2015-11-05

    Up to 25% of breast cancer patients in Asia present with de novo metastatic disease. We examined the survival trends of Asian patients with metastatic breast cancer over fifteen years. The impact of changes in patient's demography, tumor characteristics, tumor burden, and treatment on survival trend were examined. Patients with de novo metastatic breast cancer from three hospitals in Malaysia and Singapore (N = 856) were grouped by year of diagnosis: 1996-2000, 2001-2005 and 2006-2010. Step-wise multivariable Poisson regression was used to estimate the contribution of above-mentioned factors on the survival trend. Proportions of patients presenting with metastatic breast cancer were 10% in 1996-2000, 7% in 2001-2005, and 9% in 2006-2010. Patients in 2006-2010 were significantly older, appeared to have higher disease burden, and received more chemotherapy, endocrine therapy, and surgery of primary tumor. The three-year relative survival in the above periods were 20·6% (95% CI: 13·9%-28·2%), 28·8% (95% CI: 23·4%-34·2%), and 33·6% (95% CI: 28·8%-38·5%), respectively. Adjustment for treatment considerably attenuated the relative excess risk of mortality in recent years, compared to other factors. Substantial improvements in survival were observed in patients with de novo metastatic breast cancer in this study.

  7. Phase II study of lonidamine in metastatic breast cancer.

    PubMed Central

    Pronzato, P.; Amoroso, D.; Bertelli, G.; Conte, P. F.; Cusimano, M. P.; Ciottoli, G. B.; Gulisano, M.; Lionetto, R.; Rosso, R.

    1989-01-01

    Thirty patients with previously treated metastatic breast cancer were entered in a phase II study with oral lonidamine. Twenty-eight patients are evaluable for toxicity and 25 for response. A partial remission was obtained in four patients (16%) and disease stability in 11 (44%): 10 patients progressed (40%). Toxicity was acceptable, consisting mainly of myalgias (39% of patients) and asthenia (21.4%). No myelotoxicity was observed. The drug is active in previously treated metastatic breast cancer and, because of its peculiar pattern of action and toxicity, deserves to be evaluated in combination with cytotoxic chemotherapy. PMID:2930690

  8. Case report of metastatic invasive breast lobular carcinoma to the urinary bladder.

    PubMed

    Al Ibraheemi, Ahmed A

    2016-01-01

    Breast cancer is the most common cancer in women except skin cancer. The common metastatic sites include lymph node, lung, liver and bone. However, metastasis to the bladder is extremely rare. To our knowledge, this is the first case of breast cancer metastasis to urinary bladder in Jordan which is reported. Nine years after the initial diagnosis of lobular breast carcinoma, the patient suffered from left side leg edema; Ultrasonography and Computed tomography scanning showed thickening of posterior bladder wall and bilateral hydronephrosis. The biopsy of the bladder confirmed metastatic lesion from the breast. In contrast to the primary tumor, bladder metastasis showed negative expression of estrogen (ER) and progesterone (PR) receptors. However, Her2neu test was negative in both. The reported case confirms that bladder metastasis from breast cancer tend to occur late after the diagnosis of the primary tumor. Furthermore, bladder metastasis can be asymptomatic and heterogeneous in ER and PR expression in comparison with the primary tumor. This report supports the need for careful follow-up and early intervention whenever such clinical situation is suspected. This report supports further evaluation of receptor status at time of metastasis.

  9. Detection of metastatic tumors after γ-irradiation using longitudinal molecular imaging and gene expression profiling of metastatic tumor nodules.

    PubMed

    Jang, Su Jin; Kang, Joo Hyun; Lee, Yong Jin; Kim, Kwang Il; Lee, Tae Sup; Choe, Jae Gol; Lim, Sang Moo

    2016-04-01

    A few recent reports have indicated that metastatic growth of several human cancer cells could be promoted by radiotherapy. C6-L cells expressing the firefly luciferase (fLuc) gene were implanted subcutaneously into the right thigh of BALB/c nu/nu mice. C6-L xenograft mice were treated locally with 50-Gy γ-irradiation (γ-IR) in five 10-Gy fractions. Metastatic tumors were evaluated after γ-IR by imaging techniques. Total RNA from non-irradiated primary tumor (NRPT), γ-irradiated primary tumor (RPT), and three metastatic lung nodule was isolated and analyzed by microarray. Metastatic lung nodules were detected by BLI and PET/CT after 6-9 weeks of γ-IR in 6 (17.1%) of the 35 mice. The images clearly demonstrated high [18F]FLT and [18F]FDG uptake into metastatic lung nodules. Whole mRNA expression patterns were analyzed by microarray to elucidate the changes among NRPT, RPT and metastatic lung nodules after γ-IR. In particular, expression changes in the cancer stem cell markers were highly significant in RPT. We observed the metastatic tumors after γ-IR in a tumor-bearing animal model using molecular imaging methods and analyzed the gene expression profile to elucidate genetic changes after γ-IR. PMID:26892334

  10. Pulmonary tumor thrombotic microangiopathy from metastatic epithelioid angiosarcoma

    PubMed Central

    Cakir, Ebru; Yazici, Ulku; Tastepe, Irfan

    2013-01-01

    The lung is most common site for metastatic disease via hematogenous route. Tumor emboli of the vessels of the lung induces fibrocellular and fibromuscular intimal proliferation. These histopathological changes may cause pulmonary tumor trombotic microangiopaty. Few cases are diagnosed antemortem. We report a 60 year old woman with by metastatic epithelioid angiosarcoma involving the lung. Tumor cells were positive for VEGF and topoisomerase II. VEGF may be involved in the pathogenesis pulmonary tumor trombotic microangioapy and topoisomerase II positivity showed sensitivity against catalytic topoisomerase II inhibitors. PMID:23825782

  11. Exosomes enriched in stemness/metastatic-related mRNAS promote oncogenic potential in breast cancer.

    PubMed

    Rodríguez, Marta; Silva, Javier; Herrera, Alberto; Herrera, Mercedes; Peña, Cristina; Martín, Paloma; Gil-Calderón, Beatriz; Larriba, María Jesús; Coronado, M Josés; Soldevilla, Beatriz; Turrión, Víctor S; Provencio, Mariano; Sánchez, Antonio; Bonilla, Félix; García-Barberán, Vanesa

    2015-12-01

    Cancer cells efficiently transfer exosome contents (essentially mRNAs and microRNAs) to other cell types, modifying immune responses, cell growth, angiogenesis and metastasis. Here we analyzed the exosomes release by breast tumor cells with different capacities of stemness/metastasis based on CXCR4 expression, and evaluated their capacity to generate oncogenic features in recipient cells. Breast cancer cells overexpressing CXCR4 showed an increase in stemness-related markers, and in proliferation, migration and invasion capacities. Furthermore, recipient cells treated with exosomes from CXCR4-cells showed increased in the same abilities. Moreover, inoculation of CXCR4-cell-derived exosomes in immunocompromised mice stimulated primary tumor growth and metastatic potential. Comparison of nucleic acids contained into exosomes isolated from patients revealed a "stemness and metastatic" signature in exosomes of patients with worse prognosis. Finally, our data supported the view that cancer cells with stem-like properties show concomitant metastatic behavior, and their exosomes stimulate tumor progression and metastasis. Exosomes-derived nucleic acids from plasma of breast cancer patients are suitable markers in the prognosis of such patients.

  12. Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.

    PubMed

    Kawajiri, Hidemi; Takashima, Tsutomu; Kashiwagi, Shinichiro; Noda, Satoru; Onoda, Naoyoshi; Hirakawa, Kosei

    2015-01-01

    Overexpression of HER2 - found in approximately 15-20% of all breast cancers - is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer.

  13. GPI/AMF inhibition blocks the development of the metastatic phenotype of mature multi-cellular tumor spheroids.

    PubMed

    Gallardo-Pérez, Juan Carlos; Rivero-Segura, Nadia Alejandra; Marín-Hernández, Alvaro; Moreno-Sánchez, Rafael; Rodríguez-Enríquez, Sara

    2014-06-01

    Epithelial-mesenchymal transition (EMT) and cellular invasiveness are two pivotal processes for the development of metastatic tumor phenotypes. The metastatic profile of non-metastatic MCF-7 cells growing as multi-cellular tumor microspheroids (MCTSs) was analyzed by determining the contents of the EMT, invasive and migratory proteins, as well as their migration and invasiveness potential and capacity to secrete active cytokines such as the glucose phosphate isomerase/AMF (GPI/AMF). As for the control, the same analysis was also performed in MCF-7 and MDA-MB-231 (highly metastatic, MDA) monolayer cells, and in stage IIIB and IV human metastatic breast biopsies. The proliferative cell layers (PRL) of mature MCF-7 MCTSs, MDA monolayer cells and metastatic biopsies exhibited increased cellular contents (2-15 times) of EMT (β-catenin, SNAIL), migratory (vimentin, cytokeratin, and fibronectin) and invasive (MMP-1, VEGF) proteins versus MCF-7 monolayer cells, quiescent cell layers of mature MCF-7 MCTS and non-metastatic breast biopsies. The increase in metastatic proteins correlated with substantially elevated cellular abilities for migration (18-times) and invasiveness (13-times) and with the higher level (6-times) of the cytokine GPI/AMF in the extracellular medium of PRL, as compared to MCF-7 monolayer cells. Interestingly, the addition of the GPI/AMF inhibitors erythrose-4-phosphate or 6-phosphogluconate at micromolar doses significantly decreased its extracellular activity (>80%), with a concomitant diminution in the metastatic protein content and migratory tumor cell capacity, and with no inhibitory effect on tumor lactate production or toxicity on 3T3 mouse fibroblasts. The present findings provide new insights into the discovery of metabolic inhibitors to be used as complementary therapy against metastatic and aggressive tumors.

  14. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease.

    PubMed

    Dalotto-Moreno, Tomás; Croci, Diego O; Cerliani, Juan P; Martinez-Allo, Verónica C; Dergan-Dylon, Sebastián; Méndez-Huergo, Santiago P; Stupirski, Juan C; Mazal, Daniel; Osinaga, Eduardo; Toscano, Marta A; Sundblad, Victoria; Rabinovich, Gabriel A; Salatino, Mariana

    2013-02-01

    Galectin-1 (Gal1), an evolutionarily conserved glycan-binding protein, contributes to the creation of an immunosuppressed microenvironment at sites of tumor growth. In spite of considerable progress in elucidating its role in tumor-immune escape, the mechanisms underlying the inhibitory functions of Gal1 remain obscure. Here, we investigated the contribution of tumor Gal1 to tumor growth, metastasis, and immunosuppression in breast cancer. We found that the frequency of Gal1(+) cells in human breast cancer biopsies correlated positively with tumor grade, while specimens from patients with benign hyperplasia showed negative or limited Gal1 staining. To examine the pathophysiologic relevance of Gal1 in breast cancer, we used the metastatic mouse mammary tumor 4T1, which expresses and secretes substantial amounts of Gal1. Silencing Gal1 expression in this model induced a marked reduction in both tumor growth and the number of lung metastases. This effect was abrogated when mice were inoculated with wild-type 4T1 tumor cells in their contralateral flank, suggesting involvement of a systemic modulation of the immune response. Gal1 attenuation in 4T1 cells also reduced the frequency of CD4(+)CD25(+) Foxp3(+) regulatory T (T(reg)) cells within the tumor, draining lymph nodes, spleen, and lung metastases. Further, it abrogated the immunosuppressive function of T(reg) cells and selectively lowered the expression of the T-cell regulatory molecule LAT (linker for activation of T cells) on these cells, disarming their suppressive activity. Taken together, our results offer a preclinical proof of concept that therapeutic targeting of Gal1 can overcome breast cancer-associated immunosuppression and can prevent metastatic disease. PMID:23204230

  15. Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer.

    PubMed

    Brown, Wells S; Tan, Li; Smith, Andrew; Gray, Nathanael S; Wendt, Michael K

    2016-09-01

    Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096-106. ©2016 AACR. PMID:27371729

  16. Metastatic Osteosarcoma to the Breast Presenting as a Densely Calcified Mass on Mammography

    PubMed Central

    Kim, Jonghyeon; Woo, Ha Young; Kim, Eun-Kyung; Kim, Min Jung; Moon, Hee Jung

    2016-01-01

    Osteosarcoma most commonly metastasizes to the lung or the skeleton, and metastatic osteosarcoma to the breast is very rare, with only a few cases reported. Due to its rarity, little has been reported about its imaging features. In this report, we represent a 58-year-old woman with metastatic osteosarcoma to the right breast from a tibial osteosarcoma. The imaging features of the metastatic osteosarcoma to the breast by using dedicated breast imaging modalities are described. Although rare, metastatic osteosarcoma to the breast should be considered when dense calcified masses with suspicious features are seen on breast imaging in patients with a history of osteosarcoma. PMID:27064762

  17. A Review of Systemic Treatment in Metastatic Triple-Negative Breast Cancer

    PubMed Central

    Zeichner, Simon B.; Terawaki, Hiromi; Gogineni, Keerthi

    2016-01-01

    Patients with breast cancer along with metastatic estrogen and progesterone receptor (ER/PR)- and human epidermal growth factor receptor 2 (HER2)-negative tumors are referred to as having metastatic triple-negative breast cancer (mTNBC) disease. Although there have been many new treatment options approved by the Food and Drug Administration for ER/PR-positive and Her2/neu-amplified metastatic breast cancer, relatively few new agents have been approved for patients with mTNBC. There have been several head-to-head chemotherapy trials performed within the metastatic setting, and much of what is applied in clinical practice is extrapolated from chemotherapy trials in the adjuvant setting, with taxanes and anthracyclines incorporated early on in the patient’s treatment course. Select synergistic combinations can produce faster and more significant response rates compared with monotherapy and are typically used in the setting of visceral threat or symptomatic disease. Preclinical studies have implicated other possible targets and mechanisms in mTNBC. Ongoing clinical trials are underway assessing new chemotherapeutic strategies and agents, including targeted therapy and immunotherapy. In this review, we evaluate the standard systemic and future treatment options in mTNBC. PMID:27042088

  18. Applicability of Pulmonary Lobectomy in Treating Metastatic Lung Tumors

    PubMed Central

    Kitahara, Hirokazu; Shimamatsu, Shinichiro; Morodomi, Yosuke; Tagawa, Tetsuzo; Maehara, Yoshihiko

    2015-01-01

    Purpose: Although metastases to the lung from other organs are usually removed with limited lung resections (e.g., wedge resections or segmentectomies), pulmonary lobectomies are often required to remove whole pulmonary tumors. This study investigated the clinical applicability of pulmonary lobectomies to treat metastatic lung tumors. Methods: We retrospectively reviewed clinical records of 143 consecutive patients with metastatic tumors in the lung who underwent surgery in our department, including data sets for 100 patients treated for their first metastatic lung tumors. Results: Of the 100 patients, 23 received pulmonary lobectomies, 69 received wedge resections and eight received segmentectomies. Patients in the lobectomy group were more likely to be younger, have larger and/or multiple tumors, and to have tumors of musculoskeletal origin (sarcomas) than those who underwent segmentectomies or wedge resections (the limited resection group). The two groups did not significantly differ in survival (3-year survival rate; lobectomy vs limited resection: 75.2% vs 80.4%, P = 0.15), or post-operative morbidity, although the only post-operative morbidity was associated with post-operative prognosis in the lobectomy group. Conclusions: Pulmonary lobectomy is a safe and applicable surgical procedure for metastatic lung tumors when long survival is expected after the tumor resection. PMID:25641034

  19. Breast cancer at bone metastatic sites: recent discoveries and treatment targets.

    PubMed

    Hussein, Osama; Komarova, Svetlana V

    2011-06-01

    Breast carcinoma is the most common cancer of women. Bones are often involved with breast carcinoma metastases with the resulting morbidity and reduced quality of life. Breast cancer cells arriving at bone tissues mount supportive microenvironment by recruiting and modulating the activity of several host tissue cell types including the specialized bone cells osteoblasts and osteoclasts. Pathologically activated osteoclasts produce osteolytic lesions associated with bone pain, pathological fractures, cord compression and other complications of metastatic breast carcinoma at bone. Over the last decade there has been enormous growth of knowledge in the field of osteoclasts biology both in the physiological state and in the tumor microenvironment. This knowledge allowed the development and implementation of several targeted therapeutics that expanded the armamentarium of the oncologists dealing with the metastases-associated osteolytic disease. While the interactions of cancer cells with resident bone cells at the established metastatic gross lesions are well-studied, the preclinical events that underlie the progression of disseminated tumor cells into micrometastases and then into clinically-overt macrometastases are just starting to be uncovered. In this review, we discuss the established information and the most recent discoveries in the pathogenesis of osteolytic metastases of breast cancer, as well as the corresponding investigational drugs that have been introduced into clinical development.

  20. CXCL12-γ in primary tumors drives breast cancer metastasis.

    PubMed

    Ray, P; Stacer, A C; Fenner, J; Cavnar, S P; Meguiar, K; Brown, M; Luker, K E; Luker, G D

    2015-04-16

    Compelling evidence shows that chemokine C-X-C motif chemokine ligand 12 (CXCL12) drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer remain unknown. CXCL12-α, -β and -γ showed cell-type-specific differences in activating signaling through G protein-dependent pathways in cell-based assays, while CXCL12-γ had greatest effects on recruitment of the adapter protein β-arrestin 2. CXCL12-β and -γ also stimulated endothelial tube formation to a greater extent than CXCL12-α. To investigate the effects of CXCL12 isoforms on tumor growth and metastasis, we used a mouse xenograft model of metastatic human breast cancer combining CXCR4+ breast cancer cells and mammary fibroblasts secreting an isoform of CXCL12. Altough all CXCL12 isoforms produced comparable growth of mammary tumors, CXCL12-γ significantly increased metastasis to bone marrow and other sites. Breast cancer cells originating from tumors with CXCL12-γ fibroblasts upregulated RANKL (receptor activator of nuclear factor-κB ligand), contributing to bone marrow tropism of metastatic cancer cells. CXCL12-γ was expressed in metastatic tissues in mice, and we also detected CXCL12-γ in malignant pleural effusions from patients with breast cancer. In our mouse model, mammary fibroblasts disseminated to sites of breast cancer metastases, providing another mechanism to increase levels of CXCL12 in metastatic environments. These studies identify CXCL12-γ as a potent pro-metastatic molecule with important implications for cancer biology and effective therapeutic targeting of CXCL12 pathways.

  1. CXCL12-γ in Primary Tumors Drives Breast Cancer Metastasis

    PubMed Central

    Ray, Paramita; Stacer, Amanda C.; Fenner, Joseph; Cavnar, Stephen P.; Meguiar, Kaille; Brown, Martha; Luker, Kathryn E.; Luker, Gary D.

    2014-01-01

    Compelling evidence shows that chemokine CXCL12 drives metastasis in multiple malignancies. Similar to other key cytokines in cancer, CXCL12 exists as several isoforms with distinct biophysical properties that may alter signaling and functional outputs. However, effects of CXCL12 isoforms in cancer remain unknown. CXCL12-α, β, and γ showed cell-type specific differences in activating signaling through G protein-dependent pathways in cell-based assays, while CXCL12-γ had greatest effects on recruitment of the adapter protein β-arrestin 2. CXCL12-β and γ also stimulated endothelial tube formation to a greater extent than CXCL12-α. To investigate effects of CXCL12 isoforms on tumor growth and metastasis, we used a mouse xenograft model of metastatic human breast cancer combining CXCR4+ breast cancer cells and mammary fibroblasts secreting an isoform of CXCL12. While all CXCL12 isoforms produced comparable growth of mammary tumors, CXCL12-γ significantly increased metastasis to bone marrow and other sites. Breast cancer cells originating from tumors with CXCL12-γ fibroblasts upregulated RANKL, contributing to bone marrow tropism of metastatic cancer cells. CXCL12-γ was expressed in metastatic tissues in mice, and we also detected CXCL12-γ in malignant pleural effusions from patients with breast cancer. In our mouse model, mammary fibroblasts disseminated to sites of breast cancer metastases, providing another mechanism to increase levels of CXCL12 in metastatic environments. These studies identify CXCL12-γ as a potent pro-metastatic molecule with important implications for cancer biology and effective therapeutic targeting of CXCL12 pathways. PMID:24909174

  2. Inflammatory metastatic breast cancer with gallbladder metastasis: an incidental finding.

    PubMed

    Ebrahim, Hassan; Graham, David; Rice, David; Ribadeneyra, Michael; Thorner, Kim; Shipley, William; Wehmueller, Michael

    2015-07-01

    Breast cancer is the most frequently diagnosed cancer in women, with an estimated 231,840 new cases representing 14.0% of all new cancer cases in the United States in 2015. Early screening and modern techniques of imaging and diagnosis have led to a significant improvement in detecting early-stage breast cancers and to a decrease in the incidence of metastatic breast cancer (MBC). About 20%-30% of patients who are initially diagnosed with an early-stage, nonmetastatic breast cancer will subsequently develop a distant metastatic disease. Between 6%-10% of the new breast cancer cases present initially as stage IV, referred to as de novo MBC. The most common sites of breast cancer metastases are lymph nodes, chest wall, skeleton, lung, skin, and the central nervous system (CNS). Lobular carcinoma, in particular, may metastasize to the gastrointestinal tract, peritoneum, and retroperitoneum. Gallbladder metastasis from breast cancer is very rare, and only 15-20 cases have been reported in the literature. Most of those cases have been associated particularly with a lobular histology. We report an additional rare case of MBC to the gallbladder, but with a ductal histology. PMID:26270542

  3. Occult Primary Neuroendocrine Tumor Metastasis to the Breast Detected on Screening Mammogram

    PubMed Central

    Policeni, Fabiana; Pakalniskis, Brittany; Yang, Limin

    2016-01-01

    Metastatic tumors are rare in the breast. Well-differentiated neuroendocrine tumors (WDNETs) are slow-growing neoplasms that arise from neuroendocrine cells, particularly in the gastrointestinal tract and bronchial tree. Metastatic WDNET to the breast is a rare entity. We present a case report of ileal WDNET metastatic to the breast which was initially identified as a small mass in the patient's left breast on screening mammography. Targeted ultrasound identified a suspicious mass, and ultrasound-guided percutaneous core biopsy was performed. Pathology revealed metastatic WDNET. Breast magnetic resonance imaging (MRI) was then performed and demonstrated left axillary Level 2 lymphadenopathy, and liver lesions were suspicious for metastasis. The patient underwent abdominal computed tomography (CT) to evaluate for distant metastatic disease. A spiculated mass was found near the ileocecal valve, suggestive of primary ileal WDNET. In addition, CT identified multiple liver lesions, most compatible with metastasis. Indium 111 OctreoScan confirmed radiotracer uptake in the ileum consistent with primary neuroendocrine tumor. In this report, we review the imaging characteristics of metastatic WDNET to the breast by different imaging modalities including mammogram, ultrasound, and breast MRI. PMID:27761301

  4. GATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas.

    PubMed

    Cimino-Mathews, Ashley; Subhawong, Andrea P; Illei, Peter B; Sharma, Rajni; Halushka, Marc K; Vang, Russell; Fetting, John H; Park, Ben Ho; Argani, Pedram

    2013-07-01

    GATA3 plays an integral role in breast luminal cell differentiation and is implicated in breast cancer progression. GATA3 immunohistochemistry is a useful marker of breast cancer; however, its use in specific subtypes is unclear. Here, we evaluate GATA3 expression in 86 invasive ductal carcinomas including triple-negative, Her-2, and luminal subtypes, in addition to 13 metaplastic carcinomas and in 34 fibroepithelial neoplasms. In addition, we report GATA3 expression in matched primary and metastatic breast carcinomas in 30 patients with known estrogen receptor (ER), progesterone receptor (PR), and Her-2 status, including 5 with ER and/or PR loss from primary to metastasis. Tissue microarrays containing 5 to 10 cores per tumor were stained for GATA3, scored as follows: 0 (0-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). GATA3 labeling was seen in 67% (66/99) of primary ductal carcinomas including 43% of triple-negative and 54% of metaplastic carcinomas. In contrast, stromal GATA3 labeling was seen in only 1 fibroepithelial neoplasm. GATA3 labeling was seen in 90% (27/30) of primary breast carcinomas in the paired cohort, including 67% of triple-negative carcinomas. GATA3 labeling was overwhelmingly maintained in paired metastases. Notably, GATA3 was maintained in all "luminal loss" metastases, which showed ER and/or PR loss. In conclusion, GATA3 expression is maintained between matched primary and metastatic carcinomas including ER-negative cases. GATA3 can be particularly useful as a marker for metastatic breast carcinoma, especially triple-negative and metaplastic carcinomas, which lack specific markers of mammary origin. Finally, GATA3 labeling may help distinguish metaplastic carcinoma from malignant phyllodes tumors.

  5. Survival of women with metastatic breast cancer at Yale from 1920 to 1980.

    PubMed

    Todd, M; Shoag, M; Cadman, E

    1983-06-01

    The tumor registry at Yale--New Haven Hospital, which began recording data in 1920, was utilized to examine the ultimate outcome of all breast cancer patients who were initially diagnosed at Yale with metastatic breast cancer. Of the 5,898 patients with breast cancer seen from 1920 to 1980, 574 initially had metastatic cancer. The median survival of these patients increased steadily from 21 months in 1920 to 41 months in the decade from 1970 to 1980. The percentage of women actually surviving 5 years increased from 5% in the 1920s to approximately 25% in the 1960s. Despite the use of combination drug programs in the 1970s, the percentage of these patients remaining alive at 5 years remained near 25%. Firm conclusions cannot be made from a retrospective study spanning 60 years, although the trends depicted and lack of continued improvement indicate that our current therapeutic approach to metastatic breast cancer may not result in dramatic improvement in overall survival.

  6. Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain.

    PubMed

    Palmieri, Diane; Bronder, Julie L; Herring, Jeanne M; Yoneda, Toshiyuki; Weil, Robert J; Stark, Andreas M; Kurek, Raffael; Vega-Valle, Eleazar; Feigenbaum, Lionel; Halverson, Douglas; Vortmeyer, Alexander O; Steinberg, Seth M; Aldape, Kenneth; Steeg, Patricia S

    2007-05-01

    Retrospective studies of breast cancer patients suggest that primary tumor Her-2 overexpression or trastuzumab therapy is associated with a devastating complication: the development of central nervous system (brain) metastases. Herein, we present Her-2 expression trends from resected human brain metastases and data from an experimental brain metastasis assay, both indicative of a functional contribution of Her-2 to brain metastatic colonization. Of 124 archival resected brain metastases from breast cancer patients, 36.2% overexpressed Her-2, indicating an enrichment in the frequency of tumor Her-2 overexpression at this metastatic site. Using quantitative real-time PCR of laser capture microdissected epithelial cells, Her-2 and epidermal growth factor receptor (EGFR) mRNA levels in a cohort of 12 frozen brain metastases were increased up to 5- and 9-fold, respectively, over those of Her-2-amplified primary tumors. Co-overexpression of Her-2 and EGFR was also observed in a subset of brain metastases. We then tested the hypothesis that overexpression of Her-2 increases the colonization of breast cancer cells in the brain in vivo. A subclone of MDA-MB-231 human breast carcinoma cells that selectively metastasizes to brain (231-BR) overexpressed EGFR; 231-BR cells were transfected with low (4- to 8-fold) or high (22- to 28-fold) levels of Her-2. In vivo, in a model of brain metastasis, low or high Her-2-overexpressing 231-BR clones produced comparable numbers of micrometastases in the brain as control transfectants; however, the Her-2 transfectants yielded 3-fold greater large metastases (>50 microm(2); P < 0.001). Our data indicate that Her-2 overexpression increases the outgrowth of metastatic tumor cells in the brain in this model system. PMID:17483330

  7. A Phase II Study Evaluating the Role of Androgen Receptors as Targets for Therapy of Pre-treated Post-menopausal Patients With ER/PgR-negative/AR-positive or ER and/or PgRpositive/ AR-positive Metastatic Breast Cancer (ARTT)

    ClinicalTrials.gov

    2016-09-28

    Metastatic Breastcancer; Estrogen Receptor Positive Breast Cancer; Estrogen Receptor Negative Neoplasm; Progesterone Receptor Positive Tumor; Progesterone Receptor Negative Neoplasm; Androgen Receptor Gene Overexpression

  8. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy

    PubMed Central

    Williams, Carly Bess; Yeh, Elizabeth S; Soloff, Adam C

    2016-01-01

    Deleterious inflammation is a primary feature of breast cancer. Accumulating evidence demonstrates that macrophages, the most abundant leukocyte population in mammary tumors, have a critical role at each stage of cancer progression. Such tumor-associated macrophages facilitate neoplastic transformation, tumor immune evasion and the subsequent metastatic cascade. Herein, we discuss the dynamic process whereby molecular and cellular features of the tumor microenvironment act to license tissue-repair mechanisms of macrophages, fostering angiogenesis, metastasis and the support of cancer stem cells. We illustrate how tumors induce, then exploit trophic macrophages to subvert innate and adaptive immune responses capable of destroying malignant cells. Finally, we discuss compelling evidence from murine models of cancer and early clinical trials in support of macrophage-targeted intervention strategies with the potential to dramatically reduce breast cancer morbidity and mortality. PMID:26998515

  9. Photo-nano immunotherapy for metastatic breast cancer using synergistic single-walled carbon nanotubes and glycated chitosan

    NASA Astrophysics Data System (ADS)

    Zhou, Feifan; Hasanjee, Aamr; Doughty, Austin; West, Connor; Liu, Hong; Chen, Wei R.

    2015-03-01

    In our previous work, we constructed a multifunctional nano system, using single-walled carbon nanotube (SWNT) and glycated chitosan (GC), which can synergize photothermal and immunological effects. To further confirm the therapy efficacy, with a metastatic mouse mammary tumor model (4T1), we investigate the therapy effects and immune response induced by SWNT-GC, under laser irradiation. Laser+SWNT-GC treatment not only suppressed the prime tumor, but also induced antitumor immune response. It could be developed into a promising treatment modality for the metastatic breast cancer.

  10. The role of histological subtype in hormone receptor positive metastatic breast cancer: similar survival but different therapeutic approaches

    PubMed Central

    Lobbezoo, Dorien; Truin, Wilfred; Voogd, Adri; Roumen, Rudi; Vreugdenhil, Gerard; Dercksen, Marcus Wouter; van den Berkmortel, Franchette; Smilde, Tineke; van de Wouw, Agnes; van Kampen, Roel; van Riel, Johanna; Peters, Natascha; Peer, Petronella; Tjan-Heijnen, Vivianne C.G.

    2016-01-01

    Introduction This study describes the differences between the two largest histological breast cancer subtypes (invasive ductal carcinoma (IDC) and invasive (mixed) lobular carcinoma (ILC) with respect to patient and tumor characteristics, treatment-choices and outcome in metastatic breast cancer. Results Patients with ILC were older at diagnosis of primary breast cancer and had more often initial bone metastasis (46.5% versus 34.8%, P = 0.01) and less often multiple metastatic sites compared to IDC (23.7% versus 30.9%, P = 0.11). Six months after diagnosis of metastatic breast cancer, 28.1% of patients with ILC and 39.8% of patients with IDC had received chemotherapy with a longer median time to first chemotherapy for those with ILC (P = 0.001). After six months 84.8% of patients with ILC had received endocrine therapy versus 72.5% of patients with IDC (P = 0.0001). Median overall survival was 29 months for ILC and 25 months for IDC (P = 0.53). Materials and Methods We included 437 patients with hormone receptor-positive IDC and 131 patients with hormone receptor-positive ILC, all diagnosed with metastatic breast cancer between 2007–2009, irrespective of date of the primary diagnosis. Patient and tumor characteristics and data on treatment and outcome were collected. Survival curves were obtained using the Kaplan-Meier method. Conclusions Treatment strategies of hormone receptor-positive metastatic breast cancer were remarkably different for patients with ILC and IDC. Further research is required to understand tumor behavior and treatment-choices in real-life. PMID:27121067

  11. Darier-Roussy Sarcoidosis Mimicking Metastatic Breast Cancer.

    PubMed

    Viswanath, Lokesh; Pallade, Siddanna; Krishnamurthy, B; Naveen, T; Preethi, B L; Pramod, K P R; Reddy, Obula; Padma, G

    2009-01-01

    Subcutaneous sarcoidosis (also known as 'Darier-Roussy sarcoid') is a cutaneous condition characterized by numerous deep-seated nodules on the trunk and extremities. Coexistence of sarcoidosis and breast cancer are reported in the literature, but there will always be a chance of misdiagnosis. It is very crucial to obtain a tissue diagnosis of suspicious metastatic lesions. We report a case of breast cancer presenting with a subcutaneous sarcoid lesion masquerading as a metastatic lesion. A 50-year-old female patient, who had had cancer of the left breast, was on hormone therapy 2 years after treatment with surgery, radiotherapy and chemotherapy. The patient presented with a sudden onset of a forehead subcutaneous swelling mimicking metastasis which on excision biopsy was proved to be sarcoidosis. In India, sarcoidosis is reported rarely. We have to keep in mind that there is a chance of the metastatic lesions being of sarcoidosis origin or another granulomatous disease. To avoid misdiagnosis, it is better to obtain a tissue diagnosis. PMID:20737045

  12. New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers

    PubMed Central

    Kamdje, Armel Hervé Nwabo; Etet, Paul Faustin Seke; Vecchio, Lorella; Tagne, Richard Simo; Amvene, Jeremie Mbo; Muller, Jean-Marc; Krampera, Mauro; Lukong, Kiven Erique

    2014-01-01

    Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed. PMID:25516852

  13. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice.

    PubMed

    Sasaki, A; Boyce, B F; Story, B; Wright, K R; Chapman, M; Boyce, R; Mundy, G R; Yoneda, T

    1995-08-15

    Human breast cancer frequently metastasizes to the skeleton to cause osteolysis and subsequent pain, pathological fracture, and hypercalcemia. Because bone continuously releases growth factors stored in bone matrix by bone resorption during physiological remodeling and, thus, possibly provides a favorable microenvironment for metastatic breast cancer cells to proliferate, inhibitors of bone resorption used either prophylactically or in patients with established disease, therefore, would seem likely to be useful adjuvant therapy in patients with breast cancer. However, the parameters for monitoring progressive osteolytic bone disease in humans are imprecise. We examined the effects of the third generation bisphosphonate, risedronate, which is a specific inhibitor of osteoclastic bone resorption, in a bone metastasis model in nude mice in which intracardiac injection of the human breast cancer cell line MDA-231 leads to osteolytic bone metastases. Risedronate (4 micrograms/animal/day) was given s.c. to animals (a) after radiologically small but defined osteolytic metastases were observed; (b) simultaneously with MDA-231 cell inoculation through the entire experimental period; or (c) by short-term prophylactic administration before inoculation of MDA-231 cells. In all experiments, risedronate either slowed progression or inhibited the development of bone metastases assessed radiographically. Furthermore, mice treated continuously with risedronate showed significantly longer survival than did control mice. Histomorphometrical analysis revealed that osteoclast numbers were diminished at metastatic tumor sites. Unexpectedly, there was also a marked decrease in tumor burden in bone in risedronate-treated animals. In contrast, the growth of metastatic breast cancer in soft tissues surrounding bones was not affected by risedronate. Moreover, risedronate had no effects on the local growth of s.c. implanted MDA-231 breast cancers in nude mice or on MDA-231 cell proliferation

  14. Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer

    PubMed Central

    Kim, Min Soo; Jeong, Joon; Seo, Jeongbeob; Kim, Hae-Suk; Kim, Seong-Jin; Jin, Wook

    2016-01-01

    Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. We identified a new molecular and functional network present in metastasis that regulates and coordinates with TrkC. Inhibition of SOCS3-mediated JAK2 degradation by TrkC increases total JAK2/STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2/STAT3 cascade. Also, TrkC increases secretion and expression of IL-6, suggesting that this autocrine loop generated by TrkC maintains the mesenchymal state by continued activation of the JAK2/STAT3 cascade and upregulation of Twist expression. Moreover, TrkC interacts with the c-Src/Jak2 complex, which increases Twist-1 and Twist-2 levels via regulation of JAK2/STAT3 activation and JAK2/STAT3 expression. Furthermore, TrkC enhances metastatic potential of breast cancer via induction of EMT by upregulating Twist-1 and Twist-2. Additionally, TrkC significantly enhances the ability of breast cancer cells to form pulmonary metastases and primary tumor formation. Unexpectedly, we found that TrkC expression and clinical breast tumor pathological phenotypes show significant correlation. These findings suggest that TrkC plays a central role in tumorigenicity, metastasis, and self-renewal traits of metastatic breast cancer. PMID:27654855

  15. Capnocytophaga Lung Abscess in a Patient with Metastatic Neuroendocrine Tumor

    PubMed Central

    Thirumala, Raghu; Babady, N. Esther; Kamboj, Mini; Chawla, Mohit

    2012-01-01

    Capnocytophaga species are known commensals of the oral cavity of humans and animals (mainly dogs and cats) and are a rare cause of respiratory tract infections. We report a case of cavitary lung abscess caused by a Capnocytophaga species in a patient with a metastatic neuroendocrine tumor. PMID:22075586

  16. Capnocytophaga lung abscess in a patient with metastatic neuroendocrine tumor.

    PubMed

    Thirumala, Raghu; Rappo, Urania; Babady, N Esther; Kamboj, Mini; Chawla, Mohit

    2012-01-01

    Capnocytophaga species are known commensals of the oral cavity of humans and animals (mainly dogs and cats) and are a rare cause of respiratory tract infections. We report a case of cavitary lung abscess caused by a Capnocytophaga species in a patient with a metastatic neuroendocrine tumor. PMID:22075586

  17. Matrix Rigidity Induces Osteolytic Gene Expression of Metastatic Breast Cancer Cells

    PubMed Central

    Ruppender, Nazanin S.; Merkel, Alyssa R.; Martin, T. John; Sterling, Julie A.; Guelcher, Scott A.

    2010-01-01

    Nearly 70% of breast cancer patients with advanced disease will develop bone metastases. Once established in bone, tumor cells produce factors that cause changes in normal bone remodeling, such as parathyroid hormone-related protein (PTHrP). While enhanced expression of PTHrP is known to stimulate osteoclasts to resorb bone, the environmental factors driving tumor cells to express PTHrP in the early stages of development of metastatic bone disease are unknown. In this study, we have shown that tumor cells known to metastasize to bone respond to 2D substrates with rigidities comparable to that of the bone microenvironment by increasing expression and production of PTHrP. The cellular response is regulated by Rho-dependent actomyosin contractility mediated by TGF-ß signaling. Inhibition of Rho-associated kinase (ROCK) using both pharmacological and genetic approaches decreased PTHrP expression. Furthermore, cells expressing a dominant negative form of the TGF-ß receptor did not respond to substrate rigidity, and inhibition of ROCK decreased PTHrP expression induced by exogenous TGF-ß. These observations suggest a role for the differential rigidity of the mineralized bone microenvironment in early stages of tumor-induced osteolysis, which is especially important in metastatic cancer since many cancers (such as those of the breast and lung) preferentially metastasize to bone. PMID:21085597

  18. GATA3 immunohistochemistry expression in histologic subtypes of primary breast carcinoma and metastatic breast carcinoma cytology.

    PubMed

    Deftereos, Georgios; Sanguino Ramirez, Angela M; Silverman, Jan F; Krishnamurti, Uma

    2015-09-01

    GATA3 plays a role in cell proliferation and differentiation in many tissues, including breast, and it has been suggested that GATA3 expression correlates with ER expression. However, little is known on GATA3 expression in various subtypes of breast carcinoma, its utilization in cytology, and on how GATA3 performs in comparison with GCDFP-15 and mammaglobin. Eighty-four histology cases of breast carcinoma of various subtypes, including 28 triple-negative breast carcinomas, along with 20 cytology cases of metastatic breast carcinoma and 12 cytology cases of ER-positive metastatic gynecologic malignancies, were stained for GATA3, GCDFP-15, and mammaglobin. In non-triple-negative breast carcinomas (n=56), GATA3 showed 100% sensitivity, higher than GCDFP-15 (42.8%; P<0.0001) and mammaglobin (58.9%; P<0.0001), whereas staining patterns were similar for all the histologic subtypes examined. Staining scores were determined by multiplying the percentage of cancer cells staining with an intensity score of 1+, 2+, or 3+ (range, 0 to 300). In non-triple-negative carcinomas, GATA3 showed a mean score of 273.7, higher than GCDFP-15 (107.5; P<0.0001) and mammaglobin (147.7; P<0.0001). In triple-negative breast carcinomas (n=28), GATA3 showed a sensitivity of 60.7%, greater than GCDFP-15 (17.9%; P=0.0022) and mammaglobin (7.1%; P<0.0001). These results were consistent irrespective of the subtype examined. In breast carcinoma cytology cases, 100% stained with GATA3, higher than GCDFP-15 (20%; P<0.0001) and mammaglobin (45%; P<0.0001). None of the metastatic endometrial or ovarian carcinomas were positive for GATA3. Although GATA3 expression correlates with ER expression in breast, no correlation is observed in gynecologic malignancies. Thus, in working up ER-positive metastatic malignancies GATA3 demonstrates specificity for breast.

  19. Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer

    PubMed Central

    Fu, Bo; Long, Wei; Zhang, Ying; Zhang, Aifeng; Miao, Fengqin; Shen, Yuqing; Pan, Ning; Gan, Guangming; Nie, Fang; He, Youji; Zhang, Jianqiong; Teng, Gaojun

    2015-01-01

    Novel molecularly targeted agents that block the development and metastasis of human brain metastatic breast cancer hold great promise for their translational value. In this study, we constructed a novel targeting composite peptide BRBP1-TAT-KLA comprising of three elements: a brain metastatic breast carcinoma cell (231-BR)-binding peptide BRBP1, a cell penetrating peptide TAT, and a proapoptotic peptide KLA. This composite peptide efficiently internalized in 231-BR cells and consequently induced mitochondrial damage and cellular apoptosis. Exposure of 231-BR cells to BRBP1-TAT-KLA significantly decreased cell viability and increased apoptosis compared with the cells treated with the control peptides. In vivo relevance of these findings was further corroborated in the 231-BR tumor-bearing mice that demonstrated significantly delayed tumor development and metastasis following administration of BRBP1-TAT-KLA compared with those treated with TAT-KLA alone. Interestingly, BRBP1-TAT-KLA inhibited the formation of both large and micro-metastases, while TAT-KLA alone failed to significantly reduce micro-metastases in the breast cancer brain metastasis mice. BRBP1-TAT-KLA selectively homed to the tumors in vivo where it induced cellular apoptosis without significant toxicity on non-tumor tissues. Our findings therefore demonstrated the enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA, providing insights toward development of a potential therapeutic strategy for brain metastatic breast cancer. PMID:25619721

  20. Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer.

    PubMed

    Fu, Bo; Long, Wei; Zhang, Ying; Zhang, Aifeng; Miao, Fengqin; Shen, Yuqing; Pan, Ning; Gan, Guangming; Nie, Fang; He, Youji; Zhang, Jianqiong; Teng, Gaojun

    2015-01-26

    Novel molecularly targeted agents that block the development and metastasis of human brain metastatic breast cancer hold great promise for their translational value. In this study, we constructed a novel targeting composite peptide BRBP1-TAT-KLA comprising of three elements: a brain metastatic breast carcinoma cell (231-BR)-binding peptide BRBP1, a cell penetrating peptide TAT, and a proapoptotic peptide KLA. This composite peptide efficiently internalized in 231-BR cells and consequently induced mitochondrial damage and cellular apoptosis. Exposure of 231-BR cells to BRBP1-TAT-KLA significantly decreased cell viability and increased apoptosis compared with the cells treated with the control peptides. In vivo relevance of these findings was further corroborated in the 231-BR tumor-bearing mice that demonstrated significantly delayed tumor development and metastasis following administration of BRBP1-TAT-KLA compared with those treated with TAT-KLA alone. Interestingly, BRBP1-TAT-KLA inhibited the formation of both large and micro-metastases, while TAT-KLA alone failed to significantly reduce micro-metastases in the breast cancer brain metastasis mice. BRBP1-TAT-KLA selectively homed to the tumors in vivo where it induced cellular apoptosis without significant toxicity on non-tumor tissues. Our findings therefore demonstrated the enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA, providing insights toward development of a potential therapeutic strategy for brain metastatic breast cancer.

  1. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth

    PubMed Central

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  2. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth.

    PubMed

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  3. Tumor cell-driven extracellular matrix remodeling drives haptotaxis during metastatic progression

    PubMed Central

    Oudin, Madeleine J.; Jonas, Oliver; Kosciuk, Tatsiana; Broye, Liliane C.; Guido, Bruna C.; Wyckoff, Jeff; Riquelme, Daisy; Lamar, John M.; Asokan, Sreeja B.; Whittaker, Charlie; Ma, Duanduan; Langer, Robert; Cima, Michael J.; Wisinski, Kari B.; Hynes, Richard O.; Lauffenburger, Douglas A.; Keely, Patricia J.; Bear, James E.; Gertler, Frank B.

    2016-01-01

    Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo. Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and Mena, an actin regulator, and involves increases in focal complex signaling and tumor-cell-mediated extracellular matrix (ECM) remodeling. Compared to Mena, higher levels of the pro-metastatic MenaINV isoform associate with α5, which enables 3D haptotaxis of tumor cells towards the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MenaINV and FN levels were correlated in two breast cancer cohorts, and high levels of MenaINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor-cell-intrinsic mechanism that promotes metastasis through ECM remodeling and ECM guided directional migration. PMID:26811325

  4. [Interest of biological documentation on brain metastatic disease in breast cancer: A case report].

    PubMed

    Boissonneau, S; Faguer, R; Joubert, C; Fuentes, S; Metellus, P

    2015-08-01

    Breast cancer, after lung cancer, is the second major cause of brain metastases. In breast cancer, the prognosis is closely linked to the molecular subtype of the primary tumor. Targeted therapies, with or without cytotoxic treatment, have significantly modified overall survival in these patients. We report, the case of a patient suffering from breast cancer with brain metastasis in whom the biological documentation of the metastatic disease permitted to tailor the systemic treatment. Analysis of the surgical specimen revealed an immunohistochemical HER2 positive staining, which was not found in the primary tumor and therefore warranted trastuzumab administration. Another interesting insight based on this case report was to underline the phenotypic heterogeneity of the metastatic disease and its potential dynamic course as illustrated by the dissociated response to trastuzumab on body TEP-TDM in this particular patient. This case report also highlights the new place of the neurosurgeon in brain metastases management, not only as a participant in local treatment but also as a physician who is in fact involved in the delineation of the global oncological strategy in these patients as well as medical oncologists and radiation oncologists.

  5. Molecular Markers for Breast Cancer: Prediction on Tumor Behavior

    PubMed Central

    Banin Hirata, Bruna Karina; Oda, Julie Massayo Maeda; Losi Guembarovski, Roberta; Ariza, Carolina Batista; de Oliveira, Carlos Eduardo Coral; Watanabe, Maria Angelica Ehara

    2014-01-01

    Breast cancer is one of the most common cancers with greater than 1,300,000 cases and 450,000 deaths each year worldwide. The development of breast cancer involves a progression through intermediate stages until the invasive carcinoma and finally into metastatic disease. Given the variability in clinical progression, the identification of markers that could predict the tumor behavior is particularly important in breast cancer. The determination of tumor markers is a useful tool for clinical management in cancer patients, assisting in diagnostic, staging, evaluation of therapeutic response, detection of recurrence and metastasis, and development of new treatment modalities. In this context, this review aims to discuss the main tumor markers in breast carcinogenesis. The most well-established breast molecular markers with prognostic and/or therapeutic value like hormone receptors, HER-2 oncogene, Ki-67, and p53 proteins, and the genes for hereditary breast cancer will be presented. Furthermore, this review shows the new molecular targets in breast cancer: CXCR4, caveolin, miRNA, and FOXP3, as promising candidates for future development of effective and targeted therapies, also with lower toxicity. PMID:24591761

  6. Metastatic brain tumor from urothelial carcinoma of the prostatic urethra

    PubMed Central

    Morita, Kohei; Oda, Masashi; Koyanagi, Masaomi; Saiki, Masaaki

    2016-01-01

    Background: Urothelial carcinoma occurs in the bladder, upper urinary tract, and lower urinary tract, including prostatic urethra. A majority of the reported cases of intracranial metastasis from urothelial carcinoma originates from the bladder and upper urinary tract. Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. Case Description: A 72-year-old male presented with a metastatic brain tumor and a 3-year history of urothelial carcinoma of the prostatic urethra treated with cystourethrectomy and chemotherapy with gemcitabine-cisplatin. Pathological diagnosis for tumor removal was compatible with metastatic brain tumor from urothelial carcinoma. Conclusion: Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. It is an extremely rare case, however, we should be careful of brain metastasis during follow-up for urothelial carcinoma in the lower urinary tract. PMID:27512612

  7. Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

    NASA Astrophysics Data System (ADS)

    Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

    2011-03-01

    Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.

  8. Methyl Sulfone Blocked Multiple Hypoxia- and Non-Hypoxia-Induced Metastatic Targets in Breast Cancer Cells and Melanoma Cells

    PubMed Central

    Caron, Joan McIntyre; Caron, Jane McIntyre

    2015-01-01

    Metastatic cancer causes 90% of cancer deaths. Unlike many primary tumors, metastatic tumors cannot be cured by surgery alone. Metastatic cancer requires chemotherapy. However, metastatic cells are not easily killed by chemotherapy. These problems with chemotherapy are caused in part by the metastatic cell niche: hypoxia. Here we show that the molecule, methyl sulfone, normalized metastatic metabolism of hypoxic breast cancer and melanoma cells by altering several metabolic functions of the cells. Under hypoxia, methyl sulfone decreased expression of the master regulator of hypoxia, HIF-1α, and reduced levels of the glycolytic enzymes, PKM2, LDHA, GLUT1, the pro-angiogenic protein, VEGF, and the iron-sulfur metabolism molecules, miR-210 and transferrin, all of which promote metastasis. Conversely, methyl sulfone increased levels of ISCU1/2 and ferroportin, proteins associated with iron-sulfur cluster biogenesis and iron homeostasis in normal cells. These data identify methyl sulfone as a multi-targeting molecule that blocks the survival/proliferative effect of hypoxia on metastatic cells and brings normality back to cellular metabolism. PMID:26536104

  9. Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: AdnaGen AdnaTest BreastCancer Select/Detect™ versus Veridex CellSearch™ system.

    PubMed

    Andreopoulou, E; Yang, L-Y; Rangel, K M; Reuben, J M; Hsu, L; Krishnamurthy, S; Valero, V; Fritsche, H A; Cristofanilli, M

    2012-04-01

    The detection of CTCs prior to and during therapy is an independent and strong prognostic marker, and it is predictive of poor treatment outcome. A major challenge is that different technologies are available for isolation and characterization of CTCs in peripheral blood (PB). We compare the CellSearch system and AdnaTest BreastCancer Select/Detect, to evaluate the extent that these assays differ in their ability to detect CTCs in the PB of MBC patients. CTCs in 7.5 ml of PB were isolated and enumerated using the CellSearch, before new treatment. Two cutoff values of ≥2 and ≥5 CTCs/7.5 ml were used. AdnaTest requires 5 ml of PB to detect gene transcripts of tumor markers (GA733-2, MUC-1, and HER2) by RT-PCR. AdnaTest was scored positive if ≥1 of the transcript PCR products for the 3 markers were detected at a concentration ≥0.15 ng/μl. A total of 55 MBC patients were enrolled. 26 (47%) patients were positive for CTCs by the CellSearch (≥2 cutoff), while 20 (36%) were positive (≥5 cutoff). AdnaTest was positive in 29 (53%) with the individual markers being positive in 18% (GA733-2), 44% (MUC-1), and 35% (HER2). Overall positive agreement was 73% for CTC≥2 and 69% for CTC≥5. These preliminary data suggest that the AdnaTest has equivalent sensitivity to that of the CellSearch system in detecting 2 or more CTCs. While there is concordance between these 2 methods, the AdnaTest complements the CellSearch system by improving the overall CTC detection rate and permitting the assessment of genomic markers in CTCs.

  10. Palbociclib in Treating Patients With Metastatic HER-2 Positive or Triple-Negative Breast Cancer With Brain Metastasis

    ClinicalTrials.gov

    2016-05-26

    Breast Carcinoma Metastatic in the Brain; Estrogen Receptor Negative; HER2/Neu Negative; HER2/Neu Positive; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  11. Early and multiple origins of metastatic lineages within primary tumors

    PubMed Central

    Zhao, Zi-Ming; Zhao, Bixiao; Bai, Yalai; Iamarino, Atila; Gaffney, Stephen G.; Schlessinger, Joseph; Lifton, Richard P.; Rimm, David L.; Townsend, Jeffrey P.

    2016-01-01

    Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases. PMID:26858460

  12. Early and multiple origins of metastatic lineages within primary tumors.

    PubMed

    Zhao, Zi-Ming; Zhao, Bixiao; Bai, Yalai; Iamarino, Atila; Gaffney, Stephen G; Schlessinger, Joseph; Lifton, Richard P; Rimm, David L; Townsend, Jeffrey P

    2016-02-23

    Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases. PMID:26858460

  13. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers

    NASA Astrophysics Data System (ADS)

    Marrinucci, Dena; Bethel, Kelly; Kolatkar, Anand; Luttgen, Madelyn S.; Malchiodi, Michael; Baehring, Franziska; Voigt, Katharina; Lazar, Daniel; Nieva, Jorge; Bazhenova, Lyudmila; Ko, Andrew H.; Korn, W. Michael; Schram, Ethan; Coward, Michael; Yang, Xing; Metzner, Thomas; Lamy, Rachelle; Honnatti, Meghana; Yoshioka, Craig; Kunken, Joshua; Petrova, Yelena; Sok, Devin; Nelson, David; Kuhn, Peter

    2012-02-01

    Hematologic spread of carcinoma results in incurable metastasis; yet, the basic characteristics and travel mechanisms of cancer cells in the bloodstream are unknown. We have established a fluid phase biopsy approach that identifies circulating tumor cells (CTCs) without using surface protein-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. This 'HD-CTC' assay finds >5 HD-CTCs mL-1 of blood in 80% of patients with metastatic prostate cancer (n = 20), in 70% of patients with metastatic breast cancer (n = 30), in 50% of patients with metastatic pancreatic cancer (n = 18), and in 0% of normal controls (n = 15). Additionally, it finds HD-CTC clusters ranging from 2 HD-CTCs to greater than 30 HD-CTCs in the majority of these cancer patients. This initial validation of an enrichment-free assay demonstrates our ability to identify significant numbers of HD-CTCs in a majority of patients with prostate, breast and pancreatic cancers.

  14. Therapeutic Considerations in Treating HER2-Positive Metastatic Breast Cancer

    PubMed Central

    O’Sullivan, Ciara C.; Smith, Karen L.

    2014-01-01

    Despite advances in detection and treatment, metastatic breast cancer (MBC) remains the second highest cause of cancer-related death for women in the United States. Human epidermal growth factor receptor-2 (HER2) is amplified in 25–30% of breast cancers and is associated with aggressive disease and, historically, with poorer outcomes. The advent of trastuzumab, a monoclonal antibody to HER2, revolutionized the management of HER2-positive breast cancer (BC) in the metastatic and adjuvant settings. However, relapse despite adjuvant trastuzumab and resistance to trastuzumab in the metastatic setting remain substantial clinical problems for many patients with HER2-positive BC. As such, analyzing the mechanisms of trastuzumab resistance and developing new therapy to overcome trastuzumab resistance are research priorities. There has been progress, with the approval of three additional HER2-targeted agents in the last six years: lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). Other HER2-targeted therapies, including neratinib and afatinib, are in clinical development, and trials of novel agents such as heat shock protein-90 (HSP90) inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, and HER2-targeted vaccines are ongoing. In addition to developing new therapy, research is addressing several unique challenges in the management of HER2-positive MBC. In this article, we discuss advances in the treatment of HER2-positive MBC, with a focus on novel HER2-targeted therapy and HER2-targeted agents recently approved by the United States Food and Drug Administration (FDA). Additionally, we also address the management of brain metastases (BM) and hormone receptor (HR) - positive, HER2-positive MBC. PMID:25285186

  15. Phyllodes Tumor of the Breast

    SciTech Connect

    Belkacemi, Yazid Bousquet, Guilhem; Marsiglia, Hugo; Ray-Coquard, Isabelle; Magne, Nicolas; Malard, Yann; Lacroix, Magalie; Gutierrez, Cristina; Senkus, Elzbieta; Christie, David; Drumea, Karen; Lagneau, Edouard; Kadish, Sidney P.; Scandolaro, Luciano; Azria, David; Ozsahin, Mahmut

    2008-02-01

    Purpose: To better identify prognostic factors for local control and survival, as well as the role of different therapeutic options, for phyllodes tumors, a rare fibroepithelial neoplasm of the breast. Methods and Materials: Data from 443 women treated between 1971 and 2003 were collected from the Rare Cancer Network. The median age was 40 years (range, 12-87 years). Tumors were benign in 284 cases (64%), borderline in 80 cases (18%), and malignant in 79 cases (18%). Surgery consisted of breast-conserving surgery (BCS) in 377 cases (85%) and total mastectomy (TM) in 66 cases (15%). Thirty-nine patients (9%) received adjuvant radiotherapy (RT). Results: After a median follow-up of 106 months, local recurrence (LR) and distant metastases rates were 19% and 3.4%, respectively. In the malignant and borderline group (n = 159), RT significantly decreased LR (p = 0.02), and TM had better results than BCS (p = 0.0019). Multivariate analysis revealed benign histology, negative margins, and no residual disease (no RD) after initial treatment and RT delivery as independent favorable prognostic factors for local control; benign histology and low number of mitosis for disease-free survival; and pathologic tumor size tumor necrosis for overall survival. In the malignant and borderline subgroup multivariate analysis TM was the only favorable independent prognostic factor for disease-free survival. Conclusions: This study showed that phyllodes tumor patients with no RD after treatment have better local control. Benign tumors have a good prognosis after surgery alone. In borderline and malignant tumors, TM had better results than BCS. Thus, in these forms adjuvant RT should be considered according to histologic criteria.

  16. Minimal residual disease in bone marrow and peripheral blood of patients with metastatic breast cancer.

    PubMed

    Bischoff, Joachim; Rosenberg, Robert; Dahm, Michael; Janni, Wolfgang; Gutschow, Klaus

    2003-01-01

    The presence of occult micrometastases in bone marrow (BM) of patients with early breast cancer increases the risk of relapse. Detection of circulation tumor cells in peripheral blood (PB) may also influence the patient's prognosis. Few data are available on the correlation between tumor cell dissemination in BM and PB in solid epithelial tumors. Twenty-milliliter blood samples were collected from PB of 42 patients with advanced breast cancer and centrifuged using the density gradient OncoQuick (OncoQuick Greiner BioOne, Frickenhausen, Germany). The BM aspirates available from 11 of the 42 patients were centrifuged using density centrifugation Ficoll. Tumor cell detection was performed by microscopy after cytospin preparation and immunocytochemical staining with the monoclonal antibody A45-B/B3. Cytokeratin-positive cells were detected in 23 patients (55%) in the PB and in three patients (27%) in the BM. A cohort with bone lesions as the only metastatic side showed a correlation as follows: 7 of the 11 patients (64%) had negative findings in BM and PB, whereas cytokeratin-positive cells in PB were present in 3 of these 11 patients (27%). The presence of visceral metastases was associated with the detection of cytokeratin-positive cells in the PB in 20 of the 31 patients (65%) in this subgroup. The density gradient OncoQuick in combination with immunocytochemical staining allows the detection of cytokeratin-positive cells in PB of patients with advanced breast cancer. The immunocytochemical detection of cytokeratin-positive cells in PB seems to be associated with the site of metastatic manifestation.

  17. Profile of palbociclib in the treatment of metastatic breast cancer.

    PubMed

    Ehab, Moataz; Elbaz, Mohamad

    2016-01-01

    Breast cancer is the most common cancer diagnosed in women. Each year, thousands die either because of disease progression or failure of treatment. Breast cancer is classified into different subtypes based on the molecular expression of estrogen receptor (ER), progesterone receptor, and/or human epidermal growth factor receptor 2 (HER2). These receptors represent important therapeutic targets either through monoclonal antibodies or through small-molecule inhibitors directed toward them. However, up to 40% of patients develop either a primary or a secondary resistance to the current treatments. Therefore, there is an urgent need for investigating new targets in order to overcome the resistance and/or enhance the current therapies. Cell cycle is altered in many human cancers, especially in breast cancer. Cyclin-dependent kinases (CDKs), especially CDK4 and CDK6, play a pivotal role in cell cycle progression that makes them potential targets for new promising therapies. CDK inhibition has shown strong antitumor activities, ranging from cytostatic antiproliferative effects to synergistic effects in combination with other antitumor drugs. In order to overcome the drawbacks of the first-generation CDK inhibitors, recently, new CDK inhibitors have emerged that are more selective to CDK4 and CDK6 such as palbociclib, which is the most advanced CDK4/6 inhibitor in trials. In preclinical studies, palbociclib has shown a very promising antitumor activity, especially against ERα+ breast cancer subtype. Palbociclib has gained world attention, and US the Food and Drug Administration has accelerated its approval for first-line treatment in combination with letrozole for the first-line systematic treatment of postmenopausal women with ERα+/HER2- locally advanced or metastatic breast cancer. In this review, we discuss the potential role of CDK inhibition in breast cancer treatment, and focus on palbociclib progress from preclinical studies to clinical trials with mentioning the

  18. Profile of palbociclib in the treatment of metastatic breast cancer

    PubMed Central

    Ehab, Moataz; Elbaz, Mohamad

    2016-01-01

    Breast cancer is the most common cancer diagnosed in women. Each year, thousands die either because of disease progression or failure of treatment. Breast cancer is classified into different subtypes based on the molecular expression of estrogen receptor (ER), progesterone receptor, and/or human epidermal growth factor receptor 2 (HER2). These receptors represent important therapeutic targets either through monoclonal antibodies or through small-molecule inhibitors directed toward them. However, up to 40% of patients develop either a primary or a secondary resistance to the current treatments. Therefore, there is an urgent need for investigating new targets in order to overcome the resistance and/or enhance the current therapies. Cell cycle is altered in many human cancers, especially in breast cancer. Cyclin-dependent kinases (CDKs), especially CDK4 and CDK6, play a pivotal role in cell cycle progression that makes them potential targets for new promising therapies. CDK inhibition has shown strong antitumor activities, ranging from cytostatic antiproliferative effects to synergistic effects in combination with other antitumor drugs. In order to overcome the drawbacks of the first-generation CDK inhibitors, recently, new CDK inhibitors have emerged that are more selective to CDK4 and CDK6 such as palbociclib, which is the most advanced CDK4/6 inhibitor in trials. In preclinical studies, palbociclib has shown a very promising antitumor activity, especially against ERα+ breast cancer subtype. Palbociclib has gained world attention, and US the Food and Drug Administration has accelerated its approval for first-line treatment in combination with letrozole for the first-line systematic treatment of postmenopausal women with ERα+/HER2− locally advanced or metastatic breast cancer. In this review, we discuss the potential role of CDK inhibition in breast cancer treatment, and focus on palbociclib progress from preclinical studies to clinical trials with mentioning the

  19. Pulmonar collision tumor: metastatic adenoid cystic carcinoma and lung adenocarcinoma.

    PubMed

    Blanco, M; García-Fontán, E; Ríos, J; Rivo, J E; Fernández-Martín, R; Cañizares, M A

    2012-01-01

    We report an extraordinary case of collision tumor consisting of a lung adenocarcinoma and a metastatic adenoid cystic carcinoma in a 56 year-old man. He was diagnosed with a pulmonary nodule 11 years after treatment of an adenoid cystic carcinoma of the right maxillary sinus. A non-small cell carcinoma was observed when a transbronchial biopsy was performed. The other component of the nodule was only diagnosed with pathological examination of the resection specimen. PMID:21802893

  20. Pulmonar collision tumor: metastatic adenoid cystic carcinoma and lung adenocarcinoma.

    PubMed

    Blanco, M; García-Fontán, E; Ríos, J; Rivo, J E; Fernández-Martín, R; Cañizares, M A

    2012-01-01

    We report an extraordinary case of collision tumor consisting of a lung adenocarcinoma and a metastatic adenoid cystic carcinoma in a 56 year-old man. He was diagnosed with a pulmonary nodule 11 years after treatment of an adenoid cystic carcinoma of the right maxillary sinus. A non-small cell carcinoma was observed when a transbronchial biopsy was performed. The other component of the nodule was only diagnosed with pathological examination of the resection specimen.

  1. Pulmonary Metastatic Choriocarcinoma from a Burned-out Testicular Tumor.

    PubMed

    Nakazaki, Hirofumi; Tokuyasu, Hirokazu; Takemoto, Yu; Miura, Hiroshi; Yanai, Masaaki; Fukushima, Takehito; Shimizu, Eiji

    2016-01-01

    A 54-year-old man was referred to our hospital because of progressive dyspnea. Chest computed tomography showed multiple nodular shadows with a peripheral ground-glass halo. His clinical condition continued to deteriorate with the development of progressive respiratory failure requiring mechanical ventilation. A histological examination of a transbronchial lung biopsy revealed choriocarcinoma. The patient died within nine days of admission. A histological examination of the right testis during an autopsy revealed a burned-out testicular tumor consisting of a teratoma and a fibrous scar. We herein report a rare case of pulmonary multiple metastatic choriocarcinoma originating from a burned-out testicular tumor. PMID:27250057

  2. EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer

    PubMed Central

    Alvarez-Cubero, Maria J.; Nadal, Rosa; Sanchez-Rovira, Pedro; Salido, Marta; Rodríguez, María; García-Puche, Jose L.; Delgado-Rodriguez, Miguel; Solé, Francisco; García, Maria A.; Perán, Macarena; Rosell, Rafael; Marchal, Juan A.; Lorente, Jose A.

    2014-01-01

    Circulating tumor cells (CTCs) are frequently associated with epithelialmesenchymal transition (EMT). The objective of this study was to detect EMT phenotype through Vimentin (VIM) and Slug expression in cytokeratin (CK)-negative CTCs in non-metastatic breast cancer patients and to determine the importance of EGFR in the EMT phenomenon. In CK-negative CTCs samples, both VIM and Slug markers were co-expressed in the most of patients. Among patients EGFR+, half of them were positive for these EMT markers. Furthermore, after a systemic treatment 68% of patients switched from CK- to CK+ CTCs. In our experimental model we found that activation of EGFR signaling by its ligand on MCF-7 cells is sufficient to increase EMT phenotypes, to inhibit apoptotic events and to induce the loss of CK expression. The simultaneous detection of both EGFR and EMT markers in CTCs may improve prognostic or predictive information in patients with operable breast cancer. PMID:25277187

  3. EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer.

    PubMed

    Serrano, Maria J; Ortega, Francisco G; Alvarez-Cubero, Maria J; Nadal, Rosa; Sanchez-Rovira, Pedro; Salido, Marta; Rodríguez, María; García-Puche, Jose L; Delgado-Rodriguez, Miguel; Solé, Francisco; García, Maria A; Perán, Macarena; Rosell, Rafael; Marchal, Juan A; Lorente, Jose A

    2014-09-15

    Circulating tumor cells (CTCs) are frequently associated with epithelial-mesenchymal transition (EMT).The objective of this study was to detect EMT phenotype through Vimentin (VIM) and Slug expression in cytokeratin (CK)-negative CTCs in non-metastatic breast cancer patients and to determine the importance of EGFR in the EMT phenomenon. In CK-negative CTCs samples, both VIM and Slug markers were co-expressed in the most of patients. Among patients EGFR+, half of them were positive for these EMT markers. Furthermore, after a systemic treatment 68% of patients switched from CK- to CK+ CTCs. In our experimental model we found that activation of EGFR signaling by its ligand on MCF-7 cells is sufficient to increase EMT phenotypes, to inhibit apoptotic events and to induce the loss of CK expression. The simultaneous detection of both EGFR and EMT markers in CTCs may improve prognostic or predictive information in patients with operable breast cancer. PMID:25277187

  4. Autoantibodies targeting tumor-associated antigens in metastatic cancer

    PubMed Central

    Oaks, Martin; Taylor, Samuel; Shaffer, James

    2013-01-01

    In addition to the well-established effector functions of IgGs, including direct cytotoxicity and antibody-dependent cellular cytotoxicity, some populations of IgGs may exert anti-inflammatory effects. Here, we describe a population of antibodies that form in the natural course of metastatic cancer and contain glycans that terminate with sialic acid. We demonstrate that both the titer of these antibodies and their level of sialylation are relatively stable throughout the progression of metastatic melanoma. The sialylation pattern of these antibodies somehow correlates with their specificity for tumor-associated antigens, as IgGs targeting several antigens associated with infectious agents are relatively poor of sialic acid. We also show that some antibodies targeting the melanoma-associated antigen NY-ESO-1 bind to the human C-type lectin CD209 (DC-SIGN). We propose that these antibodies are candidate anti-inflammatory antibodies. The presence of anti-inflammatory antibodies in cancer patients may explain, at least in part, why tumors persist and spread in the host despite strong tumor-specific humoral responses. The elucidation of the cellular and molecular pathways involved in the induction of anti-inflammatory antibodies specific for tumor-associated antigens and their function may yield important insights into how tumors evade immune detection and progress. PMID:23894724

  5. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.

    PubMed

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-12

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.

  6. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast

    PubMed Central

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P.; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-01

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast. PMID:26625196

  7. Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells

    SciTech Connect

    Savion, N.; Disatnik, M.H.; Nevo, Z.

    1987-01-01

    Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells attach, invade, and penetrate confluent vascular endothelial cell monolayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the (/sup 35/S)O/sub 4//sup -/-labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The degradation of (/sup 35/S)O/sub 4//sup -/-labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10..mu..g/ml), arteparon (10..mu..g/ml), and heparin at a concentration of 3 ..mu..g/ml. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage haparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis.

  8. Expression of WT1, CA 125, and GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary.

    PubMed

    Tornos, Carmen; Soslow, Robert; Chen, Shirley; Akram, Muzaffar; Hummer, Amanda J; Abu-Rustum, Nadeen; Norton, Larry; Tan, Lee K

    2005-11-01

    Metastatic breast carcinoma to the ovary is sometimes difficult to differentiate from primary ovarian carcinoma. This problem is often encountered in breast carcinoma patients who develop adnexal masses. ER and PR can be positive in a high percentage of breast and ovarian carcinomas, and therefore cannot be used in the differential diagnosis of these entities. WT1 and CA125 have been identified as possible markers for ovarian cancer. However, no studies have been done that specifically compare the immunophenotype of breast carcinoma metastatic to ovary with that of primary ovarian cancer. Thirty-nine cases of metastatic breast carcinoma to the ovary, 36 primary breast carcinomas, and 42 primary ovarian carcinomas were examined immunohistochemically for the expression of WT1, CA125, carcinoembryonic antigen, MUC2, MUC1, and GCDFP. The percentage of cells stained and the intensity of staining were recorded. Thirty-two ovarian carcinomas (76%) were positive for WT1, including 31 of 33 (94%) serous carcinomas. Most of them had strong and diffuse staining. None of the breast cancers either primary or metastatic to the ovary expressed WT1. Thirty-eight (90%) ovarian carcinomas were positive for CA125, most of them with strong and diffuse staining. Most breast carcinomas were negative for CA125, with only 6 (16%) of the primary ones and 5 (12%) of the metastatic showing weak and focal positivity. All ovarian carcinomas were negative for GCDFP. Five primary breast cancers (14%) and 17 (43%) metastatic to the ovary were positive for GCDFP. Nine (21%) ovarian carcinomas, 8 (22%) primary breast carcinomas, and 13 (33%) metastatic to the ovary were positive for carcinoembryonic antigen. Almost all tumors examined were positive for MUC1 (100% ovarian carcinomas, 100% primary breast carcinomas, and 95% metastatic breast carcinomas to ovary). MUC2 was positive in 10 (24%) ovarian carcinomas, 3 (8%) primary breast cancers, and 12 (30%) metastases to the ovary. The presence of

  9. A nanoparticle formulation that selectively transfects metastatic tumors in mice

    PubMed Central

    Yang, Jian; Hendricks, William; Liu, Guosheng; McCaffery, J. Michael; Kinzler, Kenneth W.; Huso, David L.; Vogelstein, Bert; Zhou, Shibin

    2013-01-01

    Nanoparticle gene therapy holds great promise for the treatment of malignant disease in light of the large number of potent, tumor-specific therapeutic payloads potentially available for delivery. To be effective, gene therapy vehicles must be able to deliver their therapeutic payloads to metastatic lesions after systemic administration. Here we describe nanoparticles comprised of a core of high molecular weight linear polyethylenimine (LPEI) complexed with DNA and surrounded by a shell of polyethyleneglycol-modified (PEGylated) low molecular weight LPEI. Compared with a state-of-the-art commercially available in vivo gene delivery formulation, i.v. delivery of the core/PEGylated shell (CPS) nanoparticles provided more than a 16,000-fold increase in the ratio of tumor to nontumor transfection. The vast majority of examined liver and lung metastases derived from a colorectal cancer cell line showed transgene expression after i.v. CPS injection in an animal model of metastasis. Histological examination of tissues from transfected mice revealed that the CPS nanoparticles selectively transfected neoplastic cells rather than stromal cells within primary and metastatic tumors. However, only a small fraction of neoplastic cells (<1%) expressed the transgene, and the extent of delivery varied with the tumor cell line, tumor site, and host mouse strain used. Our results demonstrate that these CPS nanoparticles offer substantial advantages over previously described formulations for in vivo nanoparticle gene therapeutics. At the same time, they illustrate that major increases in the effectiveness of such approaches are needed for utility in patients with metastatic cancer. PMID:23959886

  10. Trastuzumab Administration in Patients with Metastatic Breast Cancer – Experience of a Large University Breast Center

    PubMed Central

    Hartkopf, A. D.; Brendel, M. H.; Wallwiener, M.; Taran, F.-A.; Brucker, S.; Grischke, E.-M.

    2014-01-01

    Background: Administered either alone or in combination with various cytostatic, endocrine or targeted therapies, trastuzumab significantly improves the prognosis of patients with HER2-positive breast cancer. As trastuzumab is effective across multiple lines of therapy in the metastatic setting (treatment beyond progression: TBP), it is often administered over a long period of time. The aim of this study was to evaluate the tolerability and clinical practice of long-term trastuzumab administration (> 1 year) in metastatic breast cancer patients treated in a large university breast center. Methods: Metastatic breast cancer patients who received at least 18 cycles of trastuzumab administered every three weeks at the University Gynecological Hospital of Tuebingen between 1999 and 2012 were included in this retrospective study. Typical combination drugs, side effects, and the impact of administration on left ventricular ejection fraction (LVEF) were investigated. Results: 72 patients were eligible for inclusion in the study. The mean number of administrations was 50.14 (SD: 27.51). In 53 patients the principle of TBP was followed across an average of 2.4 therapy lines. Classic cardiac risk factors were present at the beginning of trastuzumab treatment in 34 patients (47 %). Seven patients (10 %) experienced a decrease in LVEF during treatment, 9 patients (13 %) had hypersensitivity reactions. Treatment was discontinued in two patients due to side effects (1 × progressive LVEF decrease, 1 × intolerance). Summary: The administration of trastuzumab across multiple lines of therapy was generally tolerated well. Cardiac risk factors were not a limiting factor. If regular cardiac monitoring is done, trastuzumab appears not only to improve survival but also helps preserve the quality of life of patients with HER2-positive metastatic breast cancer. PMID:24976638

  11. Impedimetric detection of mutant p53 biomarker-driven metastatic breast cancers under hyposmotic pressure.

    PubMed

    Shi, Menglu; Shtraizent, Nataly; Polotskaia, Alla; Bargonetti, Jill; Matsui, Hiroshi

    2014-01-01

    In cancer cells, the oncogenic mutant p53 (mtp53) protein is present at high levels and gain-of-function (GOF) activities with more expression of mtp53 proteins contribute to tumor growth and metastasis. Robust analytical approaches that probe the degree of metastasis of cancer cells in connection with the mtp53 activity will be extremely useful not only for establishing a better cancer prognosis but also understanding the fundamental mechanism of mtp53 oncogenic action. Here we assessed the influence of mtp53 in breast cancers to the mechanical property of breast cancer cells. Recently, ovarian and kidney cancer cell lines have been shown to have higher cellular elasticity as compared to normal cells assessed by monitoring the degree of deformation under hyposmotic pressure. To make fast detection in large scale, the impedance measurement was applied to monitor the swelling ratio of cells with time. The results showed that knockdown of mtp53 leads to decrease in cell swelling. In addition, by means of two types of impedimetric detection systems we consistently detected enhancement of impedance signal in mtp53-expressing breast cancer cells. Based on this observation we hypothesize that highly expressed mtp53 in metastatic mutant breast cancers can promote tumor progression by making cells more deformable and easier to spread out through extracellular matrix. The identification via the electric measurement can be accomplished within 10 minutes. All results in this report suggest that electric probing for the extent of the mtp53 expression of breast cancer cells may serve as a meaningful fingerprint for the cancer diagnostics, and this outcome will also have an important clinical implication for the development of mtp53-based targeting for tumor detection and treatment.

  12. Development of Raman spectral markers to assess metastatic bone in breast cancer

    NASA Astrophysics Data System (ADS)

    Ding, Hao; Nyman, Jeffry S.; Sterling, Julie A.; Perrien, Daniel S.; Mahadevan-Jansen, Anita; Bi, Xiaohong

    2014-11-01

    Bone is the most common site for breast cancer metastases. One of the major complications of bone metastasis is pathological bone fracture caused by chronic bone loss and degeneration. Current guidelines for the prediction of pathological fracture mainly rely on radiographs or computed tomography, which are limited in their ability to predict fracture risk. The present study explored the feasibility of using Raman spectroscopy to estimate pathological fracture risk by characterizing the alterations in the compositional properties of metastatic bones. Tibiae with evident bone destruction were investigated using Raman spectroscopy. The carbonation level calculated by the ratio of carbonate/phosphate ν1 significantly increased in the tumor-bearing bone at all the sampling regions at the proximal metaphysis and diaphysis, while tumor-induced elevation in mineralization and crystallinity was more pronounced in the metaphysis. Furthermore, the increased carbonation level is positively correlated to bone lesion size, indicating that this parameter could serve as a unique spectral marker for tumor progression and bone loss. With the promising advances in the development of spatially offset Raman spectroscopy for deep tissue measurement, this spectral marker can potentially be used for future noninvasive evaluation of metastatic bone and prediction of pathological fracture risk.

  13. Expression of peripheral benzodiazepine receptor (PBR) in human tumors: relationship to breast, colorectal, and prostate tumor progression.

    PubMed

    Han, Zeqiu; Slack, Rebecca S; Li, Wenping; Papadopoulos, Vassilios

    2003-01-01

    High levels of peripheral-type benzodiazepine receptor (PBR), the alternative-binding site for diazepam, are part of the aggressive human breast cancer cell phenotype in vitro. We examined PBR levels and distribution in normal tissue and tumors from multiple cancer types by immunohistochemistry. Among normal breast tissues, fibroadenomas, primary and metastatic adenocarcinomas, there is a progressive increase in PBR levels parallel to the invasive and metastatic ability of the tumor (p < 0.0001). In colorectal and prostate carcinomas, PBR levels were also higher in tumor than in the corresponding non-tumoral tissues and benign lesions (p < 0.0001). In contrast, PBR was highly concentrated in normal adrenal cortical cells and hepatocytes, whereas in adrenocortical tumors and hepatomas PBR levels were decreased. Moreover, malignant skin tumors showed decreased PBR expression compared with normal skin. These results indicate that elevated PBR expression is not a common feature of aggressive tumors, but rather may be limited to certain cancers, such as those of breast, colon-rectum and prostate tissues, where elevated PBR expression is associated with tumor progression. Thus, we propose that PBR overexpression could serve as a novel prognostic indicator of an aggressive phenotype in breast, colorectal and prostate cancers.

  14. Prognostic value of serum level of interleukin-6 and interleukin-8 in metastatic breast cancer patients.

    PubMed

    Ahmed, Olal I; Adel, Azza M; Diab, Dina R; Gobran, Nagy S

    2006-01-01

    Previous studies indicated that interleukins may stimulate cancer cells growth and contribute to loco regional relapse as well as metastasis. The aim in this study was to investigate the level of interleukin-6 (IL-6) and interleukin-8 (IL-8) in metastatic breast cancer patients and find out the relation between the levels of these cytokines and the clinical out come of patients and to predict the value of these cytokines as independent prognostic factors. The present study was carried out on 40 women divided into two groups; the first group included 30 patients diagnosed as having metastatic breast cancer. The second group included 10 healthy women as controls. An immunoenzymometric assays for the quantitative measurement of human IL-6 and IL-8 were used. The serum level of IL-6 and IL-8 were measured for patients and controls. Serum level of both IL-6 and IL-8 were found to be higher in patients than in healthy volunteers. Serum IL-6 was detected in all patients and controls with a mean value of (25.3 pg/ml) versus (1.5 pg/ml) for patients and controls respectively and this difference was statistically highly significant (P < 0.001). Serum IL-8 was detected in 26 patients (86.7%) and 7 controls (70%) with a mean value of (8.96 pg/ml) versus (3.9 pg/ml) for patients and controls respectively and this difference was also statistically highly significant (P < 0.001). Tumors with size larger than 5 cm at diagnosis were associated with higher level of both IL-6 (32.8 pg/ml) and IL-8 (10.2 pg/ml) in comparison with those with size less than 5cm (IL-6 14 pg/ml) and (IL-8 7.2 pg/ml) and the difference in both cases was statistically significant (P < 0.05). Patients with more than 3 positive lymph nodes had higher level of both IL-6 and IL-8 with a mean value of 32.8 pg/ml and 10.2 pg/ml for IL-6 and IL-8 respectively, than those with less than 3 positive lymph nodes with mean value of 14 pg/ml and 6.9 pg/ml for IL-6 and IL-8 respectively and this difference was

  15. CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages

    PubMed Central

    Ball, Michael S.; Shipman, Emilie P.; Kim, Hyunjung; Liby, Karen T.; Pioli, Patricia A.

    2016-01-01

    Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer. PMID:26918785

  16. Metastatic Neuroendocrine Carcinoma of the Breast Identified by Tc-99m-HYNIC-TOC SPECT/CT: A Rare Case Report.

    PubMed

    Claimon, Apichaya; Chuthapisith, Suebwong; Samarnthai, Norasate; Pusuwan, Pawana

    2015-08-01

    The authors reported an uncommon presentation of metastatic neuroendocrine carcinoma to the breast detected by Tc-99m-HYNIC-TOC SPECT/CT in a 49 years old woman who, previously, had carcinoid tumor of left main bronchus and invasive ductal carcinoma of the right breast. Later, the patient developed left breast mass. Core needle biopsy of the mass revealed poorly differentiated invasive ductal carcinoma. The disease remained stable for 12 years without any treatment on that left breast (due to patient's rejection). On the later investigation using Tc-99m-HYNIC-TOC scintigraphy examination, rather than invasive ductal carcinoma, metastatic neuroendocrine cancer was suggested. The final diagnosis was confirmed by pathological examination after surgical excision. Multiple metastatic lesions of neuroendocrine carcinoma at lung, liver, ovaries, and bones were also depicted. Due to the good behavior of the disease, patient had been doing well for eight months, without specific treatment. This report confirmed the advantage and the accuracy of Tc-99m-HYNIC-TOC scintigraphy in detection of neuroendocrine carcinoma. Furthermore, metastatic neuroendocrine tumor should be in differential diagnosis for patient with breast mass together with history of neuroendocrine tumor

  17. Metastatic melanoma mimicking solitary fibrous tumor: report of two cases.

    PubMed

    Bekers, Elise M; van Engen-van Grunsven, Adriana C H; Groenen, Patricia J T A; Westdorp, Harm; Koornstra, Rutger H T; Bonenkamp, Johannes J; Flucke, Uta; Blokx, Willeke A M

    2014-02-01

    Malignant melanomas are known for their remarkable morphological variation and aberrant immunophenotype with loss of lineage-specific markers, especially in recurrences and metastases. Hot spot mutations in BRAF, NRAS, GNAQ, and GNA11 and mutations in KIT are oncogenic events in melanomas. Therefore, genotyping can be a useful ancillary diagnostic tool. We present one case each of recurrent and metastatic melanoma, both showing histological and immunohistochemical features of solitary fibrous tumor (SFT). Mutational analysis detected BRAF and NRAS mutations in the primary and secondary lesions, respectively. This result confirmed the diagnosis of recurrent/metastastic melanoma.

  18. Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells.

    PubMed

    Wang, Bin; Wang, Qiang; Wang, Zhe; Jiang, Jun; Yu, Shi-Cang; Ping, Yi-Fang; Yang, Jing; Xu, Sen-Lin; Ye, Xian-Zong; Xu, Chuan; Yang, Lang; Qian, Cheng; Wang, Ji Ming; Cui, You-Hong; Zhang, Xia; Bian, Xiu-Wu

    2014-10-15

    Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer.

  19. The Uncontrolled Sialylation is Related to Chemoresistant Metastatic Breast Cancer.

    PubMed

    Roncati, Luca; Barbolini, Giuseppe; Gatti, Antonietta Morena; Pusiol, Teresa; Piscioli, Francesco; Maiorana, Antonio

    2016-10-01

    Among the scientific communities, there is a convergence of results supporting a direct relationship between dysregulated sialylation and poor prognosis in many human cancers. For this reason, we have retrospectively investigated 169 cases of invasive ductal carcinoma of the breast, coming from female patients aged between 31 and 76 years old. The whole series was subdivided into two prognostic groups: the first group consisted of 138 patients, who showed a post-treatment survival time more than 5 years, while the second group was made up by 31 patients, died within 5 years despite of chemotherapy. All the surgical specimens were fixed in 10 % neutral buffered formalin, paraffin embedded and, then, submitted to routinely haematoxylin/eosin staining and to a further histochemical (Alcian Blue, DDD-Fast Blue B, Mercury Orange), immunohistochemical (ST3GAL5 sialyltransferase, Ki67, c-erbB2, ER, PR) and chemico-elemental characterization. In the 31 cases of breast cancer belonging to the second group, an overexpression of sialomucins and sialyltransferases has been detected. Our results lead us to support that in aggressive chemoresistant breast cancers, the altered expression of sialic acid, due to an uncontrolled sialylation, creates an excessive negative charge on cell membranes, which stimulates repulsion between neoplastic cells and their subsequent access into the blood stream. This event implies an early metastatization and a rapid disease progression with fatal outcome. The early application of Alcian Blue stain on diagnostic biopsies of breast cancer is able to cheaply reveal the sialomucin accumulations, providing for the disease course. PMID:27037559

  20. Weekly pegylated liposomal doxorubicin and paclitaxel in patients with metastatic breast carcinoma: A phase II study

    PubMed Central

    LEONARDI, VITA; PALMISANO, VALENTINA; PEPE, ALESSIO; USSET, ANTONELLA; MANUGUERRA, GIOVANNA; SAVIO, GIUSEPPINA; DE BELLA, MANUELA TAMBURO; LAUDANI, AGATA; ALÙ, MASSIMO; CUSIMANO, MARIA PIA; SCIANNA, CATERINA; GIRESI, ARMANDO; AGOSTARA, BIAGIO

    2010-01-01

    Pegylated liposomal doxorubicin (PLD) has the advantage of delivering active anthracycline directly to the tumor site, while exposing the patient to a lesser degree of doxorubicin-associated toxicities. Recently, a regimen in which paclitaxel is infused weekly over 1 h produced substantial antitumor activity with little myelosuppression. We designed a phase II trial to study the efficacy and toxicity of 10 mg/m2 PLD on Days 1, 8 and 15, plus 70 mg/m2 paclitaxel weekly in patients with untreated metastatic breast cancer and a high risk of cardiotoxicity. The study included 35 patients, with 31 (88.5%) evaluable for efficacy and 35 (100%) for toxicity. A total of 28 patients (80%) had two or more sites of disease. Overall, 4 complete and 16 partial responses were noted with an overall response rate of 64.5%, with 6 cases of stable and 5 cases of progressive disease. Toxicity was found to be manageable in that the only grade 3–4 side effects recorded were palmar-plantar erythrodysesthesia, 8.5%; mucositis, 2.8%; leucopenia, 12.5%; anemia, 2.8% and AST/ALT, 2.8%. No cardiotoxicity was observed. In conclusion, weekly PLD plus paclitaxel appears to be a well-tolerated and effective approach for metastatic breast cancer patients with a high risk of cardiotoxicity. PMID:22966374

  1. Activity of Nanobins Loaded with Cisplatin and Arsenic Trioxide in Primary and Metastatic Breast Cancer

    NASA Astrophysics Data System (ADS)

    Swindell, Elden Peter, III

    Despite recent advances in breast cancer screening and detection, the disease is still a leading cause of death for women of all ages. Young, African-American women are disproportionally affected with a type of breast cancer, triple-negative breast cancer, which is particularly difficult to treat and has the worst prognosis of any breast cancer subtype. These tumors often spread to the lungs, liver, bones and brains of patients, which is ultimately fatal. This dissertation presents results from a series of in vivo and in vitro experiments that investigate the clinical utility of a novel nanoparticulate formulation of cisplatin and arsenic trioxide, NB(Pt,As) for treating primary and metastatic triple-negative breast cancer. These nanobins consist of a solid, crystalline metal nanoparticle surrounded by a lipid bilayer with 80-90 nm diameter. This drug payload is extremely stable, and so NB(Pt,As) is extremely well tolerated in mice. Furthermore, NB(Pt,As) is effective in two different mouse models of breast cancer, one of primary tumor growth an another of lung metastases. A discovery presented here, that thiol containing compounds are required for drug release, may explain these seemingly incongruous results. The large amount of intracellular thiol can trigger drug release, while the low concentration of free thiols in blood is insufficient to cause drug release. To improve the treatment of brain tumors with this unique drug, we added transferrin to the surface of the nanobin using copper-catalyzed "click" chemistry, which preserves protein activity. The addition of transferrin to the nanobins enables 10 fold greater uptake in the brains of mice treated with the transferrin-targeted nanobins Tf-NB(Pt,A) compared to NB(Pt,As). By penetrating the blood brain barrier, the Tf-NB(Pt,As) was able to reduce breast cancer metastases in the brains of mice, whereas NB(Pt,As) had no effect. Taken together, these results demonstrate the intricate balance of drug release

  2. Combined analysis of copy number alterations by single-nucleotide polymorphism array and MYC status in non-metastatic breast cancer patients: comparison according to the circulating tumor cell status.

    PubMed

    Nadal, R; Salido, M; Nonell, L; Rodríguez-Rivera, M; Puigdecanet, E; Garcia-Puche, J L; Macià, M; Corominas, J M; Serrano, M J; Lorente, J A; Solé, F

    2015-02-01

    Recent technological advances have made it possible to detect circulating tumor cells (CTCs) as a prognostic marker in operable breast cancer patients. Whether the presence of CTCs in cancer patients correlates with molecular alterations in the primary tumor has not been widely explored. We identified 14 primary breast cancer specimens with known CTC status, in order to evaluate the presence of differential genetic aberrations by using SNP array assay. There was a global increase of altered genome, CNA, and copy-neutral loss of heterozygosity (cn-LOH) observed in the CTC-positive (CTC(+)) versus CTC-negative (CTC(-)) cases. As the preliminary results showed a higher proportion of copy number alteration (CNA) at 8q24 (MYC loci) and the available evidence supporting the role of MYC in the processes cancer metastases is conflicting, MYC status was determined in tissue microarray sections in a larger series of patients (n = 49) with known CTC status using FISH. MYC was altered in 62% (16/26) CTC(+) patients and in 43% (6/14) CTC(-) patients (p = 0.25). Based on the observation in our study, future studies involving a larger number of patients should be performed in order to definitively define if this correlation exists.

  3. Combined analysis of copy number alterations by single-nucleotide polymorphism array and MYC status in non-metastatic breast cancer patients: comparison according to the circulating tumor cell status.

    PubMed

    Nadal, R; Salido, M; Nonell, L; Rodríguez-Rivera, M; Puigdecanet, E; Garcia-Puche, J L; Macià, M; Corominas, J M; Serrano, M J; Lorente, J A; Solé, F

    2015-02-01

    Recent technological advances have made it possible to detect circulating tumor cells (CTCs) as a prognostic marker in operable breast cancer patients. Whether the presence of CTCs in cancer patients correlates with molecular alterations in the primary tumor has not been widely explored. We identified 14 primary breast cancer specimens with known CTC status, in order to evaluate the presence of differential genetic aberrations by using SNP array assay. There was a global increase of altered genome, CNA, and copy-neutral loss of heterozygosity (cn-LOH) observed in the CTC-positive (CTC(+)) versus CTC-negative (CTC(-)) cases. As the preliminary results showed a higher proportion of copy number alteration (CNA) at 8q24 (MYC loci) and the available evidence supporting the role of MYC in the processes cancer metastases is conflicting, MYC status was determined in tissue microarray sections in a larger series of patients (n = 49) with known CTC status using FISH. MYC was altered in 62% (16/26) CTC(+) patients and in 43% (6/14) CTC(-) patients (p = 0.25). Based on the observation in our study, future studies involving a larger number of patients should be performed in order to definitively define if this correlation exists. PMID:25286758

  4. Cooperative Treatment of Metastatic Breast Cancer Using Host-Guest Nanoplatform Coloaded with Docetaxel and siRNA.

    PubMed

    Wang, Dangge; Wang, Tingting; Xu, Zhiai; Yu, Haijun; Feng, Bing; Zhang, Junying; Guo, Chengyue; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2016-01-27

    Conventional chemotherapy shows moderate efficiency against metastatic cancer since it targets only part of the mechanisms regulating tumor growth and metastasis. Here, gold nanorod (GNR)-based host-guest nanoplatforms loaded with docetaxel (DTX) and small interfering RNA (siRNA)-p65 (referred to as DTX-loaded GNR (GDTX)/p65) for chemo-, RNA interference (RNAi), and photothermal ablation (PTA) cooperative treatment of metastatic breast cancer are reported. To prepare the nanoplatform, GNRs are first coated with cyclodextrin (CD)-grafted polyethylenimine (PEI) and then loaded with DTX and siRNA through host-guest interaction with CD and electrostatic interaction with PEI, respectively. Upon near-infrared laser irradiation, GNRs generate a significant hyperthermia effect to trigger siRNA and DTX release. DTX reduces tumor growth by inhibiting mitosis of cancer cells. Meanwhile, siRNA-p65 suppresses lung metastasis and proliferation of cancer cells by blocking the nuclear factor kappa B (NF-κB) pathway and downregulating the downstream genes matrix metalloproteinase-9 (MMP-9) and B cell lymphoma-2 (Bcl-2). It is demonstrated that GDTX/p65 in combination with laser irradiation significantly inhibits the growth and lung metastasis of 4T1 breast tumors. The antitumor results suggest promising potential of the host-guest nanoplatform for combinational treatment of metastatic cancer by using RNAi, chemotherapy, and PTA. PMID:26662850

  5. Validating of the pre-clinical mouse model for metastatic breast cancer to the mandible.

    PubMed

    Hwang, Young Sun; Han, Sang-Sun; Kim, Ki-Rim; Ye-Jin, Lee; Sun-Kyung, Lee; Kwang-Kyun, Park; Won-Yoon, Chung

    2015-01-01

    Metastatic breast carcinoma has a great tendency to spread to the mandible. It is concomitantly associated with bone destruction, food intake disorder, and a poorer prognosis. Appropriate animal models need to be developed for a better understanding of the mechanisms underlying the metastatic process of breast cancer cells to mandible and to test the effects of potential lead compounds. Here, we assessed the metastasis model of intracardiac injection using luciferase-transfected metastatic breast cancer cells (MDA-MB-231Luc+) by determining the incidences of metastasis, mCT images, and histopathological results. A high bioluminescence signal mainly detected mandibular lesions with less frequent distal femora and proximal tibiae lesions. Extensive mandibular bone destruction occurred in nude mice grafted with metastatic breast cancer cells. This type of animal model might be a useful tool in assessing therapeutic implications and the efficacy of anti-cancer drugs for osteolytic cancers.

  6. Targeted therapy in her2-positive metastatic breast cancer: a review of the literature

    PubMed Central

    Zhu, X.; Verma, S.

    2015-01-01

    Breast tumours positive for her2 (human epidermal growth factor receptor 2) represent approximately 20% of all breast cancer cases and are associated with an aggressive natural history. The advent of targeted anti-her2 therapies has dramatically improved disease control and survival in patients with metastatic her2-positive breast cancer. Targeted agents are now considered the standard of care in the first-line setting and beyond. The present review summarizes the currently available data on targeted anti-her2 therapies from completed randomized phase iii clinical trials and briefly discusses emerging advances that will address unmet needs in metastatic her2-positive breast cancer. PMID:25848336

  7. Kaiso depletion attenuates transforming growth factor-β signaling and metastatic activity of triple-negative breast cancer cells

    PubMed Central

    Bassey-Archibong, B I; Kwiecien, J M; Milosavljevic, S B; Hallett, R M; Rayner, L G A; Erb, M J; Crawford-Brown, C J; Stephenson, K B; Bédard, P-A; Hassell, J A; Daniel, J M

    2016-01-01

    Triple-negative breast cancers (TNBCs) represent a subset of breast tumors that are highly aggressive and metastatic, and are responsible for a disproportionate number of breast cancer-related deaths. Several studies have postulated a role for the epithelial-to-mesenchymal transition (EMT) program in the increased aggressiveness and metastatic propensity of TNBCs. Although EMT is essential for early vertebrate development and wound healing, it is frequently co-opted by cancer cells during tumorigenesis. One prominent signaling pathway involved in EMT is the transforming growth factor-β (TGFβ) pathway. In this study, we report that the novel POZ-ZF transcription factor Kaiso is highly expressed in TNBCs and correlates with a shorter metastasis-free survival. Notably, Kaiso expression is induced by the TGFβ pathway and silencing Kaiso expression in the highly invasive breast cancer cell lines, MDA-MB-231 (hereafter MDA-231) and Hs578T, attenuated the expression of several EMT-associated proteins (Vimentin, Slug and ZEB1), abrogated TGFβ signaling and TGFβ-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGFβR1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGFβR1 in the Kaiso-depleted cells was insufficient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGFβ-mediated pro-metastatic responses. Collectively, these findings suggest a critical role for Kaiso in TGFβ signaling and the metastasis of TNBCs. PMID:26999717

  8. Kaiso depletion attenuates transforming growth factor-β signaling and metastatic activity of triple-negative breast cancer cells.

    PubMed

    Bassey-Archibong, B I; Kwiecien, J M; Milosavljevic, S B; Hallett, R M; Rayner, L G A; Erb, M J; Crawford-Brown, C J; Stephenson, K B; Bédard, P-A; Hassell, J A; Daniel, J M

    2016-01-01

    Triple-negative breast cancers (TNBCs) represent a subset of breast tumors that are highly aggressive and metastatic, and are responsible for a disproportionate number of breast cancer-related deaths. Several studies have postulated a role for the epithelial-to-mesenchymal transition (EMT) program in the increased aggressiveness and metastatic propensity of TNBCs. Although EMT is essential for early vertebrate development and wound healing, it is frequently co-opted by cancer cells during tumorigenesis. One prominent signaling pathway involved in EMT is the transforming growth factor-β (TGFβ) pathway. In this study, we report that the novel POZ-ZF transcription factor Kaiso is highly expressed in TNBCs and correlates with a shorter metastasis-free survival. Notably, Kaiso expression is induced by the TGFβ pathway and silencing Kaiso expression in the highly invasive breast cancer cell lines, MDA-MB-231 (hereafter MDA-231) and Hs578T, attenuated the expression of several EMT-associated proteins (Vimentin, Slug and ZEB1), abrogated TGFβ signaling and TGFβ-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGFβR1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGFβR1 in the Kaiso-depleted cells was insufficient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGFβ-mediated pro-metastatic responses. Collectively, these findings suggest a critical role for Kaiso in TGFβ signaling and the metastasis of TNBCs.

  9. Investigating Mechanisms of Alkalinization for Reducing Primary Breast Tumor Invasion

    PubMed Central

    Robey, Ian F.; Nesbit, Lance A.

    2013-01-01

    The extracellular pH (pHe) of many solid tumors is acidic as a result of glycolytic metabolism and poor perfusion. Acidity promotes invasion and enhances metastatic potential. Tumor acidity can be buffered by systemic administration of an alkaline agent such as sodium bicarbonate. Tumor-bearing mice maintained on sodium bicarbonate drinking water exhibit fewer metastases and survive longer than untreated controls. We predict this effect is due to inhibition of tumor invasion. Reducing tumor invasion should result in fewer circulating tumor cells (CTCs). We report that bicarbonate-treated MDA-MB-231 tumor-bearing mice exhibited significantly lower numbers of CTCs than untreated mice (P < 0.01). Tumor pHe buffering may reduce optimal conditions for enzymes involved in tumor invasion such as cathepsins and matrix metalloproteases (MMPs). To address this, we tested the effect of transient alkalinization on cathepsin and MMP activity using enzyme activatable fluorescence agents in mice bearing MDA-MB-231 mammary xenografts. Transient alkalinization significantly reduced the fluorescent signal of protease-specific activatable agents in vivo (P ≤ 0.003). Alkalinization, however, did not affect expression of carbonic anhydrase IX (CAIX). The findings suggest a possible mechanism in a live model system for breast cancer where systemic alkalinization slows the rate of invasion. PMID:23936808

  10. HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer

    PubMed Central

    Chandran, Vineesh Indira; Eppenberger-Castori, Serenella; Venkatesh, Thejaswini; Vine, Kara Lea; Ranson, Marie

    2015-01-01

    Human epidermal growth factor receptor type 2 (HER2)-positive breast carcinoma is highly aggressive and mostly metastatic in nature though curable/manageable in part by molecular targeted therapy. Recent evidence suggests a subtype of cells within HER2-positive breast tumors that concomitantly expresses the urokinase plasminogen activator receptor (uPAR) with inherent stem cell/mesenchymal-like properties promoting tumor cell motility and a metastatic phenotype. This HER-positive/uPAR-positive subtype may be partially responsible for the failure of HER2-targeted treatment strategies. Herein we discuss and substantiate the cumulative preclinical and clinical evidence on HER2-uPAR cooperativity in terms of gene co-amplification and/or mRNA/protein co-overexpression. We then propose a regulatory signaling model that we hypothesize to maintain upregulation and cooperativity between HER2 and uPAR in aggressive breast cancer. An improved understanding of the HER2/uPAR interaction in breast cancer will provide critical biomolecular information that may help better predict disease course and response to therapy. PMID:25897424

  11. Living with Metastatic Breast Cancer: A Qualitative Analysis of Physical, Psychological, and Social Sequelae

    PubMed Central

    Mosher, Catherine E.; Johnson, Courtney; Dickler, Maura; Norton, Larry; Massie, Mary Jane; DuHamel, Katherine

    2014-01-01

    Women with metastatic breast cancer face a wide range of medical, practical, and emotional challenges that impact their quality of life. Research to date, however, has not focused on the quality-of-life concerns of metastatic breast cancer patients with significant distress. The present study examined a range of concerns among distressed metastatic breast cancer patients, including physical and emotional distress, social functioning, and existential issues. Forty-four distressed women with metastatic breast cancer wrote their deepest thoughts and feelings regarding their illness. These essays were thematically analyzed for effects of the illness on quality of life. Three themes were identified in patients’ essays. First, metastatic breast cancer and its treatment may result in a number of quality-of-life concerns, including physical symptom burden, emotional distress, body image disturbance, and disrupted daily activities. Second, social constraints on disclosure of cancer-related concerns may exacerbate patients’ distress. Third, many women experience a heightened awareness of life’s brevity and search for meaning in their cancer experience. Results highlight a range of quality-of-life concerns following a metastatic breast cancer diagnosis and suggest that addressing social constraints on cancer-related disclosure and the search for meaning may improve patients’ psychological adjustment. PMID:23528206

  12. Metronomic Chemotherapy for Metastatic Breast Cancer – a Systematic Review of the Literature

    PubMed Central

    Banys-Paluchowski, M.; Schütz, F.; Ruckhäberle, E.; Krawczyk, N.; Fehm, T.

    2016-01-01

    Conventional chemotherapy is generally administered in high doses followed by a treatment-free period to give the body needful time to recover. This “maximum tolerated dose” approach results in high response rates. However, long periods between therapy cycles can lead to development of resistance mechanisms and consequently disease progression. One of the most interesting alternative strategies is metronomic chemotherapy. This concept relies on the continuous administration of chemotherapy at low doses and aims at targeting endothelial cells in the tumor bed as well. Recently, metronomic chemotherapy has been incorporated into the recommendations issued by the German AGO expert panel (www.ago-online.de). A systematic review of PubMed/Medline, ClinicalTrials.gov, the European Clinical Trials Database (EudraCT) and the Cochrane Database was conducted. In the present review, we discuss the current evidence on metronomic chemotherapy in metastatic breast cancer. PMID:27239061

  13. Large Malignant Phyllodes Tumor of the Breast with Metastases to the Lungs.

    PubMed

    Augustyn, Alexander; Sahoo, Sunati; Wooldridge, Rachel D

    2015-05-01

    Phyllodes tumors of the breast account for less than 0.5% of breast cancers and present most commonly in women 45 to 49 years old. The importance in managing fibroepithelial lesions lies in distinguishing fibroadenomas, which are benign, from phyllodes tumors, which can be malignant and require complete surgical excision. We report the case of a 56-year-old female who presented with a rapidly enlarging mass in her right breast 18 cm in maximum dimension that completely effaced the breast and distorted the nipple. The patient underwent a successful total mastectomy after core biopsy revealed a diagnosis of phyllodes tumor. Surgical resection is the primary treatment modality; neoadjuvant and adjuvant therapies remain controversial. Here, we report the case of a large malignant phyllodes tumor metastatic to the lungs, review the literature, and discuss diagnostic modalities and adjunct nonsurgical therapies.

  14. Large Malignant Phyllodes Tumor of the Breast with Metastases to the Lungs

    PubMed Central

    Augustyn, Alexander; Sahoo, Sunati; Wooldridge, Rachel D.

    2015-01-01

    Phyllodes tumors of the breast account for less than 0.5% of breast cancers and present most commonly in women 45 to 49 years old. The importance in managing fibroepithelial lesions lies in distinguishing fibroadenomas, which are benign, from phyllodes tumors, which can be malignant and require complete surgical excision. We report the case of a 56-year-old female who presented with a rapidly enlarging mass in her right breast 18 cm in maximum dimension that completely effaced the breast and distorted the nipple. The patient underwent a successful total mastectomy after core biopsy revealed a diagnosis of phyllodes tumor. Surgical resection is the primary treatment modality; neoadjuvant and adjuvant therapies remain controversial. Here, we report the case of a large malignant phyllodes tumor metastatic to the lungs, review the literature, and discuss diagnostic modalities and adjunct nonsurgical therapies. PMID:26266007

  15. Large Malignant Phyllodes Tumor of the Breast with Metastases to the Lungs.

    PubMed

    Augustyn, Alexander; Sahoo, Sunati; Wooldridge, Rachel D

    2015-05-01

    Phyllodes tumors of the breast account for less than 0.5% of breast cancers and present most commonly in women 45 to 49 years old. The importance in managing fibroepithelial lesions lies in distinguishing fibroadenomas, which are benign, from phyllodes tumors, which can be malignant and require complete surgical excision. We report the case of a 56-year-old female who presented with a rapidly enlarging mass in her right breast 18 cm in maximum dimension that completely effaced the breast and distorted the nipple. The patient underwent a successful total mastectomy after core biopsy revealed a diagnosis of phyllodes tumor. Surgical resection is the primary treatment modality; neoadjuvant and adjuvant therapies remain controversial. Here, we report the case of a large malignant phyllodes tumor metastatic to the lungs, review the literature, and discuss diagnostic modalities and adjunct nonsurgical therapies. PMID:26266007

  16. Effects of laser immunotherapy on late-stage, metastatic breast cancer patients in a Phase II clinical trial

    NASA Astrophysics Data System (ADS)

    Ferrel, Gabriela L.; Zhou, Feifan; Li, Xiaosong; Hode, Tomas; Nordquist, Robert E.; Alleruzzo, Luciano; Chen, Wei R.

    2014-03-01

    Laser immunotherapy (LIT), a novel technique with a local intervention to induce systemic antitumor effects, was developed to treat metastatic cancers. The pre-clinical studies of LIT have shown its unique characteristics in generating a specific antitumor immunity in treating metastatic tumors in rats and mice. For late-stage, metastatic breast cancer patients, who were considered to be out of other available treatment options, we conducted a small Phase II clinical trial using LIT starting in 2009 in Lima, Peru. This Phase II study was closed in December of 2012, as acknowldged by the Ministry of Health (MOH) of Peur letter 438-2014-OGITT/INS dated March 5th, 2014. Ten patients were enrolled and received LIT in one or multiple 4-week treatment cycles. At the study closing date, four patients were alive and two of them remained cancer free. Here, following the successful conclusion of our Phase II study, we report the clinical effects of LIT on metastatic breast cancer patients. Specifically, we present the overall status of all the patients three years after the treatment and also the outcomes of two long-term surviving patients.

  17. Enhanced Survival with Implantable Scaffolds That Capture Metastatic Breast Cancer Cells In Vivo.

    PubMed

    Rao, Shreyas S; Bushnell, Grace G; Azarin, Samira M; Spicer, Graham; Aguado, Brian A; Stoehr, Jenna R; Jiang, Eric J; Backman, Vadim; Shea, Lonnie D; Jeruss, Jacqueline S

    2016-09-15

    The onset of distant organ metastasis from primary breast cancer marks the transition to a stage IV diagnosis. Standard imaging modalities often detect distant metastasis when the burden of disease is high, underscoring the need for improved methods of detection to allow for interventions that would impede disease progression. Here, microporous poly(ε-caprolactone) scaffolds were developed that capture early metastatic cells and thus serve as a sentinel for early detection. These scaffolds were used to characterize the dynamic immune response to the implant spanning the acute and chronic foreign body response. The immune cell composition had stabilized at the scaffold after approximately 1 month and changed dramatically within days to weeks after tumor inoculation, with CD11b(+)Gr1(hi)Ly6C(-) cells having the greatest increase in abundance. Implanted scaffolds recruited metastatic cancer cells that were inoculated into the mammary fat pad in vivo, which also significantly reduced tumor burden in the liver and brain. Additionally, cancer cells could be detected using a label-free imaging modality termed inverse spectroscopic optical coherence tomography, and we tested the hypothesis that subsequent removal of the primary tumor after early detection would enhance survival. Surgical removal of the primary tumor following cancer cell detection in the scaffold significantly improved disease-specific survival. The enhanced disease-specific survival was associated with a systemic reduction in the CD11b(+)Gr1(hi)Ly6C(-) cells as a consequence of the implant, which was further supported by Gr-1 depletion studies. Implementation of the scaffold may provide diagnostic and therapeutic options for cancer patients in both the high-risk and adjuvant treatment settings. Cancer Res; 76(18); 5209-18. ©2016 AACR. PMID:27635043

  18. Biomarker utility of circulating tumor cells in metastatic cutaneous melanoma.

    PubMed

    Khoja, Leila; Lorigan, Paul; Zhou, Cong; Lancashire, Matthew; Booth, Jessica; Cummings, Jeff; Califano, Raffaele; Clack, Glen; Hughes, Andrew; Dive, Caroline

    2013-06-01

    The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5 ml blood; 26% of patients had ≥ 2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥ 2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303-4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥ 2 CTCs during treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14-0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5 ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients. PMID:23223143

  19. Advances in First-Line Treatment for Patients with HER-2+ Metastatic Breast Cancer

    PubMed Central

    De Mattos-Arruda, Leticia

    2012-01-01

    Background. The prognosis for breast cancer patients overexpressing human epidermal growth factor receptor (HER)-2 has changed with anti–HER-2–targeted therapy. Although anti–HER-2 therapy with trastuzumab and chemotherapy is the standard first-line treatment, the best therapeutic regimen has yet to be defined, and new strategies are evolving. Methods. A literature review of well-established and recently published trials, reviews, and ongoing clinical trials addressing first-line treatment for HER-2+ metastatic breast cancer patients was performed. Results. Taxanes are the agents most commonly used in combination with trastuzumab, but other chemotherapy drugs, such as anthracyclines, vinorelbine, and gemcitabine and triple-combination therapies including platinum compounds, capecitabine, and taxanes have been studied. The combination of aromatase inhibitors with anti–HER-2 therapies is a new therapeutic option for some patients who coexpress HER-2 and hormone receptors, although its activity observed in randomized clinical trials seems to be inferior to that of chemotherapy plus anti–HER-2 therapies. In addition, new anti–HER-2 therapies have shown activity in HER-2+ tumors, both alone and in combination with trastuzumab. Conclusions. Trastuzumab plus chemotherapy is the current standard of care for the upfront treatment of HER-2+ breast cancer patients, though other anti–HER-2–targeting agents may appear as new standards in the upcoming years. PMID:22523199

  20. Interplay between YB-1 and IL-6 promotes the metastatic phenotype in breast cancer cells

    PubMed Central

    Castellana, Bàrbara; Aasen, Trond; Moreno-Bueno, Gema; Dunn, Sandra E.; Ramón y Cajal, Santiago

    2015-01-01

    Epithelial to mesenchymal transition (EMT) induces cell plasticity and promotes metastasis. The multifunctional oncoprotein Y-box binding protein-1 (YB-1) and the pleiotropic cytokine interleukin 6 (IL-6) have both been implicated in tumor cell metastasis and EMT, but via distinct pathways. Here, we show that direct interplay between YB-1 and IL-6 regulates breast cancer metastasis. Overexpression of YB-1 in breast cancer cell lines induced IL-6 production while stimulation with IL-6 increased YB-1 expression and YB-1 phosphorylation. Either approach was sufficient to induce EMT features, including increased cell migration and invasion. Silencing of YB-1 partially reverted the EMT and blocked the effect of IL-6 while inhibition of IL-6 signaling blocked the phenotype induced by YB-1 overexpression, demonstrating a clear YB-1/IL-6 interdependence. Our findings describe a novel signaling network in which YB-1 regulates IL-6, and vice versa, creating a positive feed-forward loop driving EMT-like metastatic features during breast cancer progression. Identification of signaling partners or pathways underlying this co-dependence may uncover novel therapeutic opportunities. PMID:26512918

  1. Rejection of metastatic 4T1 breast cancer by attenuation of Treg cells in combination with immune stimulation.

    PubMed

    Chen, Li; Huang, Tian-Gui; Meseck, Marcia; Mandeli, John; Fallon, John; Woo, Savio L C

    2007-12-01

    4T1 breast carcinoma is a highly malignant and poorly immunogenic murine tumor model that resembles advanced breast cancer in humans, and is refractory to most immune stimulation-based treatments. We hypothesize that the ineffectiveness of immune stimulatory treatment is mediated by the suppressive effects of CD4(+)CD25(+) regulatory T (Treg) cells, which can be attenuated by engaging the glucocorticoid-induced tumor necrosis factor receptor family-related protein with its natural ligand (GITRL); further, combination treatment with existing immune stimulation regimens will augment anti-tumor immunity and eradicate metastatic 4T1 tumors in mice.A soluble homodimeric form of mouse GITRL (mIg-mGITRLs) was molecularly constructed and used to treat orthotopic 4T1 tumors established in immune-competent, syngeneic Balb/c mice. When applied in combination with adenovirus-mediated intratumoral murine granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-12 (IL-12) gene delivery plus systemic 4-1BB activation, mIg-mGITRLs attenuated the immune-suppressive function of splenic Treg cells, which led to elevated interferon-gamma (IFN-gamma) production, tumor-specific cytolytic T-cell activities, tumor rejection and long-term survival in 65% of the animals without apparent toxicities. The results demonstrate that addition of mIg-mGITRLs to an immune-stimulatory treatment regimen significantly improved long-term survival without apparent toxicity, and could potentially be clinically translated into an effective and safe treatment modality for metastatic breast cancer in patients. PMID:17968355

  2. The role of tumor-associated macrophages in breast carcinoma invasion and metastasis.

    PubMed

    Yang, Ju; Li, Xiaojing; Liu, Xiuping; Liu, Yongjuan

    2015-01-01

    The main purpose of this study was to investigate the infiltration of tumor-associated macrophages (TAMs) in normal and malignant breast tissue and the draining lymph nodes, and to explore its effect on breast cancer invasion and metastasis. The infiltration densities of TAMs was observed using immunohistochemical staining of CD68 in 100 cases of breast cancer specimens and its paired adjacent non-cancer breast tissues and draining lymph modes, and then to evaluate the relation of TAMs to various clinicopathological features including patients prognosis in breast carcinoma. We observed the infiltration densities of TAMs were significantly higher in breast carcinoma tissue than in adjacent normal tissue and significantly higher in much larger size and higher stage cases. Furthermore, infiltration densities of TAMs have negative correlation with the 5-year survival rates of breast cancer patients. But in matched lymph-nodes, the infiltration densities of TAMs were significantly lower in cancerous metastatic lymph-node samples than in non-metastatic one. Therefore, our data suggests that TAMs infiltration in primary tumor promote invasion and lymphatic metastasis of breast cancer and have negative correlation with patients prognosis in breast cancer, but in lymph-node TAMs may play another role and need further study in the future.

  3. Multi-course PDT of malignant tumors: the influence on primary tumor, metastatic spreading and homeostasis of cancer patients

    NASA Astrophysics Data System (ADS)

    Sokolov, Victor V.; Chissov, Valery I.; Yakubovskaya, Raisa I.; Filonenko, E. V.; Sukhin, Garry M.; Nemtsova, E. R.; Belous, T. A.; Zharkova, Natalia N.

    1996-12-01

    The first clinical trials of photodynamic therapy (PDT) of cancer with two photosensitizers, PHOTOHEME and PHOTOSENS, were started in P.A. Hertzen Research Oncological Institute (Moscow, Russia) in 1992 and 1994. Up to now, 208 patients with primary, recurrent and metastatic malignant tumors (469) of skin (34 patients/185 tumors), breast cancer (24/101), head and neck (30/31), trachea and bronchus (31/42), esophagus (35/35), stomach (31/32), rectum (4/4), vagina and uterine cervix (7/8) and bladder (12/31) have been treated by PDT. One-hundred-thirty patients were injected with PHOTOHEME, 64 patients were injected with PHOTOSENS, 14 patients were injected with PHOTOHEME and PHOTOSENS. Totally, 302 courses of treatment were performed: 155 patients had one course and 53 patients were subjected to two to nine PDT sources with intervals from 1 to 18 months. A therapeutic effect of a one-course and multi- course PDT of malignant tumors (respiratory, digestive and urogenital systems) was evaluated clinically, histologically, roentgenologically, sonographically and endoscopically. The biochemical, hematological and immunological investigations were performed for all the patients in dynamics. Results of our study showed that a multi-course PDT method seems to be perspective in treatment of malignant tumors of basic localizations.

  4. Expression of Yes-associated protein (YAP) in metastatic breast cancer

    PubMed Central

    Kim, Hye Min; Jung, Woo Hee; Koo, Ja Seung

    2015-01-01

    The purpose of this study was to investigate the expression of Yes-associated protein (YAP) in different metastatic sites in metastatic breast cancer and to determine the clinical implications of these patterns. Immunohistochemical staining was used to investigate the expression of YAP and phospho-YAP in tissue microarrays from 122 cases of metastatic breast cancer (bone metastasis = 29, brain metastasis = 38, liver metastasis = 12, and lung metastasis = 43). The expression levels of YAP and phospho-YAP differed according to the metastatic site in metastatic breast cancer. Specifically, nuclear expression of phospho-YAP was high in brain metastasis but low in lung metastasis (P = 0.010). The effects of YAP and phospho-YAP expression on clinical outcomes were investigated by univariate analysis. This analysis showed that nuclear YAP positivity (P = 0.008) and nuclear phospho-YAP positivity (P = 0.003) were both associated with shorter overall survival. In conclusion, the level of YAP expression varies according to the metastatic site in metastatic breast cancer. Moreover, high YAP expression was correlated with poor prognosis. PMID:26617849

  5. Expression of Yes-associated protein (YAP) in metastatic breast cancer.

    PubMed

    Kim, Hye Min; Jung, Woo Hee; Koo, Ja Seung

    2015-01-01

    The purpose of this study was to investigate the expression of Yes-associated protein (YAP) in different metastatic sites in metastatic breast cancer and to determine the clinical implications of these patterns. Immunohistochemical staining was used to investigate the expression of YAP and phospho-YAP in tissue microarrays from 122 cases of metastatic breast cancer (bone metastasis = 29, brain metastasis = 38, liver metastasis = 12, and lung metastasis = 43). The expression levels of YAP and phospho-YAP differed according to the metastatic site in metastatic breast cancer. Specifically, nuclear expression of phospho-YAP was high in brain metastasis but low in lung metastasis (P = 0.010). The effects of YAP and phospho-YAP expression on clinical outcomes were investigated by univariate analysis. This analysis showed that nuclear YAP positivity (P = 0.008) and nuclear phospho-YAP positivity (P = 0.003) were both associated with shorter overall survival. In conclusion, the level of YAP expression varies according to the metastatic site in metastatic breast cancer. Moreover, high YAP expression was correlated with poor prognosis.

  6. Ulcerative paraneoplastic dermatomyositis secondary to metastatic breast cancer.

    PubMed

    Scheinfeld, Noah S

    2006-01-01

    A 40-year-old Chinese-American woman with breast carcinoma metastatic to her lungs presented with a 3-month history of erosions on her inner thighs (Figure 1) and medial left shoulder. Faint livedo reticularis was evident on her legs as well. She had difficulty in walking and raising her shoulders. Her cutaneous examination was also notable for cuticular erythema (Figure 2) and mild periorbital erythema and edema. She had no systemic or rheumatologic complaints other than some difficulty in swallowing. Her blood chemistry values were notable for a creatinine kinase of 564 IU/L (5-200 IU/L), alanine aminotransferase 161 U/L (0-40 U/L) and aspartate aminotransferase 93 U/L (0-40 U/L), and an antinuclear antibody titer of 1:2560. Other blood chemistries and antibody serologies (anti-Jo-1, anti-Mi-2 and other anti-tRNA synthetase, anti-Ro/SSA, anti-U1RNP, anti-PM/Scl, and anti-Ku) were within normal limits. A biopsy specimen was obtained from an area of intact skin close to a right thigh ulceration that showed subtle vacuolar alteration at the dermo-epidermal junction with occasional necrotic keratinocyte (Figure 3). Melanophages and telangiectases were present. Within the subcutis there was fibrin deposition and neutrophils. A diagnosis of dermatomyositis was made. The patient received oral prednisone 20 mg three times a day, and her ulcerations resolved. Her creatinine kinase, alanine aminotransferase, and aspartate aminotransferase values returned to normal over the course of 3 weeks, but her antinuclear antibody was unchanged. Radiographic studies concurrently noted that her breast cancer had recurred in her lungs; plans were made to treat her with chemotherapy. The patient was lost to close follow-up, but it was learned that her erosions had reoccurred while her prednisone was tapered and resolved when her dosage of prednisone was increased.

  7. Chronic Stress, Depression and Immunity in Spouses of Metastatic Breast Cancer Patients

    ERIC Educational Resources Information Center

    Mortimer, Jane S. Blake; Sephton, Sandra E.; Kimerling, Rachel; Butler, Lisa; Bernstein, Aaron S.; Spiegel, David

    2005-01-01

    Objective: The objective of this study was to examine how the chronicity of stress affects psychological stress-responses, depressive symptoms, and "in vivo" immunocompetence in spouses of women with metastatic breast cancer. Methods: Participants were 34 spouses of breast cancer patients. Their wives had been living with a diagnosis of recurrence…

  8. Genomic landscapes of breast fibroepithelial tumors.

    PubMed

    Tan, Jing; Ong, Choon Kiat; Lim, Weng Khong; Ng, Cedric Chuan Young; Thike, Aye Aye; Ng, Ley Moy; Rajasegaran, Vikneswari; Myint, Swe Swe; Nagarajan, Sanjanaa; Thangaraju, Saranya; Dey, Sucharita; Nasir, Nur Diyana Md; Wijaya, Giovani Claresta; Lim, Jing Quan; Huang, Dachuan; Li, Zhimei; Wong, Bernice Huimin; Chan, Jason Yong Sheng; McPherson, John R; Cutcutache, Ioana; Poore, Gregory; Tay, Su Ting; Tan, Wai Jin; Putti, Thomas Choudary; Ahmad, Buhari Shaik; Iau, Philip; Chan, Ching Wan; Tang, Anthony P H; Yong, Wei Sean; Madhukumar, Preetha; Ho, Gay Hui; Tan, Veronique Kiak Mien; Wong, Chow Yin; Hartman, Mikael; Ong, Kong Wee; Tan, Benita K T; Rozen, Steven G; Tan, Patrick; Tan, Puay Hoon; Teh, Bin Tean

    2015-11-01

    Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications. PMID:26437033

  9. Primary tumor prevalence has an impact on the constituent ratio of metastases to the jaw but not on metastatic sites

    PubMed Central

    Zhang, Fu-gui; Hua, Cheng-ge; Shen, Mo-lun; Tang, Xiu-fa

    2011-01-01

    This article provides an overview of metastases to jaws (MJ), mainly concerning the differences between American and Chinese patients, and exploring the relationship between the primary tumors' prevalence (PTP) and constituent ratio of MJ. Information concerning of 399 MJ cases in 215 papers, including one new case in our hospital, was subjected to statistic analysis. The main clinical features of MJ, such as constituent ratio of PTP and that of MJ, metastatic sites, treatments, and prognosis were summarized. Breast, lung, kidney, prostate and thyroid (in descending order) were the leading primary sites of MJ. Furthermore, the constituent ratio of MJ was found to be correlated with that of PTP in all subjects including American and Chinese subjects in our study. As to metastatic sites in the mandible, a specific “M” shaped pattern appeared regardless of the tumor type or constituent ratios of MJ were in all subjects. Almost all subjects received traditionally palliative treatments, and the prognosis was quite poor. The PTP had a significant impact on the constituent ratio of MJ. However, it was the properties of the microenvironment rather than characteristics or constituent ratios of tumor cells, that decided the metastatic sites in various tumor subjects. PMID:21789963

  10. Color-Coded Imaging of Breast Cancer Metastatic Niche Formation in Nude Mice.

    PubMed

    Suetsugu, Atsushi; Momiyama, Masashi; Hiroshima, Yukihiko; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Bouvet, Michael; Hoffman, Robert M

    2015-12-01

    We report here a color-coded imaging model in which metastatic niches in the lung and liver of breast cancer can be identified. The transgenic green fluorescent protein (GFP)-expressing nude mouse was used as the host. The GFP nude mouse expresses GFP in all organs. However, GFP expression is dim in the liver parenchymal cells. Mouse mammary tumor cells (MMT 060562) (MMT), expressing red fluorescent protein (RFP), were injected in the tail vein of GFP nude mice to produce experimental lung metastasis and in the spleen of GFP nude mice to establish a liver metastasis model. Niche formation in the lung and liver metastasis was observed using very high resolution imaging systems. In the lung, GFP host-mouse cells accumulated around as few as a single MMT-RFP cell. In addition, GFP host cells were observed to form circle-shaped niches in the lung even without RFP cancer cells, which was possibly a niche in which future metastasis could be formed. In the liver, as with the lung, GFP host cells could form circle-shaped niches. Liver and lung metastases were removed surgically and cultured in vitro. MMT-RFP cells and GFP host cells resembling cancer-associated fibroblasts (CAFs) were observed interacting, suggesting that CAFs could serve as a metastatic niche.

  11. Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition.

    PubMed

    Kim, Rae-Kwon; Suh, Yongjoon; Yoo, Ki-Chun; Cui, Yan-Hong; Hwang, Eunji; Kim, Hyun-Jin; Kang, Ju-Seop; Kim, Min-Jung; Lee, Young Yiul; Lee, Su-Jae

    2015-01-01

    Metastasis is a challenging clinical problem and the primary cause of death in breast cancer patients. However, there is no therapeutic agent against metastasis of breast cancer cells. Here we report that phloroglucinol, a natural phlorotannin component of brown algae suppresses metastatic ability of breast cancer cells. Treatment with phloroglucinol effectively inhibited mesenchymal phenotypes of basal type breast cancer cells through downregulation of SLUG without causing a cytotoxic effect. Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF-1/ERK signaling. In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice. Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance. PMID:25456733

  12. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells.

    PubMed

    Lawson, Devon A; Bhakta, Nirav R; Kessenbrock, Kai; Prummel, Karin D; Yu, Ying; Takai, Ken; Zhou, Alicia; Eyob, Henok; Balakrishnan, Sanjeev; Wang, Chih-Yang; Yaswen, Paul; Goga, Andrei; Werb, Zena

    2015-10-01

    Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated

  13. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells

    PubMed Central

    Lawson, Devon A.; Bhakta, Nirav R.; Kessenbrock, Kai; Prummel, Karin D.; Yu, Ying; Takai, Ken; Zhou, Alicia; Eyob, Henok; Balakrishnan, Sanjeev; Wang, Chih-Yang; Yaswen, Paul; Goga, Andrei; Werb, Zena

    2015-01-01

    Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality1. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours2–5. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown2. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are

  14. Targeting of Runx2 by miRNA-135 and miRNA-203 Impairs Progression of Breast Cancer and Metastatic Bone Disease

    PubMed Central

    Taipaleenmäki, Hanna; Browne, Gillian; Akech, Jacqueline; Zustin, Jozef; van Wijnen, Andre J.; Stein, Janet L.; Hesse, Eric; Stein, Gary S.; Lian, Jane B.

    2015-01-01

    Progression of breast cancer to metastatic bone disease is linked to deregulated expression of the transcription factor Runx2. Therefore, our goal was to evaluate the potential for clinical use of Runx2-targeting microRNAs (miRNAs) to reduce tumor growth and bone metastatic burden. Expression analysis of a panel of miRNAs regulating Runx2 revealed a reciprocal relationship between the abundance of Runx2 protein and two miRNAs, miR-135 and miR-203. These miRNAs are highly expressed in normal breast epithelial cells where Runx2 is not detected, and absent in metastatic breast cancer cells and tissue biopsies that express Runx2. Reconstituting metastatic MDA-MB-231-Luc cells with miR-135 and miR-203 reduced the abundance of Runx2 and expression of the metastasis-promoting Runx2 target genes IL-11, MMP-13, and PTHrP. Additionally, tumor cell viability was decreased and migration suppressed in vitro. Orthotopic implantation of MDA-MB-231-luc cells delivered with miR-135 or miR-203, followed by an intratumoral administration of the synthetic miRNAs reduced the tumor growth and spontaneous metastasis to bone. Furthermore, intratibial injection of these miRNA-delivered cells impaired tumor growth in the bone environment and inhibited bone resorption. Importantly, reconstitution of Runx2 in MDA-MB-231-luc cells delivered with miR-135 and miR-203 reversed the inhibitory effect of the miRNAs on tumor growth and metastasis. Thus, we have identified that aberrant expression of Runx2 in aggressive tumor cells is related to the loss of specific Runx2-targeting miRNAs and that a clinically relevant replacement strategy by delivery of synthetic miRNAs is a candidate therapeutic approach to prevent metastatic bone disease by this route. PMID:25634212

  15. [High dose medroxyprogesterone acetate in metastatic breast cancer. Comparative clinical, pharmacokinetic and pharmacodynamic data of different forms of administration].

    PubMed

    Blossey, H C; Wander, H E; Nagel, G A; Köbberling, J; Kleeberg, U

    1982-08-01

    In the therapy of metastatic breast cancer MAP was used with different dosages and different forms of administration. Pharmacokinetics and pharmacodynamics were investigated. MAP plasma concentrations are dose dependent with great interindividual variation. The cortisol suppressive effect is dependent on plasma concentrations with only narrow interindividual variability. The oral administration of the crystal suspension is equivalent to the administration of tablets concerning plasma levels und endocrine effects. The therapy schedule for i.m. application used here leads to lower MAP plasma concentrations and correspondingly to a minor endocrine effect than in oral therapy. Tumor effective and cortisol suppressive plasma concentrations seem to have the same level.

  16. Multimodal Approach to the Management of Metastatic Epidural Spinal Cord Compression (MESCC) Due to Solid Tumors

    SciTech Connect

    Tancioni, Flavio; Navarria, Pierina; Lorenzetti, Martin A.; Pedrazzoli, Paolo; Masci, Giovanna; Mancosu, Pietro; Alloisio, Marco; Morenghi, Emanuela; Santoro, Armando; Rodriguez y Baena, Riccardo; Scorsetti, Marta

    2010-12-01

    Purpose: To assess the impact of a multidisciplinary approach for treatment of patients with metastatic epidural spinal cord compression in terms of feasibility, local control, and survival. Methods and Materials: Eighty-nine consecutive patients treated between January 2004 and December 2007 were included. The most common primary cancers were lung, breast, and kidney cancers. Ninety-eight surgical procedures were performed. Radiotherapy was performed within the first month postoperatively. Clinical outcome was evaluated by modified visual analog scale for pain, Frankel scale for neurologic deficit, and magnetic resonance imaging or computed tomography scan. Nearly all patients (93%) had back pain before treatment, whereas major or minor preoperative neurologic deficit was present in 62 cases (63%). Results: Clinical remission of pain was obtained in the vast majority of patients (91%). Improvement of neurologic deficit was observed in 45 cases (72.5%). Local relapse occurred in 10%. Median survival was 11 months (range, 0-46 months). Overall survival at 1 year was 43.6%. Type of primary tumor significantly affected survival. Conclusions: In patients with metastatic epidural spinal cord compression, the combination of surgery plus radiotherapy is feasible and provides clinical benefit in most patients. The discussion of each single case within a multidisciplinary team has been of pivotal importance in implementing the most appropriate therapeutic approach.

  17. Differentiation of Reactive and Tumor Metastatic Lymph Nodes with Diffusion-weighted and SPIO Enhanced MRI

    PubMed Central

    Zhang, Fan; Zhu, Lei; Huang, Xinglu; Niu, Gang; Chen, Siouan

    2012-01-01

    Objectives Determination of lymphatic metastasis is of great importance for both treatment planning and patient prognosis. We aim to distinguish tumor metastatic lymph nodes (TLNs) and reactive lymph nodes (RLNs) with diffusion-weighted and superparamagnetic iron oxide (SPIO) enhanced magnetic resonance imaging (MRI). Materials and methods Ipsilateral popliteal lymph node metastasis or lymphadenitis model was established by hock injection of either luciferase-expressing 4T1 murine breast cancer cells or Complete Freund Adjuvant (CFA) in male Balb/C mice. At different time points after inoculation, bioluminescence imaging, T2-weighted, diffusion-weighted and SPIO enhanced MRI were performed. Imaging findings were confirmed by histopathological staining. Results Size enlargement was observed in both TLNs and RLNs. At day 28, TLNs showed strong bioluminescence signal and bigger size than RLNs (p < 0.01). At early stages up to day 21, both TLNs and RLNs appeared homogeneous on diffusion-weighted imaging (DWI). At day 28, TLNs showed heterogeneous apparent diffusion coefficient (ADC) map with significantly higher average ADC value of 0.41 ± 0.03 × 10−3 mm2/s than that of RLNs (0.34 ± 0.02 10−3 mm2/s, p < 0.05). On SPIO enhanced MRI, both TLNs and RLNs showed distinct T2 signal reduction at day 21 after inoculation. At day 28, TLNs demonstrated partial uptake of the iron oxide particles, which was confirmed by Prussian blue staining. Conclusions Both diffusion-weighted and SPIO enhanced MRI can distinguish tumor metastatic lymph nodes from reactive lymph nodes. However, neither method is able to detect tumor metastasis to the draining lymph nodes at early stages. PMID:22588595

  18. Sequential Metastatic Breast Cancer Chemotherapy: Should the Median be the Message?

    PubMed Central

    Jung, Su Yon; Rosenzweig, Margaret

    2013-01-01

    Background: Counseling and anticipatory guidance of the expected course of treatment for women newly diagnosed with metastatic breast cancer (MBC) are difficult due to multiple factors influencing survival following MBC therapy. In order to better tailor counseling at the onset and through the duration of MBC we used non-clinical trial data to better characterize real life experience of sequential MBC treatment. We examined the following aims: (1) What demographic and tumor characteristics are predictive of survival in MBC? (2) What is the median duration of each sequential chemotherapy regimen and subsequent survival of women following each sequence of chemotherapy regimen in MBC? Methods: Retrospective study included 792 women diagnosed from January 1999 through December 2009 at the University of Pittsburgh Cancer Institute Breast Cancer Program. Results: Median duration of sequential chemotherapy regimen and median survival from completion of sequence of chemotherapy regimens were relatively short with a wide range of treatment duration and survival. Characteristics for poor survival included hormone status, human epidermal growth factor receptor-2 (HER 2/neu) status, and increased number and type of metastatic sites. Women who took more than the second sequential chemotherapy regimens had no more than median 3 months of treatment duration and 6 months survival from treatment termination. Discussion: Median clinical response and survival shorten with sequential chemotherapy regimen but with wide ranges. The rare clinical response of the minority should not set the standard for treatment expectations. All cancer clinicians, including oncology nurses, must ensure that patients are receiving tailored counseling regarding their specific risks and benefits for sequential MBC chemotherapy. PMID:24350218

  19. Breast cancer-specific mortality in small-sized tumor with node-positive breast cancer: a nation-wide study in Korean breast cancer society.

    PubMed

    Ryu, Jai Min; Lee, Hyouk Jin; Yoon, Tae In; Lee, Eun Sook; Lee, Soo Jung; Jung, Jin Hyang; Chae, Byung Joo; Nam, Seok Jin; Lee, Jeong Eon; Lee, Se Kyung; Bae, Soo Youn; Yu, Jonghan; Kim, Seok Won

    2016-10-01

    Tumor size and number of lymph node (LN) metastases are well known as the most important prognostic factors of breast cancer. We hypothesized that very small breast cancers with LN metastasis represent a progressive biologic behavior and evaluated tumor size stratified by LN metastasis. Data between 1990 and 2010 were obtained retrospectively from the Korean Breast Cancer Society Registry with inclusion criteria of female, non-metastatic, unilateral, and T1/2 breast cancer. We collected the following variables: age at surgery, tumor size, number of LN metastases, nuclear grade (NG), lymphovascular invasion (LVI), estrogen receptor status, progesterone receptor status, and epidermal growth factor receptor-2 status. Patient characteristics were compared by means of independent t-tests for continuous variables and the Chi-square or Fisher's exact test for categorical variables. Kaplan-Meier curves, with corresponding results of log-rank tests, were constructed for breast cancer-specific survival (BCSS). Five- and eight-year breast cancer-specific mortality (BCSM) was obtained in groups of 300 patients, followed by smoothing according to the confidence interval using the lowess method. We identified 39,826 breast cancer patients who met the inclusion criteria. Among them, 1433 (3.6 %) patients died due to breast cancer. The median follow-up duration was 63.4 (3-255) months. In the multivariate analysis, age at surgery, NG, LVI, subtype, and tumor size-nodal interactions were independently associated with BCSM. The N1 group had lower BCSS for T1a than T1b. The N2+ group also had lower BCSS for T1b than T1c or T2. In the N1 group of tumors smaller than 10 mm, 5- and 8-year BCSM decreased with larger tumor size. Patients with very small tumors with LN metastasis have decreased BCSM according to increase tumor size. Small tumors with LN metastasis could have aggressive biological behavior. PMID:27590199

  20. Challenging clinical scenarios: treatment of patients with triple-negative or basal-like metastatic breast cancer.

    PubMed

    Greenberg, Sally; Rugo, Hope S

    2010-09-01

    There is now compelling evidence to suggest that the biologic features of breast tumors affect response to specific therapies. Triple-negative breast cancer (TNBC) refers to a heterogeneous group of tumors that do not express the estrogen, progesterone, or HER2/neu receptors. By gene expression analysis, most (but not all) TNBCs are categorized as basal-like. TNBCs are often associated with particularly poor outcomes, with early development of chemotherapy resistance. There have been significant improvements in the outcome of other subtypes of breast cancer, including hormone receptor-positive/HER2+ tumors, attributed to the addition of targeted therapy, including hormonal agents and trastuzumab. However, no specific targeted agents are currently available for the treatment of TNBC. This review aims to collate and describe the most recent data on both cytotoxic and targeted therapies that have demonstrated efficacy in the management of metastatic TNBC. Evidence of response to various agents in early-stage breast cancer will be included, where relevant. Targeted agents that have been investigated in the treatment of TNBC include inhibitors of poly(ADP-ribose) polymerase, angiogenesis, mammalian target of rapamycin, epidermal growth factor receptor, and Src. Several of these agents have shown considerable promise. PMID:20805062

  1. Is the Blood-Brain Barrier Relevant in Metastatic Germ Cell Tumor?

    SciTech Connect

    Azar, Jose M. Schneider, Bryan P.; Einhorn, Lawrence H.

    2007-09-01

    Purpose: Germ cell tumors are uniquely chemosensitive and curable, even with advanced metastatic disease. Central nervous system recurrence can terminate a complete remission in other chemosensitive tumors, such as small cell lung cancer, because of the blood-brain barrier (BBB). We propose to document that the BBB is also relevant in germ cell tumors despite their dramatic chemosensitivity. Methods and Materials: We present five cases illustrating the concept of the BBB in patients with metastatic testicular cancer treated with chemotherapy. Results: In our large series of patients with metastatic testicular cancer treated with chemotherapy, we identified 5 unique patients. These patients were rendered free of disease only to experience relapse in the brain alone. This included 1 patient who initially had good-risk metastatic disease by means of the International Germ Cell Collaborative Group staging system at the onset of chemotherapy. Conclusions: The BBB is relevant in patients with metastatic testicular cancer.

  2. Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

    PubMed Central

    Brodsky, Alexander S.; Fischer, Andrew; Miller, Daniel H.; Vang, Souriya; MacLaughlan, Shannon; Wu, Hsin-Ta; Yu, Jovian; Steinhoff, Margaret; Collins, Colin; Smith, Peter J. S.; Raphael, Benjamin J.; Brard, Laurent

    2014-01-01

    The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development. PMID:24732363

  3. Anti-tumor immunity generated by photodynamic therapy in a metastatic murine tumor model

    NASA Astrophysics Data System (ADS)

    Castano, Ana P.; Hamblin, Michael R.

    2005-04-01

    Photodynamic therapy (PDT) is a modality for the treatment of cancer involving excitation of photosensitizers with harmless visible light producing reactive oxygen species. The major biological effects of PDT are apoptosis of tumor cells, destruction of the blood supply and activation of the immune system. The objective of this study is to compare in an animal model of metastatic cancer, PDT alone and PDT combined with low-dose cyclophosphamide (CY). Since the tumor we used is highly metastatic, it is necessary to generate anti-tumor immunity using PDT to both cure the primary tumor and prevent death from metastasis. This immunity may be potentiated by low dose CY. In our model we used J774 cells (a Balb/c reticulum cell sarcoma line with the characteristics of macrophages) and the following PDT regimen: benzoporphyrin derivative monoacid ring A (BPD, 2mg/kg injected IV followed after 15 min by 150 J/cm2 of 690-nm light). CY (50 mg/kg i.p.) was injected 48 hours before light delivery. BPD-PDT led to complete regression of the primary tumor in more than half the mice but no permanent cures were obtained. BPD-PDT in combination with CY led to 60% permanent cures. CY alone gave no permanent cures but did provide a survival advantage. To probe permanent immunity cured animals were rechallenged with the same tumor cell line and the tumors were rejected in 71% of mice cured with BPD-PDT plus CY. We conclude that BPD-PDT in combination with CY gives best overall results and that this is attributable to immunological response activation in addition to PDT-mediated destruction of the tumor.

  4. Olive secoiridoids and semisynthetic bioisostere analogues for the control of metastatic breast cancer.

    PubMed

    Busnena, Belnaser A; Foudah, Ahmed I; Melancon, Tina; El Sayed, Khalid A

    2013-04-01

    (-)-Oleocanthal (1) and ligstroside aglycone (2) are common bioactive olive oil secoiridoids. Secoiridoid 1 has been previously reported as a c-MET inhibitor. Chemically, (-)-oleocanthal is the elenolic acid ester of the common olive phenolic alcohol tyrosol. Therefore, several analogues (4-13) were synthesized by esterification and carbamoylation of tyrosol using diverse phenolic naturally occurring in olive and heterocyclic acids as elenolic acid bioisosteres to assess the effect of replacing the acid moiety of (-)-oleocanthal. Their c-MET inhibitory activity as well as their antiproliferative, antimigratory, and anti-invasive activities against the highly metastatic human breast cancer cell line MDA-MB231 has been assessed. Ligstroside aglycone (2) showed the best antimigratory activity. Generally, tyrosol esters showed better activities versus carbamate analogues. Tyrosol sinapate (5) showed the best c-MET phosphorylation inhibitory activity in Z'-LYTE kinase assay. Both 1 and 5 competitively inhibited the ATP binding into its pocket in the c-MET catalytic domain. Compound 5 showed selective activities against tumor cells without toxicity to the non-tumorigenic human breast MCF10A epithelial cell line. Tyrosol esters with a phenolic acid containing hydrogen bond donor and/or acceptor groups at the para-position have better anticancer and c-MET inhibitory activities. Olive oil secoiridoids are excellent scaffolds for the design of novel c-MET inhibitors. PMID:23403296

  5. Phyllodes Tumor in a Lactating Breast.

    PubMed

    Murthy, Sudha S; Raju, K V V N; Nair, Haripreetha G

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  6. Phyllodes Tumor in a Lactating Breast

    PubMed Central

    Murthy, Sudha S.; Raju, K. V. V. N.; Nair, Haripreetha G.

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  7. Computer assisted biopsy of breast tumors.

    PubMed

    Arambula Cosio, Fernando; Lira Berra, Eric; Hevia Montiel, Nidiyare; Garcia Segundo, Cresencio; Garduno, Edgar; Alvarado Gonzalez, Montserrat; Quispe Siccha, Rosa Ma; Reyes Ramirez, Bartolome; Hazan Lasri, Eric

    2010-01-01

    In this paper we report our preliminary results of the development of a computer assisted system for breast biopsy. The system is based on tracked ultrasound images of the breast. A three dimensional ultrasound volume is constructed from a set of tracked B-scan images acquired with a calibrated probe. The system has been designed to assist a radiologist during breast biopsy, and also as a training system for radiology residents. A semiautomatic classification algorithm was implemented to assist the user with the annotation of the tumor on an ultrasound volume. We report the development of the system prototype, tested on a physical phantom of a breast with a tumor, made of polivinil alcohol. PMID:21097108

  8. Lobular Carcinoma of the Breast Metastatic to the Spleen and Accessory Spleen: Report of a Case.

    PubMed

    Groisman, Gabriel M

    2016-01-01

    Despite the fact that accessory spleen (also known as supernumerary spleen, splenunculus, or splenule) can be found in 10-30% of patients undergoing autopsies, metastatic disease occurring in this organ has been barely reported. A case of lobular breast carcinoma metastatic to the spleen and accessory spleen found incidentally at therapeutic splenectomy for severe anemia and thrombocytopenia is described. On microscopic examination both organs revealed severe fibrocongestive changes and extramedullary hematopoiesis with no obvious carcinomatous involvement. Cytokeratin 7, estrogen receptors, and GATA3 immunohistochemistry disclosed the presence of numerous metastatic breast carcinoma cells infiltrating the splenic parenchyma. This case demonstrates that metastatic carcinoma can be encountered, although rarely, in accessory spleens and that cytokeratin stain should be performed in sections of spleens and/or accessory spleens excised from cancer patients in which the presence of malignant epithelial cells is not recognized on routine sections. PMID:27672468

  9. Lobular Carcinoma of the Breast Metastatic to the Spleen and Accessory Spleen: Report of a Case

    PubMed Central

    2016-01-01

    Despite the fact that accessory spleen (also known as supernumerary spleen, splenunculus, or splenule) can be found in 10–30% of patients undergoing autopsies, metastatic disease occurring in this organ has been barely reported. A case of lobular breast carcinoma metastatic to the spleen and accessory spleen found incidentally at therapeutic splenectomy for severe anemia and thrombocytopenia is described. On microscopic examination both organs revealed severe fibrocongestive changes and extramedullary hematopoiesis with no obvious carcinomatous involvement. Cytokeratin 7, estrogen receptors, and GATA3 immunohistochemistry disclosed the presence of numerous metastatic breast carcinoma cells infiltrating the splenic parenchyma. This case demonstrates that metastatic carcinoma can be encountered, although rarely, in accessory spleens and that cytokeratin stain should be performed in sections of spleens and/or accessory spleens excised from cancer patients in which the presence of malignant epithelial cells is not recognized on routine sections. PMID:27672468

  10. Lobular Carcinoma of the Breast Metastatic to the Spleen and Accessory Spleen: Report of a Case

    PubMed Central

    2016-01-01

    Despite the fact that accessory spleen (also known as supernumerary spleen, splenunculus, or splenule) can be found in 10–30% of patients undergoing autopsies, metastatic disease occurring in this organ has been barely reported. A case of lobular breast carcinoma metastatic to the spleen and accessory spleen found incidentally at therapeutic splenectomy for severe anemia and thrombocytopenia is described. On microscopic examination both organs revealed severe fibrocongestive changes and extramedullary hematopoiesis with no obvious carcinomatous involvement. Cytokeratin 7, estrogen receptors, and GATA3 immunohistochemistry disclosed the presence of numerous metastatic breast carcinoma cells infiltrating the splenic parenchyma. This case demonstrates that metastatic carcinoma can be encountered, although rarely, in accessory spleens and that cytokeratin stain should be performed in sections of spleens and/or accessory spleens excised from cancer patients in which the presence of malignant epithelial cells is not recognized on routine sections.

  11. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer

    PubMed Central

    Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M.; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W. Y.; Marass, Francesco; Gale, Davina; Ali, H. Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P.; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

    2015-01-01

    Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution. PMID:26530965

  12. Metastatic Colonic Adenocarcinoma in Breast: Report of Two Cases and Review of the Literature

    PubMed Central

    Kothadia, Jiten P.; Arju, Rezina; Kaminski, Monica; Ankireddypalli, Arvind; Duddempudi, Sushil; Chow, Jonathan; Giashuddin, Shah

    2015-01-01

    Metastatic adenocarcinoma to the breast from an extramammary site is extremely rare. In the literature, the most current estimate is that extramammary metastases account for only 0.43% of all breast malignancies and that, of these extramammary sites, colon cancer metastases form a very small subset. Most commonly seen metastasis in breast is from a contralateral breast carcinoma, followed by metastasis from hematopoietic neoplasms, malignant melanoma, sarcoma, lung, prostate, and ovary and gastric neoplasms. Here we present two rare cases, in which colonic adenocarcinomas were found to metastasize to the breast. In both cases, core biopsies were obtained from the suspicious areas identified on mammogram. Histopathology revealed neoplastic proliferation of atypical glandular components within benign breast parenchyma which were morphologically consistent with metastatic adenocarcinoma. By immunohistochemical staining, it was confirmed that the neoplastic components were immunoreactive to colonic markers and nonreactive to breast markers, thus further supporting the morphologic findings. It is extremely important to make this distinction between primary breast cancer and a metastatic process, in order to provide the most effective and appropriate treatment for the patient and to avoid any harmful or unnecessary surgical procedures. PMID:25883818

  13. Metastatic endometrial endometrioid carcinoma with clear cell changes to the breast: a case report.

    PubMed

    Farghaly, Hanan

    2013-02-01

    Metastasis to breast from extramammary tissue is rare, and endometrial cancer has rarely been reported to metastasize to the breast. An extensive search in the medical literature reveals only 2 cases. They can be easily mistaken for primary breast carcinoma both clinically and radiologically, even with known history of endometrial carcinoma. This report presents a case of a 64-year-old woman who had endometrial carcinoma treated with total hysterectomy and adjuvant radiation and chemotherapy. Three years after the diagnosis, she had evidence of a solitary breast metastasis. To our knowledge, this is the third described case of endometrial cancer metastatic to the breast and the first in which the endometrial carcinoma demonstrates significant clear cell changes. This report is a reminder that although rare, endometrial carcinoma has the potential to metastasize to breast and illustrates how metastatic lesions in the breast can masquerade clinically as a primary carcinoma. Furthermore, essential guidelines necessary to distinguish primary from metastatic lesions in the breast are presented.

  14. Indication of metronomic chemotherapy for metastatic breast cancer: Clinical outcomes and responsive subtypes

    PubMed Central

    KONTANI, KEIICHI; HASHIMOTO, SHIN-ICHIRO; MURAZAWA, CHISA; NORIMURA, SHOKO; TANAKA, HIROAKI; OHTANI, MASAHIRO; FUJIWARA-HONJO, NAOMI; DATE, MANABU; TERAMOTO, KOJI; HOUCHI, HITOSHI; YOKOMISE, HIROYASU

    2016-01-01

    The survival of patients with metastatic breast cancer (MBC) has not improved, despite recent advances in therapeutic strategies. This is mainly due to the fact that cytotoxic agents cannot be administered over a long period, even if they exhibit favorable activity, due to treatment-related side effects or acquisition of tumor resistance to the administered agents. Thus, the development of therapeutic strategies that may be used over a long time period is required to improve survival. We assessed the availability and clinical outcomes of metronomic chemotherapy, which is defined as continuous or frequent treatment with low doses of cytotoxic drugs. A total of 80 patients with MBC received chemotherapy in the metastatic setting, and the clinicopathological factors and clinical outcomes were retrospectively compared between 52 patients who received metronomic regimens and 28 patients who received other cytotoxic regimens. As regards clinical outcomes, the median time-to-treatment failure (TTF) and overall survival (OS) were significantly longer in the metronomic group compared with those in the non-metronomic group (TTF, 15 vs. 4 months, P=0.0001; and OS, 53 vs. 28 months P=0.0012, respectively). In the metronomic group, none of the 18 patients who responded to the regimen had triple-negative (TN) cancer (17 had luminal-type tumors and 1 had a human epidermal factor receptor 2-type tumor). Furthermore, TTF and OS were significantly longer in patients with non-TN cancer compared with those in patients with TN cancer in the metronomic group (TTF, 16 vs. 7 months, P=0.0014; and OS, 108 vs. 20 months, P=0.000007, respectively). The proportion of patients who experienced treatment-related adverse events was significantly lower in the metronomic group compared with that in the non-metronomic group (36.5 vs. 61.5%, respectively; P=0.038). In conclusion, metronomic chemotherapy is a viable option for luminal-type MBC in terms of effectiveness and minimal toxicity, regardless

  15. Tumor-targeting Salmonella typhimurium A1-R arrests growth of breast-cancer brain metastasis.

    PubMed

    Zhang, Yong; Miwa, Shinji; Zhang, Nan; Hoffman, Robert M; Zhao, Ming

    2015-02-20

    Brain metastasis is a morbid, treatment-resistant, end-stage frequent occurrence in breast cancer patients. The aim of this study was to evaluate the efficacy of tumor-targeting Salmonella typhimurium A1-R on breast cancer brain metastases. High brain-metastatic variants of murine 4T1 breast cancer cells expressing red fluorescent protein (RFP) were injected orthotopically in the mammary fat pad in non-transgenic nude mice or in the left ventricle of non-transgenic nude mice and transgenic nude mice expressing nestin-driven green fluorescent protein (ND-GFP). ND-GFP mice express GFP in nascent blood vessels. In the orthotopically-injected mice, the primary tumor was surgically-resected in order to allow brain metastasis to develop. At various time points, the tumors and vasculature in the brain were imaged by confocal and stereo fluorescence microscopy. Some of the breast cancer cells that reached the brain extravasated and grew perivascularly and some of the cells proliferated within the vasculature. S. typhimurium A1-R significantly inhibited brain metastasis in both metastatic models and increased survival of the orthotopically-transplanted, primary-tumor-resected mice (p<0.05). The results of the present study suggest the clinical potential of bacterial therapy of breast cancer brain metastasis.

  16. Circulating Tumor Cells Count and Morphological Features in Breast, Colorectal and Prostate Cancer

    PubMed Central

    Ligthart, Sjoerd T.; Coumans, Frank A. W.; Bidard, Francois-Clement; Simkens, Lieke H. J.; Punt, Cornelis J. A.; de Groot, Marco R.; Attard, Gerhardt; de Bono, Johann S.; Pierga, Jean-Yves; Terstappen, Leon W. M. M.

    2013-01-01

    Background Presence of circulating tumor cells (CTC) in patients with metastatic breast, colorectal and prostate cancer is indicative for poor prognosis. An automated CTC (aCTC) algorithm developed previously to eliminate the variability in manual counting of CTC (mCTC) was used to extract morphological features. Here we validated the aCTC algorithm on CTC images from prostate, breast and colorectal cancer patients and investigated the role of quantitative morphological parameters. Methodology Stored images of samples from patients with prostate, breast and colorectal cancer, healthy controls, benign breast and colorectal tumors were obtained using the CellSearch system. Images were analyzed for the presence of aCTC and their morphological parameters measured and correlated with survival. Results Overall survival hazard ratio was not significantly different for aCTC and mCTC. The number of CTC correlated strongest with survival, whereas CTC size, roundness and apoptosis features reached significance in univariate analysis, but not in multivariate analysis. One aCTC/7.5 ml of blood was found in 7 of 204 healthy controls and 9 of 694 benign tumors. In one patient with benign tumor 2 and another 9 aCTC were detected. Significance of the study CTC can be identified and morphological features extracted by an algorithm on images stored by the CellSearch system and strongly correlate with clinical outcome in metastatic breast, colorectal and prostate cancer. PMID:23826219

  17. Oncology nursing support for safe and effective use of eribulin in metastatic breast cancer.

    PubMed

    Donovan, Diana; Urquhart, Laura; Hopkins, Una; Knight, Sandra; Moore, Laura

    2014-01-01

    Nurse practitioners play important roles in breast cancer prevention, early detection, therapeutic efficacy, and surveillance. Assessment of a patient's health status is part of the nine nurse practitioner core competencies updated in 2012 by the National Organization of Nurse Practitioner Faculties. Although adverse events are common in treatment for metastatic breast cancer (MBC), proactive management strategies can limit the number and/or severity of adverse events. Additionally, knowledge of common metastatic sites and clinical signs/symptoms of recurrence provides one of the first-line strategies for successful treatment. We review five case studies of women with MBC who were managed successfully with eribulin mesylate in late lines of therapy after at least two chemotherapeutic regimens for advanced breast cancer that included both an anthracycline and a taxane in either the adjuvant or metastatic setting. PMID:24855406

  18. Potent efficacy of metronomic topotecan and pazopanib combination therapy in preclinical models of primary or late stage metastatic triple-negative breast cancer

    PubMed Central

    Man, Shan; Bocci, Guido; Kerbel, Robert S.

    2015-01-01

    Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1α and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple-negative breast cancer patients. PMID:26623560

  19. A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

    PubMed

    Blau, C Anthony; Ramirez, Arturo B; Blau, Sibel; Pritchard, Colin C; Dorschner, Michael O; Schmechel, Stephen C; Martins, Timothy J; Mahen, Elisabeth M; Burton, Kimberly A; Komashko, Vitalina M; Radenbaugh, Amie J; Dougherty, Katy; Thomas, Anju; Miller, Christopher P; Annis, James; Fromm, Jonathan R; Song, Chaozhong; Chang, Elizabeth; Howard, Kellie; Austin, Sharon; Schmidt, Rodney A; Linenberger, Michael L; Becker, Pamela S; Senecal, Francis M; Mecham, Brigham H; Lee, Su-In; Madan, Anup; Ronen, Roy; Dutkowski, Janusz; Heimfeld, Shelly; Wood, Brent L; Stilwell, Jackie L; Kaldjian, Eric P; Haussler, David; Zhu, Jingchun

    2016-01-01

    Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs. PMID:26733551

  20. A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

    PubMed

    Blau, C Anthony; Ramirez, Arturo B; Blau, Sibel; Pritchard, Colin C; Dorschner, Michael O; Schmechel, Stephen C; Martins, Timothy J; Mahen, Elisabeth M; Burton, Kimberly A; Komashko, Vitalina M; Radenbaugh, Amie J; Dougherty, Katy; Thomas, Anju; Miller, Christopher P; Annis, James; Fromm, Jonathan R; Song, Chaozhong; Chang, Elizabeth; Howard, Kellie; Austin, Sharon; Schmidt, Rodney A; Linenberger, Michael L; Becker, Pamela S; Senecal, Francis M; Mecham, Brigham H; Lee, Su-In; Madan, Anup; Ronen, Roy; Dutkowski, Janusz; Heimfeld, Shelly; Wood, Brent L; Stilwell, Jackie L; Kaldjian, Eric P; Haussler, David; Zhu, Jingchun

    2016-01-01

    Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs.

  1. A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer

    PubMed Central

    Blau, C. Anthony; Ramirez, Arturo B.; Blau, Sibel; Pritchard, Colin C.; Dorschner, Michael O.; Schmechel, Stephen C.; Martins, Timothy J.; Mahen, Elisabeth M.; Burton, Kimberly A.; Komashko, Vitalina M.; Radenbaugh, Amie J.; Dougherty, Katy; Thomas, Anju; Miller, Christopher P.; Annis, James; Fromm, Jonathan R.; Song, Chaozhong; Chang, Elizabeth; Howard, Kellie; Austin, Sharon; Schmidt, Rodney A.; Linenberger, Michael L.; Becker, Pamela S.; Senecal, Francis M.; Mecham, Brigham H.; Lee, Su-In; Madan, Anup; Ronen, Roy; Dutkowski, Janusz; Heimfeld, Shelly; Wood, Brent L.; Stilwell, Jackie L.; Kaldjian, Eric P.; Haussler, David; Zhu, Jingchun

    2016-01-01

    Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient’s evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs. PMID:26733551

  2. VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity.

    PubMed

    Rao, Meghana; Song, Wenqiang; Jiang, Aixiang; Shyr, Yu; Lev, Sima; Greenstein, David; Brantley-Sieders, Dana; Chen, Jin

    2012-01-01

    VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.

  3. VAMP-Associated Protein B (VAPB) Promotes Breast Tumor Growth by Modulation of Akt Activity

    PubMed Central

    Rao, Meghana; Song, Wenqiang; Jiang, Aixiang; Shyr, Yu; Lev, Sima; Greenstein, David; Brantley-Sieders, Dana; Chen, Jin

    2012-01-01

    VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer. PMID:23049696

  4. Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2016-02-18

    Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

  5. Priming the 'soil' for breast cancer metastasis: the pre-metastatic niche.

    PubMed

    Psaila, Bethan; Kaplan, Rosandra N; Port, Elisa R; Lyden, David

    The long prevailing model of metastasis recognizes the importance of both "seed" and "soil" for metastatic progression [1]. Much attention has focused on understanding the molecular and genetic factors that confer an intrinsic metastatic advantage to certain tumor cells. Meanwhile, changes occurring within distant tissues, creating a "soil" conducive for tumor invasion, have been largely neglected. Bone marrow-derived hematopoietic progenitor cells (HPCs) recently emerged as key players in initiating these early changes, creating a receptive microenvironment at designated sites for distant tumor growth and establishing the "Pre-Metastatic Niche" [2]. This insight into the earliest stages in the metastatic cascade revises our concept of the metastatic "microenvironment" to include physiological cells recruited from the bone marrow. Moreover, the concept of pre-metastatic tissues as 'niches' similar to physiological stem cell niches establishes a paradigm in which disseminated tumor cells may reside within a highly defined microcosm, both supportive and regulatory, and which may confer specific functions on indwelling cells. Understanding the cellular and molecular cross-talk between "seed" and "soil" may further our understanding of the factors that govern both site-specific patterning in metastasis and the phenomenon of tumor dormancy. This may lead to therapeutic strategies to detect and prevent metastasis at its earliest inception.

  6. Experimental Study of Magnetic Multi-Walled Carbon Nanotube-Doxorubicin Conjugate in a Lymph Node Metastatic Model of Breast Cancer

    PubMed Central

    Ji, Jian; Liu, Minfeng; Meng, Yue; Liu, Runqi; Yan, Yan; Dong, Jianyu; Guo, Zhaoze; Ye, Changsheng

    2016-01-01

    Background The lymphatic system plays a significant role in the defense of a subject against breast cancer and is one of the major pathways for the metastasis of breast cancer. To improve the prognosis, many means, including surgery, radiotherapy, and chemotherapy, have been used. However, the combination of all these modalities has limited efficacy. Lymph nodes, therefore, have become an exceptionally potential target organ in cancer chemotherapy. Material/Methods A lymph node metastatic model of breast cancer was established in BALB/c mice. Magnetic multi-walled carbon nanotube carrier with good adsorption and lymph node-targeting capacity was prepared and conjugated with doxorubicin to make the magnetic multi-walled carbon nanotube-doxorubicin suspension. Dispersions of doxorubicin, magnetic multi-walled carbon nanotube-doxorubicin, and magnetic multi-walled carbon nanotube were injected into lymph node metastatic mice to compare their inhibitory effects on tumor cells in vivo. Inhibition of these dispersions on EMT-6 breast cancer cells was detected via MTT assay in vitro. Results Although no significant difference was found between the effects of doxorubicin and magnetic multi-walled carbon nanotube-doxorubicin with the same concentration of doxorubicin on EMT-6 breast cancer cells in vitro, in terms of sizes of metastatic lymph nodes and xenograft tumors, apoptosis in metastatic lymph nodes, and adverse reactions, the magnetic multi-walled carbon nanotube-doxorubicin group differed significantly from the other groups. Conclusions The magnetic multi-walled carbon nanotube-doxorubicin clearly played an inhibitory role in lymph node metastases to EMT-6 breast cancer cells. PMID:27385226

  7. Experimental Study of Magnetic Multi-Walled Carbon Nanotube-Doxorubicin Conjugate in a Lymph Node Metastatic Model of Breast Cancer.

    PubMed

    Ji, Jian; Liu, Minfeng; Meng, Yue; Liu, Runqi; Yan, Yan; Dong, Jianyu; Guo, Zhaoze; Ye, Changsheng

    2016-01-01

    BACKGROUND The lymphatic system plays a significant role in the defense of a subject against breast cancer and is one of the major pathways for the metastasis of breast cancer. To improve the prognosis, many means, including surgery, radiotherapy, and chemotherapy, have been used. However, the combination of all these modalities has limited efficacy. Lymph nodes, therefore, have become an exceptionally potential target organ in cancer chemotherapy. MATERIAL AND METHODS A lymph node metastatic model of breast cancer was established in BALB/c mice. Magnetic multi-walled carbon nanotube carrier with good adsorption and lymph node-targeting capacity was prepared and conjugated with doxorubicin to make the magnetic multi-walled carbon nanotube-doxorubicin suspension. Dispersions of doxorubicin, magnetic multi-walled carbon nanotube-doxorubicin, and magnetic multi-walled carbon nanotube were injected into lymph node metastatic mice to compare their inhibitory effects on tumor cells in vivo. Inhibition of these dispersions on EMT-6 breast cancer cells was detected via MTT assay in vitro. RESULTS Although no significant difference was found between the effects of doxorubicin and magnetic multi-walled carbon nanotube-doxorubicin with the same concentration of doxorubicin on EMT-6 breast cancer cells in vitro, in terms of sizes of metastatic lymph nodes and xenograft tumors, apoptosis in metastatic lymph nodes, and adverse reactions, the magnetic multi-walled carbon nanotube-doxorubicin group differed significantly from the other groups. CONCLUSIONS The magnetic multi-walled carbon nanotube-doxorubicin clearly played an inhibitory role in lymph node metastases to EMT-6 breast cancer cells. PMID:27385226

  8. Experimental Study of Magnetic Multi-Walled Carbon Nanotube-Doxorubicin Conjugate in a Lymph Node Metastatic Model of Breast Cancer.

    PubMed

    Ji, Jian; Liu, Minfeng; Meng, Yue; Liu, Runqi; Yan, Yan; Dong, Jianyu; Guo, Zhaoze; Ye, Changsheng

    2016-07-07

    BACKGROUND The lymphatic system plays a significant role in the defense of a subject against breast cancer and is one of the major pathways for the metastasis of breast cancer. To improve the prognosis, many means, including surgery, radiotherapy, and chemotherapy, have been used. However, the combination of all these modalities has limited efficacy. Lymph nodes, therefore, have become an exceptionally potential target organ in cancer chemotherapy. MATERIAL AND METHODS A lymph node metastatic model of breast cancer was established in BALB/c mice. Magnetic multi-walled carbon nanotube carrier with good adsorption and lymph node-targeting capacity was prepared and conjugated with doxorubicin to make the magnetic multi-walled carbon nanotube-doxorubicin suspension. Dispersions of doxorubicin, magnetic multi-walled carbon nanotube-doxorubicin, and magnetic multi-walled carbon nanotube were injected into lymph node metastatic mice to compare their inhibitory effects on tumor cells in vivo. Inhibition of these dispersions on EMT-6 breast cancer cells was detected via MTT assay in vitro. RESULTS Although no significant difference was found between the effects of doxorubicin and magnetic multi-walled carbon nanotube-doxorubicin with the same concentration of doxorubicin on EMT-6 breast cancer cells in vitro, in terms of sizes of metastatic lymph nodes and xenograft tumors, apoptosis in metastatic lymph nodes, and adverse reactions, the magnetic multi-walled carbon nanotube-doxorubicin group differed significantly from the other groups. CONCLUSIONS The magnetic multi-walled carbon nanotube-doxorubicin clearly played an inhibitory role in lymph node metastases to EMT-6 breast cancer cells.

  9. Breast malignant phyllodes tumor with rare pelvic metastases and long-term overall survival

    PubMed Central

    Shan, Jinlan; Zhang, Shizhen; Wang, Zhen; Fu, Yanbiao; Li, Ling; Wang, Xiaochen

    2016-01-01

    Abstract Background: Malignant phyllodes tumor (PT) is a rare fibro epithelial neoplasm of the breast, which is poor prognosis due to high risk of recurrence and distant metastasis. Methods: We report a case of malignant PT. It had recurred locally five times, and the sixth relapse was occurred 54 months after first diagnosis, presenting a huge pelvic mass (14 cm × 11 cm) by CT scan. Histopathological examination has demonstrated a metastatic phyllodes tumor. After postoperative chemotherapy treatment, a longer survival has been achieved, which is more than 72 months. Results: Our case report describes a breast PT with several local recurrences and a rare metastasis (pelvic cavity), but long-term overall survival was achieved after surgery and chemotherapy. Conclusion: We conclude that trustworthy prognosticators that identify patients with excessive potential of aggressive clinical course should be explored. Moreover, proper treatment could prolong overall survival of metastatic PT patients. PMID:27661051

  10. Application of a Drug-Induced Apoptosis Assay to Identify Treatment Strategies in Recurrent or Metastatic Breast Cancer

    PubMed Central

    Bosserman, Linda; Rogers, Karl; Willis, Carl; Davidson, Dirk; Whitworth, Pat; Karimi, Misagh; Upadhyaya, Gargi; Rutledge, James; Hallquist, Allan; Perree, Mathieu; Presant, Cary A.

    2015-01-01

    Background A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes. Methods In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users), or elect to not use the test (non-users). Results The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73%) used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR) rate compared to non-users (38.1% vs 0%, p = 0.04) and a higher disease control (CR+PR+Stable) rate (81% vs 25%, p<0.01). Time to relapse was longer in users 7.4 mo compared to non-users 2.2 mo (p<0.01). Conclusions The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay. Trial Registration Clinicaltrials.gov NCT

  11. Comprehensive molecular portraits of human breast tumors

    PubMed Central

    2012-01-01

    Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer. PMID:23000897

  12. PERTUZUMAB FOR THE TREATMENT OF PATIENTS WITH PREVIOUSLY UNTREATED HER2-POSITIVE METASTATIC BREAST CANCER

    PubMed Central

    Smith, M.B.; Reardon, J.; Olson, E.M.

    2013-01-01

    SUMMARY Pertuzumab is a humanized monoclonal antibody directed at the dimerization domain of the receptor tyrosine-protein kinase erbB-2 (HER2) receptor. It possesses a unique and complimentary mechanism of action compared to trastuzumab, which has historically been the cornerstone of therapy for HER2-amplified breast cancer. Clinical trials demonstrate improved outcomes, with minimal increases in toxicity with the addition of pertuzumab to trastuzumab in patients with HER2-positive metastatic breast cancer, indicating the advantage of dual HER2 receptor blockade. Pertuzumab is approved as first-line therapy in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer, with future opportunities to investigate its efficacy in other stages of breast cancer, as well as in the treatment of other malignancies. PMID:23170307

  13. Metabolic Plasticity of Metastatic Breast Cancer Cells: Adaptation to Changes in the Microenvironment1

    PubMed Central

    Simões, Rui V.; Serganova, Inna S.; Kruchevsky, Natalia; Leftin, Avigdor; Shestov, Alexander A.; Thaler, Howard T.; Sukenick, George; Locasale, Jason W.; Blasberg, Ronald G.; Koutcher, Jason A.; Ackerstaff, Ellen

    2015-01-01

    Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR) to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of 13C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA) cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS) in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only) > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells), leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1) provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2) lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism. PMID:26408259

  14. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models

    PubMed Central

    Liu, Huiping; Patel, Manishkumar R.; Prescher, Jennifer A.; Patsialou, Antonia; Qian, Dalong; Lin, Jiahui; Wen, Susanna; Chang, Ya-Fang; Bachmann, Michael H.; Shimono, Yohei; Dalerba, Piero; Adorno, Maddalena; Lobo, Neethan; Bueno, Janet; Dirbas, Frederick M.; Goswami, Sumanta; Somlo, George; Condeelis, John; Contag, Christopher H.; Gambhir, Sanjiv Sam; Clarke, Michael F.

    2010-01-01

    To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. These advances in BCSC imaging revealed that CD44+ cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. PMID:20921380

  15. The CT20 peptide causes detachment and death of metastatic breast cancer cells by promoting mitochondrial aggregation and cytoskeletal disruption

    PubMed Central

    Lee, M W; Bassiouni, R; Sparrow, N A; Iketani, A; Boohaker, R J; Moskowitz, C; Vishnubhotla, P; Khaled, A S; Oyer, J; Copik, A; Fernandez-Valle, C; Perez, J M; Khaled, A R

    2014-01-01

    Metastasis accounts for most deaths from breast cancer, driving the need for new therapeutics that can impede disease progression. Rationally designed peptides that take advantage of cancer-specific differences in cellular physiology are an emerging technology that offer promise as a treatment for metastatic breast cancer. We developed CT20p, a hydrophobic peptide based on the C terminus of Bax that exhibits similarities with antimicrobial peptides, and previously reported that CT20p has unique cytotoxic actions independent of full-length Bax. In this study, we identified the intracellular actions of CT20p which precede cancer cell-specific detachment and death. Previously, we found that CT20p migrated in the heavy membrane fractions of cancer cell lysates. Here, using MDA-MB-231 breast cancer cells, we demonstrated that CT20p localizes to the mitochondria, leading to fusion-like aggregation and mitochondrial membrane hyperpolarization. As a result, the distribution and movement of mitochondria in CT20p-treated MDA-MB-231 cells was markedly impaired, particularly in cell protrusions. In contrast, CT20p did not associate with the mitochondria of normal breast epithelial MCF-10A cells, causing little change in the mitochondrial membrane potential, morphology or localization. In MDA-MB-231 cells, CT20p triggered cell detachment that was preceded by decreased levels of α5β1 integrins and reduced F-actin polymerization. Using folate-targeted nanoparticles to encapsulate and deliver CT20p to murine tumors, we achieved significant tumor regression within days of peptide treatment. These results suggest that CT20p has application in the treatment of metastatic disease as a cancer-specific therapeutic peptide that perturbs mitochondrial morphology and movement ultimately culminating in disruption of the actin cytoskeleton, cell detachment, and loss of cell viability. PMID:24853427

  16. Combining capecitabine and bevacizumab in metastatic breast cancer: a comprehensive review.

    PubMed

    Miles, David; Zielinski, Christoph; Martin, Miguel; Vrdoljak, Eduard; Robert, Nicholas

    2012-03-01

    Both capecitabine and bevacizumab are established agents in the treatment of metastatic breast cancer, but until recently clinical data supporting their use in combination were limited. We review available data on the capecitabine-bevacizumab combination in breast cancer, particularly results from the RIBBON-1 trial in the first-line setting, and we discuss these findings in light of previous studies. We also examine ongoing trials investigating capecitabine-bevacizumab combination therapy. PMID:22257791

  17. The inhibitory effect of roasted licorice extract on human metastatic breast cancer cell-induced bone destruction.

    PubMed

    Lee, Sun Kyoung; Park, Kwang-Kyun; Park, Jung Han Yoon; Lim, Soon Sung; Chung, Won-Yoon

    2013-12-01

    The aim of this study was to determine whether the ethanol extract of roasted licorice (rLE) could inhibit breast cancer-mediated bone destruction. rLE treatment reduced the viability of MDA-MB-231 human metastatic breast cancer cells but did not show any cytotoxicity in hFOB1.19 human osteoblastic cells and murine bone marrow-derived macrophages (BMMs). rLE inhibited expression and secretion of receptor activator of nuclear factor κB ligand (RANKL) as well as the mRNA and protein expression of cyclooxygenase-2 in osteoblastic cells exposed to the conditioned medium of breast cancer cells. rLE dramatically inhibited RANKL-induced osteoclastogenesis in BMMs, thereby reducing osteoclast-mediated pit formation. Moreover, treatment with licochalcone A and isoliquiritigenin as the active components, whose contents are increased by the roasting process, remarkably suppressed RANKL-induced osteoclast formation in BMMs, respectively. Furthermore, orally administered rLE substantially blocked tumor growth and bone destruction in mice inoculated with breast cancer cells in the tibiae. Serum levels of tartrate-resistant acid phosphatase and C-terminal cross-linking telopeptide of type I collagen and trabecular bone morphometric parameters were reversed to almost the same levels as the control mice by the rLE treatment. In conclusion, rLE may be a beneficial agent for preventing and treating bone destruction in patients with breast cancer.

  18. Magnetic Fluorescent Nanoformulation for Intracellular Drug Delivery to Human Breast Cancer, Primary Tumors, and Tumor Biopsies: Beyond Targeting Expectations.

    PubMed

    El-Boubbou, Kheireddine; Ali, Rizwan; Bahhari, Hassan M; AlSaad, Khaled O; Nehdi, Atef; Boudjelal, Mohamed; AlKushi, Abdulmohsen

    2016-06-15

    We report the development of a chemotherapeutic nanoformulation made of polyvinylpyrrolidone-stabilized magnetofluorescent nanoparticles (Fl-PMNPs) loaded with anticancer drugs as a promising drug carrier homing to human breast cancer cells, primary tumors, and solid tumors. First, nanoparticle uptake and cell death were evaluated in three types of human breast cells: two metastatic cancerous MCF-7 and MDA-MB-231 cells and nontumorigenic MCF-10A cells. While Fl-PMNPs were not toxic to cells even at the highest concentrations used, Dox-loaded Fl-PMNPs showed significant potency, effectively killing the different breast cancer cells, albeit at different affinities. Interestingly and superior to free Dox, Dox-loaded Fl-PMNPs were found to be more effective in killing the metastatic cells (2- to 3-fold enhanced cytotoxicities for MDA-MB-231 compared to MCF-7), compared to the normal noncancerous MCF-10A cells (up to 8-fold), suggesting huge potentials as selective anticancer agents. Electron and live confocal microscopy imaging mechanistically confirmed that the nanoparticles were successfully endocytosed and packaged into vesicles inside the cytoplasm, where Dox is released and then translocated to the nucleus exerting its cytotoxic action and causing apoptotic cell death. Furthermore, commendable and enhanced penetration in 3D multilayered primary tumor cells derived from primary lesions as well as in patient breast tumor biopsies was observed, killing the tumor cells inside. The designed nanocarriers described here can potentially open new opportunities for breast cancer patients, especially in theranostic imaging and hyperthermia. While many prior studies have focused on targeting ligands to specific receptors to improve efficacies, we discovered that even with passive-targeted tailored delivery system enhanced toxic responses can be attained. PMID:27269304

  19. Magnetic Fluorescent Nanoformulation for Intracellular Drug Delivery to Human Breast Cancer, Primary Tumors, and Tumor Biopsies: Beyond Targeting Expectations.

    PubMed

    El-Boubbou, Kheireddine; Ali, Rizwan; Bahhari, Hassan M; AlSaad, Khaled O; Nehdi, Atef; Boudjelal, Mohamed; AlKushi, Abdulmohsen

    2016-06-15

    We report the development of a chemotherapeutic nanoformulation made of polyvinylpyrrolidone-stabilized magnetofluorescent nanoparticles (Fl-PMNPs) loaded with anticancer drugs as a promising drug carrier homing to human breast cancer cells, primary tumors, and solid tumors. First, nanoparticle uptake and cell death were evaluated in three types of human breast cells: two metastatic cancerous MCF-7 and MDA-MB-231 cells and nontumorigenic MCF-10A cells. While Fl-PMNPs were not toxic to cells even at the highest concentrations used, Dox-loaded Fl-PMNPs showed significant potency, effectively killing the different breast cancer cells, albeit at different affinities. Interestingly and superior to free Dox, Dox-loaded Fl-PMNPs were found to be more effective in killing the metastatic cells (2- to 3-fold enhanced cytotoxicities for MDA-MB-231 compared to MCF-7), compared to the normal noncancerous MCF-10A cells (up to 8-fold), suggesting huge potentials as selective anticancer agents. Electron and live confocal microscopy imaging mechanistically confirmed that the nanoparticles were successfully endocytosed and packaged into vesicles inside the cytoplasm, where Dox is released and then translocated to the nucleus exerting its cytotoxic action and causing apoptotic cell death. Furthermore, commendable and enhanced penetration in 3D multilayered primary tumor cells derived from primary lesions as well as in patient breast tumor biopsies was observed, killing the tumor cells inside. The designed nanocarriers described here can potentially open new opportunities for breast cancer patients, especially in theranostic imaging and hyperthermia. While many prior studies have focused on targeting ligands to specific receptors to improve efficacies, we discovered that even with passive-targeted tailored delivery system enhanced toxic responses can be attained.

  20. Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis

    PubMed Central

    Calvo, A; Catena, R; Noble, MS; Carbott, D; Gil-Bazo, I; Gonzalez-Moreno, O; Huh, J-I; Sharp, R; Qiu, T-H; Anver, MR; Merlino, G; Dickson, RB; Johnson, MD; Green, JE

    2009-01-01

    Metastasis is the primary cause of death in patients with breast cancer. Overexpression of c-myc in humans correlates with metastases, but transgenic mice only show low rates of micrometastases. We have generated transgenic mice that overexpress both c-myc and vascular endothelial growth factor (VEGF) (Myc/VEGF) in the mammary gland, which develop high rates of pulmonary macrometastases. Gene expression profiling revealed a set of deregulated genes in Myc/VEGF tumors compared to Myc tumors associated with the increased metastatic phenotype. Cross-comparisons between this set of genes with a human breast cancer lung metastasis gene signature identified five common targets: tenascin-C (TNC), matrix metalloprotease-2, collagen-6-A1, mannosidase-α-1A and HLA-DPA1. Signaling blockade or knockdown of TNC in MDA-MB-435 cells resulted in a significant impairment of cell migration and anchorage-independent cell proliferation. Mice injected with clonal MDA-MB-435 cells with reduced expression of TNC demonstrated a significant decrease (P < 0.05) in (1) primary tumor growth; (2) tumor relapse after surgical removal of the primary tumor and (3) incidence of lung metastasis. Our results demonstrate that VEGF induces complex alterations in tissue architecture and gene expression. The TNC signaling pathway plays an important role in mammary tumor growth and metastases, suggesting that TNC may be a relevant target for therapy against metastatic breast cancer. PMID:18504437

  1. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis.

    PubMed

    Pollari, Sirkku; Käkönen, Sanna-Maria; Edgren, Henrik; Wolf, Maija; Kohonen, Pekka; Sara, Henri; Guise, Theresa; Nees, Matthias; Kallioniemi, Olli

    2011-01-01

    Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, an understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidences for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L: -serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L: -serine in mammalian tissues. Consistently, we observed that the proliferation of MDA-MB-231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L: -serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L: -serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions.

  2. Total En Bloc Spondylectomy for Primary and Metastatic Spine Tumors.

    PubMed

    Mesfin, Addisu; El Dafrawy, Mostafa H; Jain, Amit; Hassanzadeh, Hamid; Kebaish, Khaled M

    2015-11-01

    This study reports the surgical and clinical outcomes of spinal tumors managed with total en bloc spondylectomy. The authors searched their prospectively maintained database for patients undergoing total en bloc spondylectomy between 2001 and 2013. Ten patients (9 men, 1 woman; average age, 50.7 years; range, 42-68 years) were identified. The authors obtained demographic information, surgical outcomes (estimated blood loss, complications), and clinical outcomes (recurrence, survival). All patients had pain and were classified as American Spinal Injury Association grade E. The lesions were located in the thoracic (8 patients) and lumbar (2 patients) spine. Anterior column reconstruction was performed with strut allograft (7 patients), mesh cage (2 patients), and polymethyl methacrylate (1 patient). An average of 2.3 (range, 2-4) of 6 portions of the vertebrae were involved, according to the Kostuik classification. Mean estimated blood loss, operative time, and hospital stay were 3.5 L, 500 minutes, and 7.8 days, respectively. Perioperative complications included pleural tear (2 patients) and aortic tear, vena cava tear, retained sponge, pulmonary embolism, urinary tract infection, pneumothorax, anterior column support failure, and prominent instrumentation requiring removal (1 patient each). Postoperatively, all patients remained classified as American Spinal Injury Association grade E. Two patients had recurrence at distant spinal segments, and 1 had a new lesion in the thigh. Five patients had died (mean, 34.5 months after surgery), and 5 were alive a mean of 19.6 months after surgery (range, 6-48 months). Total en bloc spondylectomy is challenging, but in appropriately selected patients, it can be used to treat primary and metastatic spinal lesions.

  3. Autocrine control of MIP-2 secretion from metastatic breast cancer cells is mediated by CXCR2: a mechanism for possible resistance to CXCR2 antagonists.

    PubMed

    Erin, Nuray; Nizam, Esra; Tanrıöver, Gamze; Köksoy, Sadi

    2015-02-01

    CXCR2 interacts with a wide range of chemokines and CXCR2 antagonists may have therapeutic value for treatment-resistant metastatic carcinomas. We aimed to explore regulation of activity of CXCR2 and its ligand, MIP-2, in metastatic breast carcinoma. We used mouse breast carcinoma cells metastasize to brain (4TBM), liver (4TLM), and heart (4THM) and explored the extra- and intracellular mechanisms effecting MIP-2 secretion using CXCR2 antagonist and inhibitors of downstream signaling molecules. 4TBM, 4TLM, and 4THM cells include cancer stem cell features and metastasize extensively. We also determined kinetics of MIP-2 secretion in 4T1 and non-metastatic 67NR mouse breast carcinoma cells. We found that there is an autocrine-inhibition of MIP-2 secretion. Specifically, metastatic cells selectively express CXCR2 only, and not CXCR1 and attenuating CXCR2 activity with SB225002 increased MIP-2 secretion. This may be due to the inhibition of protein kinase C (PKC) activity since RO318220; a specific inhibitor of PKC also increased MIP-2 secretion. Attenuating CXCR2 activity with SB225002, otherwise suppressed proliferation of 4THM and 4TBM cells. Tumor explants and cancer-associated fibroblasts obtained from 4TLM, 4THM, and 4TBM primary tumors secreted high levels of MIP-2. Surprisingly, CXCR2 expression was low in 4TLM cells demonstrating that liver metastatic cells might be resistant to the anti-tumoral effects of CXCR2 antagonists. Our results demonstrated that resistance to anti-proliferative effects of CXCR2 may also arise from feedback increases in MIP-2 secretion. Activation of PI3 K pathway augments MIP-2 secretion, hence possible resistance to the antitumor effects of CXCR2 antagonists might be prevented with inhibitors of PI3 K.

  4. Overexpression of Metastatic Related MicroRNAs, Mir-335 and Mir-10b, by Staphylococcal Enterotoxin B in the Metastatic Breast Cancer Cell Line

    PubMed Central

    Heidary, Mohammad Foad; Mahmoodzadeh Hosseini, Hamideh; Mehdizadeh Aghdam, Elnaz; Nourani, Mohammad Reza; Ranjbar, Reza; Mirnejad, Reza; Imani Fooladi, Abbas Ali

    2015-01-01

    Purpose: One of the advanced cancer therapy strategies is immune-stimulating compound based immunotherapy Staphylococcal enterotoxin B (SEB) is one of the potent superantigens, which can efficiently activate antitumor immune response to eradicate tumor growth and inhibit metastasis. Herein, we evaluated the effect of SEB on the expression of two master microRNAs, mir-335 and mir-10b, involved in metastasis. Methods: A metastatic breast cancer cell line MDA-MB231was treated with four different concentrations of SEB, including 10, 102, 103 and 104 ng/ml, for 24 and 48 hours. To identify the cytotoxic effect of SEB, treated cells were examined by MTT assay. The stem loop RT-PCR (TaqMan) was used to analyze the mir-335 and mir-10b expression. Results: Results showed that SEB significantly increased the expression of mir-335 both after 24 and 48 hours (pv < 0.001 and pv < 0.05, respectively). No significant differences were found in the mir-10b expression. Conclusion: Moreover, our findings demonstrated no cytotoxic effect of SEB on the treated cells. Our results suggest that SEB probably induces its anti-metastatic effect via the expression regulation of the main genes which contributes to metastasis. PMID:26236665

  5. Estrium Whey induced hepatitis in a patient with metastatic breast cancer: Case report

    PubMed Central

    Velasco, Maria Jose; Molina, Julian

    2012-01-01

    Estrium Whey is an alternative nutritional support therapy for women. It’s enhanced with specific nutrients including phytoestrogens, folate, antioxidants and fiber to support healthy estrogen detoxification and hormone balance. We describe the first case of hepatotoxicity due to Estrium Whey in a 51-year old female with metastatic breast cancer with clinical, laboratory and histopathological changes. PMID:23355919

  6. Transcriptional regulation of tenascin-W by TGF-beta signaling in the bone metastatic niche of breast cancer cells.

    PubMed

    Chiovaro, Francesca; Martina, Enrico; Bottos, Alessia; Scherberich, Arnaud; Hynes, Nancy E; Chiquet-Ehrismann, Ruth

    2015-10-15

    Tenascin-W is a matricellular protein with a dynamically changing expression pattern in development and disease. In adults, tenascin-W is mostly restricted to stem cell niches, and is also expressed in the stroma of solid cancers. Here, we analyzed its expression in the bone microenvironment of breast cancer metastasis. Osteoblasts were isolated from tumor-free or tumor-bearing bones of mice injected with MDA-MB231-1833 breast cancer cells. We found a fourfold upregulation of tenascin-W in the osteoblast population of tumor-bearing mice compared to healthy mice, indicating that tenascin-W is supplied by the bone metastatic niche. Transwell and co-culture studies showed that human bone marrow stromal cells (BMSCs) express tenascin-W protein after exposure to factors secreted by MDA-MB231-1833 breast cancer cells. To study tenascin-W gene regulation, we identified and analyzed the tenascin-W promoter as well as three evolutionary conserved regions in the first intron. 5'RACE analysis of mRNA from human breast cancer, glioblastoma and bone tissue showed a single tenascin-W transcript with a transcription start site at a noncoding first exon followed by exon 2 containing the ATG translation start. Site-directed mutagenesis of a SMAD4-binding element in proximity of the TATA box strongly impaired promoter activity. TGFβ1 induced tenascin-W expression in human BMSCs through activation of the TGFβ1 receptor ALK5, while glucocorticoids were inhibitory. Our experiments show that tenascin-W acts as a niche component for breast cancer metastasis to bone by supporting cell migration and cell proliferation of the cancer cells.

  7. Targeted Delivery of MicroRNA125a-5p by Engineered Lipid Nanoparticles for the Treatment of HER2 Positive Metastatic Breast Cancer.

    PubMed

    Hayward, Stephen L; Francis, David M; Kholmatov, Parviz; Kidambi, Srivatsan

    2016-03-01

    MicroRNAs (miRNAs) are endogenous regulators of gene expression that play a pivotal role in biological processes spanning from global homeostasis to disease onset and progression. The ability to manipulate and induce cellular reequilibrium of deregulated miRNA expression profiles by inhibition of oncogenic miRNA or overexpression of tumor suppressor miRNA is a promising cancer strategy, but is currently hindered in application by the lack of nonviral delivery systems. Here we present a lipid nanoparticle (LNP) platform surface coated with Hyaluronic Acid (HA) for the delivery of mature tumor suppressor MicroRNA125a-5p to treat HER2 positive metastatic breast cancer. The delivery platform actively targets patient-derived metastatic breast cancer cells (21MT-1) isolated from the metastatic pleural effusion over normal breast tissue via an intrinsic HA-CD44 mediated endocytosis event, and has the ability to escape from the intracellular endolysosomal pathway for potent gene silencing. Knockdown of the HER2 proto-oncogene at the level of transcription and translation was achieved following HA-LNP mediated transfection with MicroRNA125a-5p. In addition, the PI3K/AKT and MAPK hyperactivated signaling pathways, cellular proliferation, and migration potential were also potently suppressed. Furthermore, the therapeutic efficacy of MicroRNA125a-5p by the HA-LNP platform was demonstrated to be significantly improved as compared to a commercial transfection reagent. This study highlights the therapeutic potential of MicroRNA125a-5p as a standalone treatment of HER2+ metastatic breast cancer via a translational nonviral delivery platform. These findings have major implications on future gene therapy regimens for breast cancer.

  8. Concordant HER2 status between metastatic breast cancer cells in CSF and primary breast cancer tissue.

    PubMed

    Park, In Hae; Kwon, Youngmee; Ro, Jae Y; Lee, Keun Seok; Ro, Jungsil

    2010-08-01

    It is not known whether the HER2 status of malignant CSF cells coincides with that of the original breast carcinoma cells. We investigated whether CSF cytology specimens were suitable to evaluate HER2 status by fluorescence in situ hybridization (FISH) in patient with leptomeningeal metastasis (LM). Both formalin-fixed paraffin-embedded (FFPE) breast cancer tissue and liquid based CSF cytology specimens were evaluated for HER2 status in 16 patients with LM. We evaluated HER2 gene amplification using FISH on destained CSF cytology slides containing a minimum of 20 malignant cells per slide, and compared these with the HER2 status by immunohistochemistry (IHC) or FISH in FFPE tissues. HER2 was considered positive when the HER2:CEP17 ratio was >or=2.0 or IHC 3+. Of 16 cases, four were HER2 positive and 12 were HER2 negative by FISH analysis in CSF cytology. All CSF-positive cases were HER2 positive by IHC in FFPE tissue. Of 12 HER2 FISH-negative cases in CSF cytology, 10 were HER2 negative (IHC 0 or 1+) and two were IHC 2+ in FFPE tissue. Two IHC 2+ cases had HER2:CEP17 ratios of 1.27 and 2.1, respectively, by FISH in FFPE tissue. As a result, the HER2 status concordance rate between metastatic breast cancer cells in CSF and FFPE primary tissue by IHC and FISH was very high. When CSF cytology specimens were appropriately prepared and had adequate cellularity without dry artifacts, the CSF cytology was suitable to evaluate HER2 status by FISH analysis in patients with LM.

  9. 'Inflammatory breast cancer' due to metastatic adenocarcinoma of lung.

    PubMed

    Ninan, Jacob; Naik, Vinay; George, Gemy Maria

    2016-01-01

    A 67-year-old woman with a history of lung adenocarcinoma presented with 3 weeks of redness, pain, swelling and skin changes in her right breast. Her vital signs and physical examination were within physiological limits except for the right breast. She had extensive red streaks radiating from the right nipple with peau d'orange appearance of her overlying skin. Her breast was tender on examination and did not have any associated cervical or axillary lymphadenopathy. Her mammography revealed thickening of the skin, increased parenchymal markings and shrinkage the breast. Multiple skin biopsies demonstrated moderately differentiated lung adenocarcinoma with lymphovascular invasion. The patient made an informed decision to undergo radiotherapy following discussion with her oncologist and breast surgeon. She succumbed to her illness 2 months after the diagnosis of metastasis to her breast. PMID:27587745

  10. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells.

    PubMed

    Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi; Shah, Khalid

    2015-06-01

    Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications.

  11. Imaging changes following stereotactic radiosurgery for metastatic intracranial tumors: differentiating pseudoprogression from tumor progression and its effect on clinical practice

    PubMed Central

    Kleinberg, Lawrence; Rigamonti, Daniele

    2014-01-01

    Stereotactic radiosurgery has become standard adjuvant treatment for patients with metastatic intracranial lesions. There has been a growing appreciation for benign imaging changes following radiation that are difficult to distinguish from true tumor progression. These imaging changes, termed pseudoprogression, carry significant implications for patient management. In this review, we discuss the current understanding of pseudoprogression in metastatic brain lesions, research to differentiate pseudoprogression from true progression, and clinical implications of pseudoprogression on treatment decisions. PMID:24233257

  12. Metastatic Male Ductal Breast Cancer Mimicking Obstructing Primary Colon Cancer

    PubMed Central

    Koleilat, Issam; Syal, Anil; Hena, Muhammad

    2010-01-01

    Male breast cancer comprises only about 1% of all breast cancers. Commonly, sites of metastases include the central nervous system, lungs, bones, and even liver. In females, extrahepatic gastrointestinal metastases are unusual but have been reported with various clinical presentations. We are reporting the first case of a male patient with a history of ductal breast carcinoma that developed colonic metastasis and presented with mechanical large bowel obstruction masquerading as primary colon cancer. PMID:23675178

  13. [Two Surgical Techniques for Metastatic Brain Tumors:Minimum Resection and Removal with Safety Margin].

    PubMed

    Nakasu, Yoko; Mitsuya, Koichi; Hayashi, Nakamasa; Ito, Ichiro

    2016-03-01

    Successful resection of cerebral metastases is based on good basic neurosurgical techniques, in conjunction with technologies for tumor localization. A clear understanding about the border zone pathology of metastatic lesions leads to two different techniques for safe and effective tumor removal. There is no capsule or pseudocapsule around the metastatic brain tumors. The border zone is widely heterogeneous, especially in lesions after stereotactic irradiation. Resection can be performed in a circumferential and en bloc fashion with sufficient safety margin of the normal brain in non-eloquent area. However, enucleation should be done without surrounding brain damage in and near eloquent areas.

  14. Diarrhoea Caused by Diffuse Metastatic Lobular Breast Cancer

    PubMed Central

    Bakker, Sjoerd F.; Moolenaar, Willem; van Santen, Marije M.; Hendriks, Mathijs P.

    2016-01-01

    A 70-year-old woman with a history of lobular breast cancer presented to our Outpatient Clinic with diarrhoea for the past 3 years. Clinical examination and laboratory research were normal. Colonoscopy showed diffuse mild erythema and a decreased vascular pattern. Biopsies from the ascending colon, transverse colon, and descending colon showed metastases of lobular breast carcinoma. Although gastrointestinal metastases are rare in breast cancer, our case emphasizes the need for further diagnostic efforts in patients with gastrointestinal symptoms and a history of breast carcinoma. PMID:27313924

  15. Emerging drug discovery approaches for selective targeting of “precursor” metastatic breast cancer cells: highlights and perspectives

    PubMed Central

    AAlaoui-Jamali, Moulay; Bijian, Krikor; Batist, Gerald

    2011-01-01

    Breast cancer is a prevalent disease and a major cause of morbidity and cancer-related deaths among women worldwide. A significant number of patients at the time of primary diagnosis present metastatic disease, at least to locoregional lymph nodes, which results in somewhat unpredictable prognosis that often prompts adjuvant systemic therapies of various kinds. The time course of distant recurrence is also unpredictable with some patients sustaining a recurrence within months after diagnosis, even during adjuvant treatments, while others can experience recurrence years or decades after initial diagnosis. To date, clinically approved therapeutics yielded marginal benefits for patients with systemic metastatic breast disease, since despite high clinical responses to various therapies, the patients virtually always become resistant and tumor relapses. Molecular profiling studies established that breast cancer is highly heterogeneous and encompasses diverse histological and molecular subtypes with distinct biological and clinical implications in particular in relation to the incidence of progression to metastasis. The latter has been recognized to result from late genetic events during the multistep progression proposed by the dominant theory of carcinogenesis. However, there is evidence that the dissemination of primary cancer can also be initiated at a very early stage of cancer development, originating from rare cell variants, possibly cancer stem-like cells (CSC), with invasive potential. These precursor metastatic cancer cells with stem-like properties are defined by their ability to self-renew and to regenerate cell variants, which have high plasticity and intrinsic invasive properties required for dissemination and tropism toward specific organs. Equally relevant to the CSC hypothesis for metastasis formation is the epithelial-mesenchymal transition (EMT) process, which is critical for the acquisition of cancer cell invasive behavior and for selection/gain of

  16. Tumor progression: analysis of the instability of the metastatic phenotype, sensitivity to radiation and chemotherapy

    SciTech Connect

    Welch, D.R.

    1984-01-01

    The major complications for tumor therapy are 1) tumor spread (metastasis); 2) the mixed nature of tumors (heterogeneity); and 3) the capacity of tumors to evolve (progress). To study these tumor characteristics, the rat 13762NF mammary adenocarcinoma was cloned and studied for metastatic properties and sensitivities to therapy (chemotherapy, radiation and hyperthermia). The cell clones were heterogeneous and no correlation between metastatic potential and therapeutic sensitivities was observed. Further, these phenotypes were unstable during pasage in vitro; yet, the changes were clone dependent and reproducible using different cryoprotected cell stocks. To understand the phenotypic instability, subclones were isolated from low and high passage cell clones. The results demonstrated that 1) tumor cells are heterogeneous for multiple phenotypes; 2) tumor cells are unstable for multiple phenotypes; 3) the magnitude, direction and time of occurrence of phenotypic drift is clone dependent; 4) the sensitivity of cell clones to ionizing radiation (..gamma.. or heat) and chemotherapy agents is independent of their metastatic potential; 5) shifts in metastatic potential and sensitivity to therapy may occur simultaneously but are not linked; and 6) tumor cells independently diverge to form several subpopulations with unique phenotypic profiles.

  17. Management of an invasive and metastatic Sertoli cell tumor with associated myelotoxicosis in a dog

    PubMed Central

    Withers, Sita S.; Lawson, Corinne M.; Burton, Andrew G.; Rebhun, Robert B.; Steffey, Michele A.

    2016-01-01

    We describe the surgical and post-operative management of a large, invasive, and metastatic functional Sertoli cell tumor in a 9-year-old cryptorchid male Labrador retriever dog. Despite residual disease after surgery, bone marrow recovery occurred without administration of bone marrow stimulants and serum estradiol accurately predicted tumor recurrence. PMID:26933269

  18. Tumor attributes predicting cutaneous metastatic destiny: a report of two interesting cases.

    PubMed

    Gurumurthi, Ravichandran; Thirumalai, Raja; Easow, Jose M; Mohan, Subhashini

    2014-07-01

    Cutaneous metastases are the result of complex interaction between the tumor cells ("seed") and the host environment ("soil"). Metastases to the skin can be an early sign of internal malignancy or represent recurrence of the primary tumor and portends a poorer prognosis. Invasion and metastasis are the hallmarks of on cogenesis. Skin is the largest organ in the body, but the incidence of metastases is low. With advances in molecular biology, factors responsible for the initiation and perpetuation of metastatic tumor cells at distant sites are being elucidated. The concept of "pre-metastatic niche" and interaction between various chemokines has given a new outlook in understanding the organ specificity of metastatic tumor cells. We present two cases of cutaneous metastases with interesting clinical findings correlating with its biologic subtypes.

  19. Optical Detection and Virotherapy of Live Metastatic Tumor Cells in Body Fluids with Vaccinia Strains

    PubMed Central

    Minev, Boris R.; Zimmermann, Martina; Aguilar, Richard J.; Zhang, Qian; Sturm, Julia B.; Fend, Falko; Yu, Yong A.; Cappello, Joseph; Lauer, Ulrich M.; Szalay, Aladar A.

    2013-01-01

    Metastatic tumor cells in body fluids are important targets for treatment, and critical surrogate markers for evaluating cancer prognosis and therapeutic response. Here we report, for the first time, that live metastatic tumor cells in blood samples from mice bearing human tumor xenografts and in blood and cerebrospinal fluid samples from patients with cancer were successfully detected using a tumor cell-specific recombinant vaccinia virus (VACV). In contrast to the FDA-approved CellSearch system, VACV detects circulating tumor cells (CTCs) in a cancer biomarker-independent manner, thus, free of any bias related to the use of antibodies, and can be potentially a universal system for detection of live CTCs of any tumor type, not limited to CTCs of epithelial origin. Furthermore, we demonstrate for the first time that VACV was effective in preventing and reducing circulating tumor cells in mice bearing human tumor xenografts. Importantly, a single intra-peritoneal delivery of VACV resulted in a dramatic decline in the number of tumor cells in the ascitic fluid from a patient with gastric cancer. Taken together, these results suggest VACV to be a useful tool for quantitative detection of live tumor cells in liquid biopsies as well as a potentially effective treatment for reducing or eliminating live tumor cells in body fluids of patients with metastatic disease. PMID:24019862

  20. Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth

    PubMed Central

    Adamo, Hanibal; Thysell, Elin; Jernberg, Emma; Stattin, Pär; Widmark, Anders; Wikström, Pernilla; Bergh, Anders

    2016-01-01

    Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer. PMID:27280718

  1. Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism.

    PubMed

    Sartorius, C A; Hanna, C T; Gril, B; Cruz, H; Serkova, N J; Huber, K M; Kabos, P; Schedin, T B; Borges, V F; Steeg, P S; Cittelly, D M

    2016-06-01

    Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02-fold, P<0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These

  2. Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer.

    PubMed

    Herman, Joseph M; Hoffman, John P; Thayer, Sarah P; Wolff, Robert A

    2015-05-01

    New combinations of cytotoxic chemotherapy have been proven to increase response rates and survival times compared with single-agent gemcitabine for patients with metastatic pancreatic cancer. These responses have been dramatic for a subset of patients, therefore raising questions about the management of limited metastatic disease with surgery or other ablative methods. Similarly, for patients having a complete radiographic response to chemotherapy in the metastatic compartment, whether to consider local therapy in the form of radiation or surgery for the primary tumor is now an appropriate question. Therefore, collaboration among experts in surgery, medical oncology, and radiation oncology has led to the development of guiding principles for local therapies to the primary intact pancreatic tumor for patients with limited metastatic disease and those who have had a significant response after systemic therapy.

  3. Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes.

    PubMed

    Tabariès, Sébastien; Dupuy, Fanny; Dong, Zhifeng; Monast, Anie; Annis, Matthew G; Spicer, Jonathan; Ferri, Lorenzo E; Omeroglu, Atilla; Basik, Mark; Amir, Eitan; Clemons, Mark; Siegel, Peter M

    2012-08-01

    We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes.

  4. Radium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone

    PubMed Central

    2014-01-01

    Background Hormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo. Methods The US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer. Results A 44-year-old white woman with metastatic breast cancer who was estrogen receptor–positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in 18F-FDG PET/CT and 18F-NaF bone PET/CT. The patient derived clinical benefit from therapy. Conclusion We have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA–approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a

  5. Exogenous regucalcin suppresses the proliferation of human breast cancer MDA-MB-231 bone metastatic cells in vitro.

    PubMed

    Yamaguchi, Masayoshi; Murata, Tomiyasu

    2015-11-01

    Regucalcin serves a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. The regucalcin gene, which is localized on the X chromosome, consists of seven exons and six introns. Reductions in the gene expression of regucalcin have been suggested to serve a role in hepatocarcinogenesis in animal models and human patients, indicating a potential role as a suppressor protein in cancer. The aim of the current study was to investigate the effect of exogenous regucalcin on cell proliferation in the cloned human breast cancer MDA‑MB‑231 bone metastatic cell line in vitro. The proliferation of MDA‑MB‑231 cells was suppressed following the addition of regucalcin (0.1‑10 nM) in vitro. The suppression of proliferation was not enhanced in the presence of tumor necrosis factor‑α, PD98059, staurosporine, Bay K8644, wortmannin, 5,6‑dichloro‑1‑β‑D‑ribofuranosylbenzimidazole or gemcitabine. Exogenous regucalcin did not induce cell death in MDA‑MB‑231 cells in vitro. These data suggest that exogenous regucalcin possesses suppressive effects on the proliferation of human breast cancer MDA‑MB‑231 bone metastatic cells, and that this effect may be mediated through various intracellular signaling pathways in vitro. Exogenous regucalcin is suggested to function as a suppressor in cancer cell proliferation.

  6. [Early detection of leptomeningeal metastasis in patients with metastatic breast carcinoma: validation of CA 15-3 measurement in cerebrospinal fluid].

    PubMed

    Gauchez, A-S; Pez, E; Boutonnat, J; Bourre, J-C; Pelletier, L; Payan, R; Mousseau, M

    2007-01-01

    Fifteen per cent of metastatic breast cancer will develop symptomatic leptomeningeal metastases. The introduction of trastuzumab (Herceptin) therapy has improved the response rates of survival of patients with metastatic breast cancer overexpressing HER2. Although previous studies are retrospective and of limited number, involving small study groups and different types of patient management, several authors have reported a 30% incidence of leptomeningeal metastases in patients with metastatic breast cancer overexpressing HER2 who were treated with trastuzumab, while 70 to 80% of cases of the disease were controlled systemically. In order to improve control of the disease at the level of the central nervous system (CNS), routine detection of leptomeningeal metastases in high-risk patients could be offered. CA 15-3 in cerebrospinal fluid (CSF) detection might be useful in helping to diagnose CNS metastases, particularly where cytology results are negative--which applies to 30% of cases--because tumor markers are more sensitive in detecting the tumor process. Our study validate CA 15-3 measurement in CSF and reference values were given. PMID:18039611

  7. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma

    PubMed Central

    Eyles, Jo; Puaux, Anne-Laure; Wang, Xiaojie; Toh, Benjamin; Prakash, Celine; Hong, Michelle; Tan, Tze Guan; Zheng, Lin; Ong, Lai Chun; Jin, Yi; Kato, Masashi; Prévost-Blondel, Armelle; Chow, Pierce; Yang, Henry; Abastado, Jean-Pierre

    2010-01-01

    Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8+ T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients. PMID:20501944

  8. Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

    ClinicalTrials.gov

    2016-07-10

    Functional Pancreatic Neuroendocrine Tumor; Malignant Somatostatinoma; Merkel Cell Carcinoma; Metastatic Adrenal Gland Pheochromocytoma; Metastatic Carcinoid Tumor; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2A; Multiple Endocrine Neoplasia Type 2B; Neuroendocrine Neoplasm; Non-Functional Pancreatic Neuroendocrine Tumor; Pancreatic Glucagonoma; Pancreatic Insulinoma; Recurrent Adrenal Cortex Carcinoma; Recurrent Adrenal Gland Pheochromocytoma; Recurrent Merkel Cell Carcinoma; Somatostatin-Producing Neuroendocrine Tumor; Stage III Adrenal Cortex Carcinoma; Stage III Thyroid Gland Medullary Carcinoma; Stage IIIA Merkel Cell Carcinoma; Stage IIIB Merkel Cell Carcinoma; Stage IV Adrenal Cortex Carcinoma; Stage IV Merkel Cell Carcinoma; Stage IVA Thyroid Gland Medullary Carcinoma; Stage IVB Thyroid Gland Medullary Carcinoma; Stage IVC Thyroid Gland Medullary Carcinoma; Thymic Carcinoid Tumor; VIP-Producing Neuroendocrine Tumor; Well Differentiated Adrenal Cortex Carcinoma; Zollinger Ellison Syndrome

  9. Synergistic anti-tumor effects of zoledronic acid and radiotherapy against metastatic hepatocellular carcinoma.

    PubMed

    Morii, Kazuhiko; Aoyama, Yuhki; Nakamura, Shinichiro; Okushin, Hiroaki

    2015-01-01

    A 72-year-old man with advanced hepatocellular carcinoma and decompensated hepatitis C virus-related cirrhosis suffered from a metastatic femoral fracture. After undergoing radiotherapy, he was only treated with supportive care, except for the administration of zoledronic acid (ZA). Thereafter, the initially elevated serum α-fetoprotein and des-gamma carboxyprothrombin levels declined to within the normal ranges. Hepatic and metastatic adrenal tumors, distant from the radiation field, exhibited a surprising regression. ZA is known to inhibit the activity of osteoclasts, bone-residential macrophages, and has been reported to have a direct anti-tumor effect. ZA may adjust the immunological milieu in tumor microenvironments by inhibiting the tumor-associated macrophages. Because radiotherapy can enhance the presentation of tumor-associated antigens, ZA and radiotherapy may exert synergistic anti-tumor effects. PMID:26466697

  10. Comparative genomic analysis of primary tumors and metastases in breast cancer

    PubMed Central

    Bertucci, François; Carbuccia, Nadine; Monneur, Audrey; Charafe-Jauffret, Emmanuelle; Goncalves, Anthony; Viens, Patrice; Birnbaum, Daniel; Chaffanet, Max

    2016-01-01

    Personalized medicine uses genomic information for selecting therapy in patients with metastatic cancer. An issue is the optimal tissue source (primary tumor or metastasis) for testing. We compared the DNA copy number and mutational profiles of primary breast cancers and paired metastases from 23 patients using whole-genome array-comparative genomic hybridization and next-generation sequencing of 365 “cancer-associated” genes. Primary tumors and metastases harbored copy number alterations (CNAs) and mutations common in breast cancer and showed concordant profiles. The global concordance regarding CNAs was shown by clustering and correlation matrix, which showed that each metastasis correlated more strongly with its paired tumor than with other samples. Genes with recurrent amplifications in breast cancer showed 100% (ERBB2, FGFR1), 96% (CCND1), and 88% (MYC) concordance for the amplified/non-amplified status. Among all samples, 499 mutations were identified, including 39 recurrent (AKT1, ERBB2, PIK3CA, TP53) and 460 non-recurrent variants. The tumors/metastases concordance of variants was 75%, higher for recurrent (92%) than for non-recurrent (73%) variants. Further mutational discordance came from very different variant allele frequencies for some variants. We showed that the chosen targeted therapy in two clinical trials of personalized medicine would be concordant in all but one patient (96%) when based on the molecular profiling of tumor and paired metastasis. Our results suggest that the genotyping of primary tumor may be acceptable to guide systemic treatment if the metastatic sample is not obtainable. However, given the rare but potentially relevant divergences for some actionable driver genes, the profiling of metastatic sample is recommended. PMID:27028851

  11. Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs.

    PubMed

    Halvorsen, E C; Hamilton, M J; Young, A; Wadsworth, B J; LePard, N E; Lee, H N; Firmino, N; Collier, J L; Bennewith, K L

    2016-06-01

    Regulatory T cells (Tregs) play a crucial physiological role in the regulation of immune homeostasis, although recent data suggest Tregs can contribute to primary tumor growth by suppressing antitumor immune responses. Tregs may also influence the development of tumor metastases, although there is a paucity of information regarding the phenotype and function of Tregs in metastatic target organs. Herein, we demonstrate that orthotopically implanted metastatic mammary tumors induce significant Treg accumulation in the lungs, which is a site of mammary tumor metastasis. Tregs in the primary tumor and metastatic lungs express high levels of C-C chemokine receptor type 5 (CCR5) relative to Tregs in the mammary fat pad and lungs of tumor-free mice, and Tregs in the metastatic lungs are enriched for CCR5 expression in comparison to other immune cell populations. We also identify that C-C chemokine ligand 8 (CCL8), an endogenous ligand of CCR5, is produced by F4/80(+) macrophages in the lungs of mice with metastatic primary tumors. Migration of Tregs toward CCL8 ex vivo is reduced in the presence of the CCR5 inhibitor Maraviroc. Importantly, treatment of mice with Maraviroc (MVC) reduces the level of CCR5(+) Tregs and metastatic tumor burden in the lungs. This work provides evidence of a CCL8/CCR5 signaling axis driving Treg recruitment to the lungs of mice bearing metastatic primary tumors, representing a potential therapeutic target to decrease Treg accumulation and metastatic tumor growth.

  12. Alvespimycin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors

    ClinicalTrials.gov

    2013-04-09

    and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Melanoma; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  13. Combining Fulvestrant with Low-Dose Capecitabine is Effective and Tolerable in Woman with Metastatic Breast Cancer.

    PubMed

    Nakai, Maki; Takei, Hiroyuki; Yanagihara, Keiko; Yamashita, Koji; Uchida, Eiji

    2016-01-01

    Although the use of endocrine therapy in combination with intravenous chemotherapy has not been standardized, the combination of fulvestrant and chemotherapy may be promising. A 62-year-old woman came to our hospital's outpatient clinic with extensive ascites. Approximately 10 years earlier, she had undergone mastectomy and sentinel lymph node biopsy. Pathologically invasive lobular carcinoma, with a maximum diameter of 28 mm, had been diagnosed in the left breast. The cancer had a histological grade of 2, was positive for estrogen receptor (95% or more positive cells), and was negative for both progesterone receptor (less than 1% positive cells) and human epidermal growth factor receptor 2. For 5 years the patient underwent adjuvant endocrine therapy with tamoxifen and then with anastrozole. Four years 2 months after adjuvant endocrine therapy had been completed, she felt abdominal distention, and her symptoms gradually worsened. A series of intensive examinations indicated that the invasive lobular carcinoma had metastasized to the peritoneum, pleura, uterus, and bone. Aromatase inhibitor was administered as a first-line therapy for the metastatic disease and was accompanied by denosumab injected every 28 days. For 2 months after the start of treatment with anastrozole, the ascites did not decrease and tumor markers increased. Because anastrozole had not been effective, fulvestrant (500 mg) and low-dose capecitabine (500 mg) were administered for the first 21 days of a 28-day cycle; this regimen had been shown by a phase 2 trial to be effective and tolerable in patients with metastatic breast cancer. The patient felt an improvement in abdominal distention, and the tumor markers decreased 2 weeks after the start of this combination therapy. By 10 months after the start of the combined therapy the ascites had decreased and pleural effusion had completely disappeared. The uterine wall became thinner, and the endometrial cavity became smaller. Tumor markers continued

  14. [Salivary gland-like tumors of the breast].

    PubMed

    Otterbach, F; Schmid, K W

    2006-09-01

    A subset of rare benign and malignant breast tumors with and without myoepithelial differentiation are morphologically and histogenetically similar to salivary gland tumors, but may differ in incidence and clinical behavior. The clinicopathological, immunohistochemical, molecular and prognostic features of ten salivary gland-like tumor entities of the breast are discussed and compared with their respective counterparts in the salivary glands.

  15. Patient-Reported Outcomes in Metastatic Breast Cancer: A Review of Industry-Sponsored Clinical Trials

    PubMed Central

    Krohe, Meaghan; Hao, Yanni; Lamoureux, Roger E.; Galipeau, Nina; Globe, Denise; Foley, Catherine; Mazar, Iyar; Solomon, Jeffrey; Shields, Alan L.

    2016-01-01

    INTRODUCTION Patient-reported outcome (PRO) measures serve to capture vital patient information not otherwise obtained by primary study endpoints. This paper examines how PROs are utilized as endpoints in industry-sponsored metastatic breast cancer clinical trials. METHODS A search was conducted in the clinicaltrials.gov web site for trials involving common treatments for metastatic breast cancer. Thirty-eight clinical trials were identified which included a PRO endpoint in the study, and data were extracted and summarized. RESULTS Overall, 17 unique PRO questionnaires and 14 concepts of measurement were identified as secondary or exploratory endpoints. The Functional Assessment of Cancer Therapy—Breast was the most frequently utilized questionnaire, commonly implemented to assess quality of life. The EORTC QLQ-C30 was also frequently used to measure quality of life or pain. CONCLUSION This review shares insights into the role of PROs in trials for metastatic breast cancer from which treatment developers and other stakeholders can enhance successful implementation of the patient voice into future trials. PMID:27441001

  16. Molecular detection of peripheral blood breast cancer mRNA transcripts as a surrogate biomarker for circulating tumor cells.

    PubMed

    Lasa, Adriana; Garcia, Arnal; Alonso, Carmen; Millet, Pilar; Cornet, Mónica; Ramón y Cajal, Teresa; Baiget, Montserrat; Barnadas, Agusti

    2013-01-01

    Circulating tumor cells (CTCs) are becoming a scientifically recognized indicator of primary tumors and/or metastasis. These cells can now be accurately detected and characterized as the result of technological advances. We analyzed the presence of CTCs in the peripheral blood of patients with metastatic breast cancer by real-time reverse-transcription PCR (RT-qPCR) using a panel of selected genes. The analysis of a single marker, without an EpCAM based enrichment approach, allowed the positive identification of 35% of the metastatic breast cancer patients. The analysis of five genes (SCGB2, TFF1, TFF3, Muc1, KRT20) performed in all the samples increased the detection to 61%. We describe a sensitive, reproducible and easy to implement approach to characterize CTC in patients with metastasic breast cancer.

  17. Inhibition of metastatic tumor growth by targeted delivery of antioxidant enzymes.

    PubMed

    Nishikawa, Makiya; Hyoudou, Kenji; Kobayashi, Yuki; Umeyama, Yukari; Takakura, Yoshinobu; Hashida, Mitsuru

    2005-12-01

    To develop effective anti-metastatic therapy, targeted or sustained delivery of catalase was examined in mice. We found that mouse lung with metastatic colonies of adenocarcinoma colon26 cells exhibited reduced catalase activity. The interaction of the tumor cells with macrophages or hepatocytes generated detectable amounts of ROS, and increased the activity of matrix metalloproteinases. Hepatocyte-targeted delivery of catalase was successfully achieved by galactosylation, which was highly effective in inhibiting the hepatic metastasis of colon26 cells. PEGylation, which increased the retention of catalase in the circulation, effectively inhibited the pulmonary metastasis of the cells. To examine which processes in tumor metastasis are inhibited by catalase derivatives, the tissue distribution and proliferation of tumor cells in mice was quantitatively analyzed using firefly luciferase-expressing tumor cells. An injection of PEG-catalase just before the inoculation of melanoma B16-BL6/Luc cells significantly reduced the number of the tumor cells in the lung at 24 h. Daily dosing of PEG-catalase greatly inhibited the proliferation of the tumor cells, and increased the survival rate of the tumor-bearing mice. These results indicate that targeted or sustained delivery of catalase to sites where tumor cells metastasize is a promising approach for inhibiting metastatic tumor growth. PMID:16256238

  18. Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome.

    PubMed

    Drews-Elger, Katherine; Iorns, Elizabeth; Dias, Alexandra; Miller, Philip; Ward, Toby M; Dean, Sonja; Clarke, Jennifer; Campion-Flora, Adriana; Rodrigues, Daniel Nava; Reis-Filho, Jorge S; Rae, James M; Thomas, Dafydd; Berry, Deborah; El-Ashry, Dorraya; Lippman, Marc E

    2014-11-01

    The mechanisms by which breast cancer (BrC) can successfully metastasize are complex and not yet fully understood. Our goal was to identify tumor-induced stromal changes that influence metastatic cell behavior, and may serve as better targets for therapy. To identify stromal changes in cancer-bearing tissue, dual-species gene expression analysis was performed for three different metastatic BrC xenograft models. Results were confirmed by immunohistochemistry, flow cytometry, and protein knockdown. These results were validated in human clinical samples at the mRNA and protein level by retrospective analysis of cohorts of human BrC specimens. In pre-clinical models of BrC, systemic recruitment of S100A8+ myeloid cells-including myeloid-derived suppressor cells (MDSCs)-was promoted by tumor-derived factors. Recruitment of S100A8+ myeloid cells was diminished by inhibition of tumor-derived factors or depletion of MDSCs, resulting in fewer metastases and smaller primary tumors. Importantly, these MDSCs retain their ability to suppress T cell proliferation upon co-culture. Secretion of macrophage inhibitory factor (MIF) activated the recruitment of S100A8+ myeloid cells systemically. Inhibition of MIF, or depletion of MDSCs resulted in delayed tumor growth and lower metastatic burden. In human BrC specimens, increased mRNA and protein levels of S100A8+ infiltrating cells are highly associated with poor overall survival and shorter metastasis free survival of BrC patients, respectively. Furthermore, analysis of nine different human gene expression datasets confirms the association of increased levels of S100A8 transcripts with an increased risk of death. Recruitment of S100A8+ myeloid cells to primary tumors and secondary sites in xenograft models of BrC enhances cancer progression independent of their suppressive activity on T cells. In clinical samples, infiltrating S100A8+ cells are associated with poor overall survival. Targeting these molecules or associated pathways

  19. Propranolol Hydrochloride in Treating Patients With Locally Recurrent or Metastatic Solid Tumors That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-09-28

    Male Breast Cancer; Recurrent Melanoma; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific; Hepatocellular Carcinoma

  20. Variation in the Attitudes of Medical Oncologists Toward Research Biopsies in Patients With Metastatic Breast Cancer

    PubMed Central

    Seah, Davinia S.; Scott, Sarah; Guo, Hao; Najita, Julie; Lederman, Ruth; Frank, Elizabeth; Sohl, Jessica; Stadler, Zsofia; Silverman, Stuart; Peppercorn, Jeffrey; Winer, Eric; Come, Steve

    2015-01-01

    Background. Tissue from research biopsies provides access to insights into tumor biology. We aimed to determine medical oncologists’ (MOs’) attitudes toward research biopsies in patients with metastatic breast cancer (MBC). Materials and Methods. A total of 309 breast MOs from National Cancer Institute (NCI)-designated cancer centers were invited to complete a self-administered survey about their attitudes toward approaching patients for research purpose-only biopsies (RPOBs), performed as a standalone procedure, or additional biopsies, performed with a clinically indicated biopsy. The MOs were asked to predict what proportion of their MBC patients would consider undergoing research biopsies. Results. Of the 309 MOs, 221 (72%) responded. Of these 221 MOs, 30 were ineligible, leaving 191 eligible responders. Nearly all the MOs reported they were comfortable approaching patients regarding research biopsies of blood or skin. One fifth of MOs were uncomfortable approaching patients for RPOBs of the breast. One half of MOs were uncomfortable approaching patients for RPOBs of the liver. A significant variation was found in the perceptions by MOs of their patients’ willingness to undergo research biopsies. The factors associated with increased comfort in approaching patients for research biopsies included fewer years in practice, caring for patients who had undergone recent research biopsies, and the predicted willingness of patients to consent to biopsies. The risk of a biopsy and biopsy-related pain were the most common reasons for reluctance to refer patients for research biopsies. Conclusion. Significant variation exists, even at NCI centers, in the comfort level of MOs in approaching MBC patients for research biopsies. MOs’ attitudes toward research biopsies might be a modifiable factor in increasing tissue collection for research. Implications for Practice: Tissue-based research is critical in advancing our understanding of cancer biology, and obtaining

  1. Functional Imaging of HER2-Positive Metastatic Breast Cancer Using 64Cu-DOTA-Trastuzumab Positron Emission Tomography

    PubMed Central

    Mortimer, Joanne E.; Bading, James R.; Colcher, David M.; Conti, Peter S.; Frankel, Paul H.; Carroll, Mary I.; Tong, Shan; Poku, Erasmus; Miles, Joshua K.; Shively, John E.; Raubitschek, Andrew A.

    2014-01-01

    Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion which may not be representative of the larger tumor mass or other sites of disease. Our long-range goal is to develop positron emission tomography (PET) of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET-CT of 64Cu-DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. Methods Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for ≥ 4 mo underwent complete staging, including 18F-fluorodeoxyglucose (FDG)/PET-CT. For 6 of the 8 patients, 64Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg trastuzumab) was preceded by trastuzumab infusion (45 mg). PET-CT (PET scan duration 1 h) was performed 21-25 (“Day 1”) and 47-49 (“Day 2”) h after 64Cu-DOTA-trastuzumab injection. Scan fields of view were chosen based on 18F-FDG/PET-CT. Lesions visualized relative to adjacent tissue on PET were considered PET-positive; analysis was limited to lesions identifiable on CT. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). Results Liver uptake of 64Cu was reduced approximately 75% with the 45 mg trastuzumab pre-dose, without significant effect on tumor uptake. The study included 89 CT-positive lesions; detection sensitivity was 77, 89 and 93% for Day 1, Day 2 and 18F-FDG, respectively. On average, tumor uptake was similar for 64Cu-DOTA-trastuzumab and 18F-FDG [SUVmax (mean, range): Day 1 (8.1, 3.0-22.5, n=48); Day 2 (8.9, 0.9-28.9, n=38); 18F-FDG (9.7, 3.3-25.4, n=56)], but the extent of same-lesion uptake was not

  2. Prostate-specific membrane antigen expression in tumor-associated vasculature of breast cancers.

    PubMed

    Wernicke, Alla Gabriella; Varma, Sonal; Greenwood, Eleni A; Christos, Paul J; Chao, K S Clifford; Liu, He; Bander, Neil H; Shin, Sandra J

    2014-06-01

    Prostate-specific membrane antigen (PSMA) has been found to be expressed in the tumor-associated neovasculature of multiple solid tumor types including breast cancers. However, thus far, the number of cases studied from some tumor types has been limited. In this study, we set out to assess PSMA expression in the tumor-associated vasculature associated with invasive breast carcinomas in a sizable cohort of patients. One hundred and six patients with AJCC stage 0-IV breast cancer were identified. Ninety-two of these patients had primary breast cancer [invasive breast carcinoma with or without co-existing ductal carcinoma in situ (DCIS) (74) or DCIS alone (18)]. In addition, 14 patients with breast cancer metastases to the brain were identified. Immunohistochemical staining for PSMA and CD31 was performed on parallel representative tumor sections in each case. Tumor-associated vascular endothelial cell PSMA immunoreactivity was semi-quantitatively assessed based on two parameters: overall percent of endothelial positivity and staining intensity. PSMA expression for tumor-associated vascular endothelial cells was scored 0 if there was no detectable PSMA expression, 1 if PSMA staining was detectable in 5-50%, and 2 if PSMA expression was positive in >50% of microvessels. CD 31 staining was concurrently reviewed to confirm the presence of vasculature in each case. Tumor-associated vasculature was PSMA-positive in 68/92 (74%) of primary breast cancers and in 14/14 (100%) of breast cancers metastatic to brain. PSMA was not detected in normal breast tissue or carcinoma cells. All but 2 cases (98%) showed absence of PSMA expression in normal breast tissue-associated vasculature. The 10-year overall survival was 88.7% (95% CI = 80.0%, 93.8%) in patients without brain metastases. When overall survival (OS) was stratified based on PSMA score group, patients with PSMA scores of 0, 1, and 2 had 10-year OS of 95.8%, 96.0%, and 79.7%, respectively (p = 0.12). When PSMA scores

  3. Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma

    PubMed Central

    Tham, Muly; Khoo, Karen; Yeo, Kim Pin; Kato, Masashi; Prevost-Blondel, Amelle; Angeli, Veronique; Abastado, Jean-Pierre

    2015-01-01

    Surgical resection of tumors is often followed by regrowth at the primary site and metastases may emerge rapidly following removal of the primary tumor. Macrophages are important drivers of tumor growth, and here we investigated their involvement in postoperative relapse as well as explore macrophage depletion as an adjuvant to surgical resection. RETAAD mice develop spontaneous metastatic melanoma that begins in the eye. Removal of the eyes as early as 1 week of age did not prevent the development of metastases; rather, surgery led to increased proliferation of tumor cells locally and in distant metastases. Surgery-induced increase in tumor cell proliferation correlated with increased macrophage density within the tumor. Moreover, macrophages stimulate tumor sphere formation from tumor cells of post-surgical but not control mice. Macrophage depletion with a diet containing the CSF-1R specific kinase inhibitor Ki20227 following surgery significantly reduced postoperative tumor recurrence and abrogated enhanced metastatic outgrowth. Our results confirm that tumor cells disseminate early, and show that macrophages contribute both to post-surgical tumor relapse and growth of metastases, likely through stimulating a population of tumor-initiating cells. Thus macrophage depletion warrants exploration as an adjuvant to surgical resection. PMID:25762633

  4. International guidelines for management of metastatic breast cancer (MBC) from the European School of Oncology (ESO)-MBC Task Force: Surveillance, staging, and evaluation of patients with early-stage and metastatic breast cancer.

    PubMed

    Lin, Nancy U; Thomssen, Christoph; Cardoso, Fatima; Cameron, David; Cufer, Tanja; Fallowfield, Lesley; Francis, Prudence A; Kyriakides, Stella; Pagani, Olivia; Senkus, Elzbieta; Costa, Alberto; Winer, Eric P

    2013-06-01

    In clinical practice, the surveillance and follow-up of patients with breast cancer (BC) is quite variable. At the 7th European Breast Cancer Conference, the ESO-MBC Task Force convened a series of lectures, followed by open debate, on the use of physical examination, imaging, and laboratory tests in patients with early-stage BC, and for restaging evaluations and follow-up among patients with MBC. Based on the available data, the Task Force recommends against intensive, routine radiologic or blood-based surveillance (with the exception of mammography) in patients with early-stage BC. As systemic therapies for MBC continue to improve, this question might be re-visited in the context of a carefully controlled clinical trial in specific BC subtypes. For patients with MBC, response to therapy should generally be assessed 2-3 months after initiation of treatment, and thereafter every 2-4 months for endocrine therapy or every 2-4 cycles for chemotherapy, depending on the dynamics of the disease, the location and extent of metastatic involvement, and type of treatment. Additional testing should be performed irrespective of the planned intervals if progression of disease is suspected (e.g. in the case of specific symptoms). Use of tumor markers is not recommended for surveillance of early-stage patients, but may be helpful in monitoring response to therapy in patients with metastatic disease. However, change in tumor markers alone should not be used for decision-making. Moving forward, enhanced efforts to document quality of life over time should be made in order to more fully evaluate the risk/benefit ratio of available options.

  5. Small cell neuroendocrine tumor of the breast in a 40 year-old woman: a case report

    PubMed Central

    2010-01-01

    Introduction Small cell neuroendocrine cancer of the breast is a rare tumor with less than 30 cases reported in the literature. The morphological and immunohistochemical patterns of this tumor are similar to small cell neuroendocrine cancer of the lung. For this reason, it is often difficult to distinguish a primary small cell neuroendocrine cancer of the breast from a metastatic lesion from other sites. Case presentation We report and characterize with immunohistochemical techniques a case of primary small cell neuroendocrine cancer of the breast occurring in a 40-year-old Caucasian woman. A palpable and mobile 3.0 cm tumor was located in the upper-outer quadrant of her right breast. Lumpectomy and subsequent radical mastectomy with axillary lymph node resection were performed. Microscopically, the tumor consisted predominantly of a diffuse proliferation of small oat cells. The tumor cells were positive for neuroendocrine markers chromogranin A and synaptophysin. One of 16 lymph nodes was metastatic. A correct treatment needs to be chosen. Conclusions It has recently been demonstrated that early small cell neuroendocrine cancer of the breast shows a good prognosis with adjuvant treatments with high disease free survival. Our patient is alive and well without disease eight years after treatment. We performed an adjuvant therapy with the classic scheme doxorubicin and cyclophosphamide, followed by carboplatin and etoposide. A more extensive review is required to define a standard treatment protocol for this rare neoplasm. PMID:20591162

  6. Hypofractionated Image Guided Radiation Therapy in Treating Patients With Stage IV Breast Cancer

    ClinicalTrials.gov

    2016-06-24

    Central Nervous System Metastases; Invasive Ductal Breast Carcinoma; Invasive Ductal Breast Carcinoma With Predominant Intraductal Component; Invasive Lobular Breast Carcinoma; Invasive Lobular Breast Carcinoma With Predominant in Situ Component; Liver Metastases; Lobular Breast Carcinoma in Situ; Lung Metastases; Male Breast Cancer; Medullary Ductal Breast Carcinoma With Lymphocytic Infiltrate; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Recurrent Breast Cancer; Stage IV Breast Cancer; Tubular Ductal Breast Carcinoma; Tumors Metastatic to Brain

  7. IDENTIFYING AND TARGETING TUMOR-INITIATING CELLS IN THE TREATMENT OF BREAST CANCER

    PubMed Central

    Wei, Wei; Lewis, Michael T.

    2015-01-01

    Breast cancer is the most common cancer in women (exclusive of skin cancer), and is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - due to traits that tumor cells possess prior to treatment, or acquired, - due to traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSC). TICs have the capacity to self-renew and regenerate new tumors that consist of all clonally-derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies, and survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow resulting in disease relapse. It is also hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative to achieve cure. In this review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy, as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear important for TIC function that may represent promising therapeutic targets. PMID:25876646

  8. Establishment and evaluation of a new highly metastatic tumor cell line 5a-D-Luc-ZsGreen expressing both luciferase and green fluorescent protein.

    PubMed

    Sudo, Hitomi; Tsuji, Atsushi B; Sugyo, Aya; Takuwa, Hiroyuki; Masamoto, Kazuto; Tomita, Yutaka; Suzuki, Norihiro; Imamura, Takeshi; Koizumi, Mitsuru; Saga, Tsuneo

    2016-02-01

    Breast cancer is the most common cancer in women. Although advances in diagnostic imaging for early detection, surgical techniques and chemotherapy have improved overall survival, the prognosis of patients with metastatic breast cancer remains poor. Understanding cancer cell dynamics in the metastatic process is important to develop new therapeutic strategies. Experimental animal models and imaging would be powerful tools for understanding of the molecular events of multistep process of metastasis. In the present study, to develop a new cancer cell line that is applicable to bioluminescence and fluorescence imaging, we transfected the expression vector of a green fluorescent protein ZsGreen1 into a metastatic cell line 5a-D-Luc, which is a subclone of the MDA-MB-231 breast cancer cell line expressing luciferase, and established a new tumor cell line 5a-D-Luc-ZsGreen expressing both luciferase and ZsGreen1. The 5a-D-Luc-ZsGreen cells proliferate more rapidly and have a more invasive phenotype compared with 5a-D-Luc cells following intracardiac injection. Metastasis sites were easily detected in the whole body by bioluminescence imaging and in excised tissues by ex vivo fluorescence imaging. The fluorescence of 5a-D-Luc-ZsGreen cells was not lost after formalin fixation and decalcification. It enabled us to easily evaluate tumor spread and localization at the cellular level in microscopic analysis. The strong fluorescence of 5a-D-Luc-ZsGreen cells allowed for real-time imaging of circulating tumor cells in cerebral blood vessels of live animals immediately after intracardiac injection of cells using two-photon laser-scanning microscopy. These findings suggest that the 5a-D-Luc-ZsGreen cells would be a useful tool for research on mechanisms of metastatic process in animal models. PMID:26691676

  9. Establishment and evaluation of a new highly metastatic tumor cell line 5a-D-Luc-ZsGreen expressing both luciferase and green fluorescent protein.

    PubMed

    Sudo, Hitomi; Tsuji, Atsushi B; Sugyo, Aya; Takuwa, Hiroyuki; Masamoto, Kazuto; Tomita, Yutaka; Suzuki, Norihiro; Imamura, Takeshi; Koizumi, Mitsuru; Saga, Tsuneo

    2016-02-01

    Breast cancer is the most common cancer in women. Although advances in diagnostic imaging for early detection, surgical techniques and chemotherapy have improved overall survival, the prognosis of patients with metastatic breast cancer remains poor. Understanding cancer cell dynamics in the metastatic process is important to develop new therapeutic strategies. Experimental animal models and imaging would be powerful tools for understanding of the molecular events of multistep process of metastasis. In the present study, to develop a new cancer cell line that is applicable to bioluminescence and fluorescence imaging, we transfected the expression vector of a green fluorescent protein ZsGreen1 into a metastatic cell line 5a-D-Luc, which is a subclone of the MDA-MB-231 breast cancer cell line expressing luciferase, and established a new tumor cell line 5a-D-Luc-ZsGreen expressing both luciferase and ZsGreen1. The 5a-D-Luc-ZsGreen cells proliferate more rapidly and have a more invasive phenotype compared with 5a-D-Luc cells following intracardiac injection. Metastasis sites were easily detected in the whole body by bioluminescence imaging and in excised tissues by ex vivo fluorescence imaging. The fluorescence of 5a-D-Luc-ZsGreen cells was not lost after formalin fixation and decalcification. It enabled us to easily evaluate tumor spread and localization at the cellular level in microscopic analysis. The strong fluorescence of 5a-D-Luc-ZsGreen cells allowed for real-time imaging of circulating tumor cells in cerebral blood vessels of live animals immediately after intracardiac injection of cells using two-photon laser-scanning microscopy. These findings suggest that the 5a-D-Luc-ZsGreen cells would be a useful tool for research on mechanisms of metastatic process in animal models.

  10. Tumor homogeneity between primary and metastatic sites for BRAF status in metastatic melanoma determined by immunohistochemical and molecular testing.

    PubMed

    Boursault, Lucile; Haddad, Véronique; Vergier, Béatrice; Cappellen, David; Verdon, Severine; Bellocq, Jean-Pierre; Jouary, Thomas; Merlio, Jean-Philippe

    2013-01-01

    BRAF inhibitors have demonstrated improvement of overall survival in patients with metastatic melanoma and BRAF(V600) mutations. In order to evaluate BRAF tumor heterogeneity between primary and metastatic site, we have evaluated the performance of immunohistochemistry (IHC) with an anti-BRAF(V600E) antibody in both localization by comparison with high resolution melting analysis followed by Sanger sequencing in a parallel blinded study. A total of 230 samples distributed as primary melanoma (n = 88) and different types of metastatic samples (n = 142) were studied in 99 patients with advanced or metastatic melanoma (stage III or IV). The prevalence of each BRAF mutation was c.1799T>A, BRAF(V600E) (45.2%), c.1799_1800TG>AA, BRAF(V600E2) (3.0%), c.1798_1799GT>AA, BRAF(V600K) (3.0%), c.1801 A>G, BRAF(K601E) (1.3%), c.1789_1790CT>TC, BRAF(L597S) (0.4%), c.1780G>A, BRAF(D594N) (0.9%) respectively. IHC was positive in 109/112 samples harboring BRAF(V600E/E2) mutations and negative in other cases. The cytoplasmic staining was either strongly positive in tumor cells of BRAF(V600E) mutated cases. It appeared strong brown, different from the vesicular grey cytoplasmic pigmentation of melanophages. Concordance between the two techniques was 96.4%. Sensitivity of IHC for detecting the BRAF(V600E/E2) mutations was 97.3%, while specificity was 100%. Both our IHC and molecular study demonstrated homogeneity between primary and metastatic sites for BRAF status in melanoma. This study also provides evidence that IHC may be a cost-effective first-line method for BRAF(V600E) detection. Thereafter, molecular techniques should be used in negative, ambiguous or non-contributive cases.

  11. Infused Therapy and Survival in Older Patients Diagnosed with Metastatic Breast Cancer who Received Trastuzumab

    PubMed Central

    Griffiths, Robert I; Lalla, Deepa; Herbert, Robert J; Doan, Justin F; Brammer, Melissa G; Danese, Mark D

    2011-01-01

    We used Surveillance, Epidemiology, and End Results-Medicare data (2000-2006) to describe treatment and survival in women diagnosed with metastatic breast cancer (MBC) who received trastuzumab. There were 610 patients with a mean age of 74 years. Overall, 32% received trastuzumab alone and 47% received trastuzumab plus a taxane. In multivariate analysis, trastuzumab plus chemotherapy was associated with a lower adjusted cancer mortality rate (Hazard Ratio [HR] 0.54; 95% Confidence Interval [CI] 0.39-0.74; p < .001) than trastuzumab alone among patients who received trastuzumab as part of first-line therapy. Adding chemotherapy to first-line trastuzumab for metastatic breast cancer is associated with improved cancer survival. PMID:21929325

  12. Efficacy of Bevacizumab-Capecitabine in Combination for the First-Line Treatment of Metastatic Breast Cancer

    PubMed Central

    Dyar, Stephen; Moreno-Aspitia, Alvaro

    2011-01-01

    There is an ongoing need for development of new chemotherapeutic regimens for metastatic breast cancer [mBC], especially when tumors lack therapeutic targets such as the estrogen or progesterone receptor [ER/PR], or the human epidermal growth factor receptor-2 [HER2]. Capecitabine is an orally bioavailable fluoropyrimidine approved for monotherapy in mBC, and bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor which has shown to be active in mBC and tolerable in combination with other chemotherapeutics. The combination of these two agents has been explored in multiple phase II and III clinical studies, with improvements in progression-free survival and overall response rates noted as compared to capecitabine monotherapy. However, the use of bevacizumab in combination with capecitabine and other chemotherapy agents for mBC remains beset with controversy due to safety concerns, cost issues, and pending regulatory decisions. PMID:22174585

  13. DEAD-box helicase DP103 defines metastatic potential of human breast cancers

    PubMed Central

    Shin, Eun Myoung; Sin Hay, Hui; Lee, Moon Hee; Goh, Jen Nee; Tan, Tuan Zea; Sen, Yin Ping; Lim, See Wee; Yousef, Einas M.; Ong, Hooi Tin; Thike, Aye Aye; Kong, Xiangjun; Wu, Zhengsheng; Mendoz, Earnest; Sun, Wei; Salto-Tellez, Manuel; Lim, Chwee Teck; Lobie, Peter E.; Lim, Yoon Pin; Yap, Celestial T.; Zeng, Qi; Sethi, Gautam; Lee, Martin B.; Tan, Patrick; Goh, Boon Cher; Miller, Lance D.; Thiery, Jean Paul; Zhu, Tao; Gaboury, Louis; Tan, Puay Hoon; Hui, Kam Man; Yip, George Wai-Cheong; Miyamoto, Shigeki; Kumar, Alan Prem; Tergaonkar, Vinay

    2014-01-01

    Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-β–activated kinase-1 (TAK1) phosphorylation of NF-κB–activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB–mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment. PMID:25083991

  14. Lung endothelial dipeptidyl peptidase IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells

    PubMed Central

    1993-01-01

    Attachment of circulating tumor cells to endothelial cell adhesion molecules restricted to select vascular compartments is thought to be responsible for site-specific metastasis. Lung-metastatic rat R3230AC- MET breast and RPC-2 prostate carcinoma cells bound outside-out endothelial cell membrane vesicles, prepared by perfusion of the rat lung vasculature with a low-strength formaldehyde solution, in significantly higher numbers than their nonmetastatic counterparts R3230AC-LR and RPC-LR. In contrast, vesicles derived from the vasculature of a nonmetastasized organ (e.g., hind leg muscle) showed no binding preference for either of the four tumor cell lines. Lung- derived endothelial vesicles were used here to generate mAbs against lung endothelial cell adhesion molecules. The first group of mice were actively immunized against lung endothelial vesicles, whereas the second group was injected with syngeneic mouse antiserum against leg endothelial vesicles before active immunization with lung endothelial vesicles. 17 hybridoma supernatants obtained from the two fusions bound lung vesicles with at least a 10-fold higher affinity than leg vesicles. Seven (four obtained by a passive/active immunization protocol) stained rat capillary endothelia. One mAb, mAb 8.6A3, inhibited specific adhesion of lung-derived vesicles to lung-metastatic breast and prostate carcinoma cells. Purification of the antigen (endothelial cell adhesion molecule) from rat lung extracts revealed a protein with a 110-kD mol wt. NH2-terminal sequencing established identity with dipeptidyl peptidase IV which had been reported to serve as a fibronectin-binding protein. These results indicate that vesicles obtained from in situ perfused organs are a convenient immunogen for the production of antibodies to compartment-specific endothelial cell surface molecules, and reinforce the concept that endothelial cell surface components are selectively recognized by circulating cancer cells during metastasis

  15. The perivascular niche regulates breast tumor dormancy

    PubMed Central

    Peinado, Héctor; Mori, Hidetoshi; Matei, Irina R.; Evason, Kimberley J.; Brazier, Hélène; Almeida, Dena; Koller, Antonius; Hajjar, Katherine A.; Stainier, Didier Y.R.; Chen, Emily I.; Lyden, David

    2013-01-01

    In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant, and what ‘wakes them up’, are fundamental problems in tumor biology. To address these questions, we utilized metastasis assays in mice to show that dormant DTCs reside upon microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumor-promoting, endothelial tip cell-derived factors. Our work reveals that stable microvasculature constitutes a ‘dormant niche,’ whereas sprouting neovasculature sparks micrometastatic outgrowth. PMID:23728425

  16. Relation between primary tumor FDG avidity and site of first distant metastasis in patients with breast cancer

    PubMed Central

    Lim, Chae Hong; Moon, Seung Hwan; Cho, Young Seok; Im, Young-Hyuck; Choe, Yearn Seong; Kim, Byung-Tae; Lee, Kyung-Han

    2016-01-01

    Abstract Identification of tumor imaging features associated with metastatic pattern may allow better understanding of cancer dissemination. Here, we investigated how primary tumor 18F-fluorodeoxyglucose (FDG) avidity influences the first site of breast cancer metastasis. Subjects were 264 patients with advanced breast cancer who underwent positron emission tomography/computed tomography at diagnosis and had metastasis at presentation (n = 193) or metastatic relapse after surgery (n = 71). Primary tumor FDG avidity (maximum SUV [SUVmax] ≥10.1) was compared with histology and first metastatic sites. The most common site of first metastasis was the bone, occurring in 62.7% of patients with metastasis at presentation and 38.0% of those with metastatic relapse. First metastasis to lung occurred in 30.1% and 35.2%, and to liver in 25.4% and 15.2% of respective groups. In patients with metastasis at presentation, primary tumors were FDG avid in 98/193 cases, and this was associated with more frequent first metastasis to lung (37.8% vs 22.1%; P = 0.018). In patients with metastasis relapse, primary tumors were FDG avid in 31/71 cases, and this was associated with more frequent first metastasis to lung (48.4% vs 25.0%; P = 0.041) and liver (29.0% vs 5.0%; P = 0.008). In patients with metastasis relapse, primary tumors that were FDG avid but hormone receptor negative had more first metastasis to lung (57.9% vs 26.9%; P = 0.016). FDG-avid primary breast tumors have favored first spread to the lung and liver, which suggests that tumor cells with heightened glycolytic activity better colonize these organs. PMID:27512840

  17. Relation between primary tumor FDG avidity and site of first distant metastasis in patients with breast cancer.

    PubMed

    Lim, Chae Hong; Moon, Seung Hwan; Cho, Young Seok; Im, Young-Hyuck; Choe, Yearn Seong; Kim, Byung-Tae; Lee, Kyung-Han

    2016-08-01

    Identification of tumor imaging features associated with metastatic pattern may allow better understanding of cancer dissemination. Here, we investigated how primary tumor F-fluorodeoxyglucose (FDG) avidity influences the first site of breast cancer metastasis.Subjects were 264 patients with advanced breast cancer who underwent positron emission tomography/computed tomography at diagnosis and had metastasis at presentation (n = 193) or metastatic relapse after surgery (n = 71). Primary tumor FDG avidity (maximum SUV [SUVmax] ≥10.1) was compared with histology and first metastatic sites.The most common site of first metastasis was the bone, occurring in 62.7% of patients with metastasis at presentation and 38.0% of those with metastatic relapse. First metastasis to lung occurred in 30.1% and 35.2%, and to liver in 25.4% and 15.2% of respective groups. In patients with metastasis at presentation, primary tumors were FDG avid in 98/193 cases, and this was associated with more frequent first metastasis to lung (37.8% vs 22.1%; P = 0.018). In patients with metastasis relapse, primary tumors were FDG avid in 31/71 cases, and this was associated with more frequent first metastasis to lung (48.4% vs 25.0%; P = 0.041) and liver (29.0% vs 5.0%; P = 0.008). In patients with metastasis relapse, primary tumors that were FDG avid but hormone receptor negative had more first metastasis to lung (57.9% vs 26.9%; P = 0.016).FDG-avid primary breast tumors have favored first spread to the lung and liver, which suggests that tumor cells with heightened glycolytic activity better colonize these organs.

  18. Monitoring of tumor growth and metastasis potential in MDA-MB-435s/ tk-luc human breast cancer xenografts

    NASA Astrophysics Data System (ADS)

    Chang, Ya-Fang; Lin, Yi-Yu; Wang, Hsin-Ell; Liu, Ren-Shen; Pang, Fei; Hwang, Jeng-Jong

    2007-02-01

    Molecular imaging of reporter gene expression provides a rapid, sensitive and non-invasive monitoring of tumor behaviors. In this study, we reported the establishment of a novel animal model for longitudinal examination of tumor growth kinetics and metastatic spreading in vivo. The highly metastatic human breast carcinoma MDA-MB-435s cell line was engineered to stably express herpes simplex virus type 1 thymidine kinase (HSV-1- tk) and luciferase ( luc). Both 131I-FIAU and D-luciferin were used as reporter probes. For orthotopic tumor formation, MDA-MB-435s/ tk-luc cells were implanted into the first nipple of 6-week-old female NOD/SCID mice. For metastatic study, cells were injected via the lateral tail vein. Mice-bearing MDA-MB-435s/ tk-luc tumors were scanned for tumor growth and metastatsis using Xenogen IVIS50 system. Gamma scintigraphy and whole-body autoradiography were also applied to confirm the tumor localization. The results of bioluminescence imaging as well as histopathological finding showed that tumors could be detected in femur, spine, ovary, lungs, kidney, adrenal gland, lymph nodes and muscle at 16 weeks post i.v. injection, and correlated photons could be quantified. This MDA-MB-435s/ tk-luc human breast carcinoma-bearing mouse model combined with multimodalities of molecular imaging may facilitate studies on the molecular mechanisms of cancer invasion and metastasis.

  19. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer.

    PubMed

    Gunasinghe, N P A Devika; Wells, Alan; Thompson, Erik W; Hugo, Honor J

    2012-12-01

    As yet, there is no cure for metastatic breast cancer. Historically, considerable research effort has been concentrated on understanding the processes of metastasis, how a primary tumour locally invades and systemically disseminates using the phenotypic switching mechanism of epithelial to mesenchymal transition (EMT); however, much less is understood about how metastases are then formed. Breast cancer metastases often look (and may even function) as 'normal' breast tissue, a bizarre observation against the backdrop of the organ structure of the lung, liver, bone or brain. Mesenchymal to epithelial transition (MET), the opposite of EMT, has been proposed as a mechanism for establishment of the metastatic neoplasm, leading to questions such as: Can MET be clearly demonstrated in vivo? What factors cause this phenotypic switch within the cancer cell? Are these signals/factors derived from the metastatic site (soil) or expressed by the cancer cells themselves (seed)? How do the cancer cells then grow into a detectable secondary tumour and further disseminate? And finally--Can we design and develop therapies that may combat this dissemination switch? This review aims to address these important questions by evaluating long-standing paradigms and novel emerging concepts in the field of epithelial mesencyhmal plasticity.

  20. Tamoxifen-resistant, ER-positive MAC 51 cell line with a high metastatic potential developed from a spontaneous breast cancer mouse model.

    PubMed

    Kumar, Jerald Mahesh; Kombairaju, Ponvijay; Nagarajan, P; Subramanian, Thanumalayan; Jose, Jedy; Ganapathy, Hullathy Subban; Ohsugi, Takeo

    2012-11-01

    We developed and characterized an estrogen-responsive and ER-positive murine breast cancer cell line (MAC51) from a spontaneous breast cancer animal model. These cells are overexpressed with K8, K18 and K19 proteins in an immunofluoresence assay. Upregulation of ER alpha was observed in the immunofluoresence assay, real-time PCR analysis and western blot assay. A colocalization experiment in MAC 51 showed cytoplasmic colocalization of K18 and K19 proteins with ER α. Real-time analysis of tumor samples from engrafted animals, MAC 51, metastatic liver and metastatic ovary revealed overexpression of K8 and K18 compared to the respective controls. A hormone responsive experiment in immunodeficient mice showed highly significant decreases in estrogen and tumor volume after 14 days ovariectomization. The tumorogenicity assay showed higher (3 × 10 (5)) and lower (3 × 10(4)) concentrations of MAC 51 cells that developed tumors within 2 weeks post-transplantation. Tumor morphology and histology resembled a sarcoma pattern but our spontaneous model appeared in an adenocarcinoma pattern. Metastasis to different organs occurred through hematogenous and lymphatic routes. We assessed the potency of the anticancer effect in MAC 51 cells by treating various anticancer drugs with E2, followed by studying apoptotic gene expression profiles. E2 and E2+ tamoxifen-treated cells showed upregulation of apoptotic genes caspase 1, 3, 9, P53 and Bcl-xl but the tamoxifen- and paclitaxel-treated cells did not upregulate the apoptotic genes. Tamoxifen-resistant, ER-positive and high metastatic potential cell lines from murine origin are very rare. Also, estrogen greatly induced apoptosis in this cell line, hence MAC 51 has a greater application potential to evaluate low doses of estrogen with other targeted therapeutic drugs to treat breast cancer.

  1. Gene expression patterns associated with the metastatic phenotype in rodent and human tumors.

    PubMed

    Nestl, A; Von Stein, O D; Zatloukal, K; Thies, W G; Herrlich, P; Hofmann, M; Sleeman, J P

    2001-02-15

    Using subtractive technology, we have generated metastasis-associated gene expression profiles for rat mammary and pancreatic adenocarcinomas. Several genes whose expression is thought to be related to tumor progression such as c-Met, urokinase-type plasminogen activator receptor, ezrin, HMG-1, oncomodulin, cathepsin, and caveolin were thereby isolated. Half of the metastasis-associated clones showed no significant homology to genes with known function. Notably, several of the metastasis-associated clones were also expressed in metastatic lines but not in nonmetastatic lines of other tumor models. Furthermore, in situ hybridization using selected clones documents the relevance of these results for human cancer because strong expression in tumor cells including metastases was detected in human colorectal cancer samples and, to a lesser extent, in mammary cancer samples. These data support the concept that tumors express a "metastatic program" of genes. PMID:11245467

  2. Reconstruction of the natural history of metastatic cancer and assessment of the effects of surgery: Gompertzian growth of the primary tumor.

    PubMed

    Hanin, Leonid; Bunimovich-Mendrazitsky, Svetlana

    2014-01-01

    This work deals with retrospective reconstruction of the individual natural history of solid cancer and assessment of the effects of treatment on metastatic progression. This is achieved through a mathematical model of cancer progression accounting for the growth of the primary tumor, shedding of metastases, their dormancy and growth at secondary sites. To describe dynamics of the primary tumor, we used the Gompertz law, a parsimonious model of tumor growth accounting for its saturation. Parameters of the model were estimated from the age and volume of the primary tumor at surgery and volumes of detectable bone metastases collected from one breast cancer patient and one prostate cancer patient. This allowed us to estimate, for each patient, the ages at cancer onset and inception of all detected metastases, the expected metastasis latency time, parameters of the Gompertzian growth of the primary tumor, and the rates of growth of metastases before and after surgery. We found that for both patients: (1) onset of metastasis occurred when primary tumor was undetectable; (2) inception of all surveyed metastases except one occurred before surgery; and most importantly, (3) resection of the primary tumor led to a dramatic increase in the rate of growth of metastases. The model provides an excellent fit to the observed volumes of bone metastases in both patients. Our results agree well with those obtained previously based on exponential growth of the primary tumor, which serves as model validation. Our findings support the notion of metastatic dormancy and indirectly confirm the existence of stem-like cancer cells in breast and prostate tumors. We also explored the logistic law of primary tumor growth; however, it degenerated into the exponential law for both patients analyzed. The conclusions of this work are supported by a vast body of experimental, clinical and epidemiological knowledge accumulated over the last century. PMID:24211826

  3. A metastatic glomus jugulare tumor. A temporal bone report

    SciTech Connect

    El Fiky, F.M.; Paparella, M.M.

    1984-01-01

    The clinicopathologic findings in the temporal bone of a patient with a highly malignant metastasizing glomus jugulare tumor are reported. The patient exhibited all the symptoms of primary malignant tumors of the ear, including facial paralysis, otorrhea, pain, hearing loss, tinnitus, dizziness, and vertigo. He was treated with cobalt irradiation followed by radium implant in the ear canal for a residual tumor; then a left-sided radical mastoidectomy was performed.

  4. Metastatic cardiac tumor manifested by persistent ST-segment elevation with coexisting reciprocal changes on electrocardiography.

    PubMed

    Cheon, Dae Young; Park, Kyoung-Ha; Hong, Seong Eun; Lee, Soo Haeng; Jang, Seung Hun; Park, Woo Jung

    2014-01-01

    In cases with metastatic invasion of the heart, electrocardiographic abnormalities are commonly seen. However, most of these electrocardiographic changes are nonspecific; certain findings may be highly suggestive of myocardial involvement of the tumor. We report a patient with lung cancer who presented with persistent ST-segment elevation with coexisting reciprocal changes on electrocardiography due to myocardial invasion of the lung cancer.

  5. FRIZZLED7 Is Required for Tumor Inititation and Metastatic Growth of Melanoma Cells

    PubMed Central

    Tiwary, Shweta; Xu, Lei

    2016-01-01

    Metastases are thought to arise from cancer stem cells and their tumor initiating abilities are required for the establishment of metastases. Nevertheless, in metastatic melanoma, the nature of cancer stem cells is under debate and their contribution to metastasis formation remains unknown. Using an experimental metastasis model, we discovered that high levels of the WNT receptor, FZD7, correlated with enhanced metastatic potentials of melanoma cell lines. Knocking down of FZD7 in a panel of four melanoma cell lines led to a significant reduction in lung metastases in animal models, arguing that FZD7 plays a causal role during metastasis formation. Notably, limiting dilution analyses revealed that FZD7 is essential for the tumor initiation of melanoma cells and FZD7 knockdown impeded the early expansion of metastatic melanoma cells shortly after seeding, in accordance with the view that tumor initiating ability of cancer cells is required for metastasis formation. FZD7 activated JNK in melanoma cell lines in vitro and the expression of a dominant negative JNK suppressed metastasis formation in vivo, suggesting that FZD7 may promote metastatic growth of melanoma cells via activation of JNK. Taken together, our findings uncovered a signaling pathway that regulates the tumor initiation of melanoma cells and contributes to metastasis formation in melanoma. PMID:26808375

  6. Polymethylmethacrylate-augmented screw fixation for stabilization in metastatic spinal tumors. Technical note.

    PubMed

    Jang, Jee Soo; Lee, Sang Ho; Rhee, Chang Hun; Lee, Seung Hoon

    2002-01-01

    Screw fixation augmented with polymethylmethacrylate (PMMA) or some other biocompatible bone cement has been used in patients with osteoporosis requiring spinal fusion. No clinical studies have been conducted on PMMA-augmented screw fixation for stabilization of the vertebral column in patients with metastatic spinal tumors. The purpose of this study was to determine whether screw fixation augmented with PMMA might be suitable in patients treated for multilevel metastatic spinal tumors. Ten patients with metastatic spinal tumors involving multiple vertebral levels underwent stabilization procedures in which PMMA was used to augment screw fixation after decompression of the spinal cord. Within 15 days, partial or complete relief from pain was obtained in all patients postoperatively. Two of four patients in whom neurological deficits caused them to be nonambulatory before surgery were able to ambulate postoperatively. Neither collapse of the injected vertebral bodies nor failure of the screw fixation was observed during the mean follow-up period of 6.7 months. Screw fixation augmented with PMMA may offer stronger stabilization and facilitate the instrumentation across short segments in the treatment of multilevel metastatic spinal tumors. PMID:11795702

  7. Measures of outcome in metastatic breast cancer: insights from a real-world scenario.

    PubMed

    Bonotto, Marta; Gerratana, Lorenzo; Poletto, Elena; Driol, Pamela; Giangreco, Manuela; Russo, Stefania; Minisini, Alessandro M; Andreetta, Claudia; Mansutti, Mauro; Pisa, Federica E; Fasola, Gianpiero; Puglisi, Fabio

    2014-06-01

    No gold standard treatment exists for metastatic breast cancer (MBC). Clinical decision making is based on knowledge of prognostic and predictive factors that are extrapolated from clinical trials and, sometimes, are not reliably transferable to a real-world scenario. Moreover, misalignment between endpoints used in drug development and measures of outcome in clinical practice has been noted. The roles of overall survival (OS) and progression-free survival (PFS) as primary endpoints in the context of clinical trials are the subjects of lively debate. Information about these parameters in routine clinical practice is potentially useful to design new studies and/or to interpret the results of clinical research. This study analyzed the impact of patient and tumor characteristics on the major measures of outcome across different lines of treatment in a cohort of 472 patients treated for MBC. OS, PFS, and postprogression survival (PPS) were analyzed. The study showed how biological and clinical characteristics may have different prognostic value across different lines of therapy for MBC. After first-line treatment, the median PPS of luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2)-positive groups was longer than 12 months. The choice of OS as a primary endpoint for clinical trials could not be appropriate with these subtypes. In contrast, OS could be an appropriate endpoint when PPS is expected to be low (e.g., triple-negative subtype after the first line; other subtypes after the third line). The potential implications of these findings are clinical and methodological.

  8. Prognostic Impact of Time to Ipsilateral Breast Tumor Recurrence after Breast Conserving Surgery

    PubMed Central

    Gosset, Marie; Hamy, Anne-Sophie; Mallon, Peter; Delomenie, Myriam; Mouttet, Delphine; Pierga, Jean-Yves; Lae, Marick; Fourquet, Alain; Rouzier, Roman; Reyal, Fabien; Feron, Jean-Guillaume

    2016-01-01

    Background The poor prognosis of patients who experience ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) is established. A short time between primary cancer and IBTR is a prognostic factor but no clinically relevant threshold was determined. Classification of IBTR may help tailor treatment strategies. Purpose We determined a specific time frame, which differentiates IBTR into early and late recurrence, and identified prognostic factors for patients with IBTR at time of the recurrence. Methods We analyzed 2209 patients with IBTR after BCS. We applied the optimal cut-points method for survival data to determine the cut-off times to IBTR. A subgroup analysis was performed by hormone receptor (HR) status. Survival analyses were performed using a Cox proportional hazard model to determine clinical features associated with distant-disease-free survival (DDFS) after IBTR. We therefor built decision trees. Results On the 828 metastatic events observed, the majority occurred within the first 3 months after IBTR: 157 in the HR positive group, 98 in the HR negative group. We found different prognostic times to IBTR: 49 months in the HR positive group, 33 in the HR negative group. After multivariate analysis, time to IBTR was the first discriminant prognostic factor in both groups (HR 0.65 CI95% [0.54–0.79] and 0.42 [0.30–0.57] respectively). The other following variables were significantly correlated with the DDFS: the initial number of positive lymph nodes for both groups, the initial tumor size and grade for HR positive tumors. Conclusion A short interval time to IBTR is the strongest factor of poor prognosis and reflects occult distant disease. It would appear that prognosis after IBTR depends more on clinical and histological parameters than on surgical treatment. A prospective trial in a low-risk group of patients to validate the safety of salvage BCS instead of mastectomy in IBTR is needed. PMID:27494111

  9. A rare cause in etiology of left atrial mass: metastatic testicular germ cell tumor

    PubMed Central

    Huseyin, Serhat; Okyay, Ahmet; Hacıbekiroğlu, İlhan; Tastekin, Ebru; Yılmaztepe, Mustafa; Taylan, Gökay; Canbaz, Suat; Çiçin, İrfan

    2016-01-01

    Although intracardiac metastasis of germ cell tumors is rare, it can be localized in the right or left heart by disseminating spread and give their cardiac symptoms depending on the location of metastatic mass. We present a 38-year-old male patient with a preliminary diagnosis of testicular tumor who was followed by the medical oncology clinic with cerebrovascular event and heart failure symptoms. PMID:27212979

  10. FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma

    PubMed Central

    2012-01-01

    Background Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed. Methods Fifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases. FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3–6 signals) of the locus specific FGFR-1 gene. Results Three (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3–6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals. The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIα was not amplified in all cases. Conclusions 1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of

  11. Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion

    PubMed Central

    Roselli, Séverine; Pundavela, Jay; Demont, Yohann; Faulkner, Sam; Keene, Sheridan; Attia, John; Jiang, Chen Chen; Zhang, Xu Dong; Walker, Marjorie M.; Hondermarck, Hubert

    2015-01-01

    The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion. PMID:25871389

  12. Bronchial carcinoid tumors metastatic to the sella turcica and review of the literature.

    PubMed

    Moshkin, Olga; Rotondo, Fabio; Scheithauer, Bernd W; Soares, Mark; Coire, Claire; Smyth, Harley S; Goth, Miklos; Horvath, Eva; Kovacs, Kalman

    2012-06-01

    We review here the literature on neuroendocrine neoplasms metastatic to the pituitary and present an example of the disease. Metastasis of bronchial carcinoid tumors to the sellar region are rare. Herein, we describe the case of a 63-year-old woman who presented with constant cough and headaches. She had previously been operated for carcinoid tumor of the lung. During the preoperative investigation, a CT scan of the head revealed a sellar mass. Six months after a left lower lobectomy, the sellar lesion was removed by transsphenoidal surgery. The two tumors were evaluated by histology, immunohistochemistry and electron microscopy. Both showed identical morphologic features, those of carcinoid tumor. Immunohistochemistry revealed immunoreactivity for the endocrine markers, synaptophysin and chromogranin, as well as CD-56, serotonin, bombesin and vascular endothelial growth factor. The sellar neoplasm showed nuclear immunopositivity for thyroid transcription factor-1, supporting the diagnosis of a metastatic bronchial carcinoid tumor. In conclusion, this is the first report of a serotonin- and bombesin-immunopositive atypical bronchial carcinoid tumor metastatic to the sella. PMID:22485018

  13. Selective gene-expression profiling of migratory tumor cells in vivo predicts clinical outcome in breast cancer patients

    PubMed Central

    2012-01-01

    Introduction Metastasis of breast cancer is the main cause of death in patients. Previous genome-wide studies have identified gene-expression patterns correlated with cancer patient outcome. However, these were derived mostly from whole tissue without respect to cell heterogeneity. In reality, only a small subpopulation of invasive cells inside the primary tumor is responsible for escaping and initiating dissemination and metastasis. When whole tissue is used for molecular profiling, the expression pattern of these cells is masked by the majority of the noninvasive tumor cells. Therefore, little information is available about the crucial early steps of the metastatic cascade: migration, invasion, and entry of tumor cells into the systemic circulation. Methods In the past, we developed an in vivo invasion assay that can capture specifically the highly motile tumor cells in the act of migrating inside living tumors. Here, we used this assay in orthotopic xenografts of human MDA-MB-231 breast cancer cells to isolate selectively the migratory cell subpopulation of the primary tumor for gene-expression profiling. In this way, we derived a gene signature specific to breast cancer migration and invasion, which we call the Human Invasion Signature (HIS). Results Unsupervised analysis of the HIS shows that the most significant upregulated gene networks in the migratory breast tumor cells include genes regulating embryonic and tissue development, cellular movement, and DNA replication and repair. We confirmed that genes involved in these functions are upregulated in the migratory tumor cells with independent biological repeats. We also demonstrate that specific genes are functionally required for in vivo invasion and hematogenous dissemination in MDA-MB-231, as well as in patient-derived breast tumors. Finally, we used statistical analysis to show that the signature can significantly predict risk of breast cancer metastasis in large patient cohorts, independent of well

  14. Total enbloc spondylectomy for metastatic high grade spinal tumors: Early results

    PubMed Central

    Patil, Sanganagouda S; Nene, Abhay M

    2016-01-01

    Background: High grade metastatic spinal tumors are most common and are invasive. These patients can succumb to disease progression if not treated timely. Although considered as invasive and morbid, total enbloc spondylectomy (TES) in selected cases has better survival rates. The authors describe the results of TES for high grade metastatic spinal tumors. Materials and Methods: Five patients (four females and one male) underwent TES for solitary metastatic vertebral lesion between November 2012 and January 2014. These patients presented to us with spinal instability, unrelenting severe spinal pain and/or with severe progressive radiculopathy. Average age was 46.2 years (range 39–62 years). After complete investigations, computed tomography scan, magnetic resonance imaging scan and positron emission tomography (PET) scan, it was confirmed that these patients had high grade solitary vertebral metastatic tumor. Results: Average duration of followup was 18 months (range 16–20 months). The average preoperative visual analog scale score of 9.4 (range 9–10) improved to 2 (range 1–4) at last followup. Average blood loss was 1440 mL (range 1000–2000 mL). Average duration of surgery was 198 min (range 180–240 min). Significant pain relief was noticed in each patient in the immediate postoperative period and during followups. These patients attained complete functional activities of daily living with in a month. The imaging showed implants in situ, no recurrence of tumor, and no activity on PET scan at the final followup. Conclusion: The present series shows favorable short term results of TES for solitary, metastatic, high grade vertebral body tumors by a team approach. PMID:27512215

  15. Reactivity of a monoclonal antibody with tissues and tumors from the human breast. Immunohistochemical localization of a new antigen and clinicopathologic correlations.

    PubMed

    Mariani-Costantini, R; Barbanti, P; Colnaghi, M I; Ménard, S; Clemente, C; Rilke, F

    1984-04-01

    The reactions of a monoclonal antibody to the MCF7 breast cancer cell line were immunohistochemically studied on a variety of breast tumors, primary and metastatic, on mammary epithelium and on nonneoplastic breast lesions. A high proportion of positive reactions was observed in ductal, lobular, and tubular carcinomas as well as in mammary Paget's disease. Mucinous, medullary, and papillary carcinomas showed a low incidence of reactivity. Carcinomas with metaplasia, carcinoids, and nonepithelial breast tumors were unreactive with the antibody. Positive immunostaining was documented also in nodal and extranodal metastatic lesions. The staining of nodal metastases was correlated with the positive reaction of the primary tumor. Reactivity was widely distributed in normal breast epithelial cells and in benign breast lesions. Staining of nonneoplastic mammary epithelial was associated with reactivity of adjacent neoplastic tissues. Staining differences between nonneoplastic and neoplastic mammary tissues were related to the intensity and cytologic distribution of the labeling. Heterogeneous reactivity of morphologically similar cells was documented in nonneoplastic and neoplastic breast epithelial cells as well as in nodal and extranodal breast carcinoma metastases. Immunohistologically detectable antigen was not correlated with prognostic factors such as histologic grade or nodal status. A retrospective study of T1NO cases failed to substantiate any prognostic value for the reactivity of primary breast tumors with this monoclonal antibody.

  16. Primary extraskeletal Ewing's sarcoma/primitive neuroectodermal tumor of breast

    PubMed Central

    Srivastava, Smita; Arora, Jyoti; Parakh, Anushri; Goel, Ruchika Kumar

    2016-01-01

    Extraskeletal Ewing's sarcoma (EES) is a rare soft tissue tumor that is morphologically indistinguishable from skeletal ES. We report a case of a 25-year-old female with recurrent EES/primitive neuroectodermal tumor of right breast with imaging findings on mammogram, ultrasound, magnetic resonance imaging breast, and positron emission tomography–computed tomography. PMID:27413270

  17. Interstitial laser photocoagulation of breast tumors

    NASA Astrophysics Data System (ADS)

    Pickard, David C. O.; Bown, Stephen G.; Briggs, Gavin M.; Hall-Craggs, Margret A.

    2001-10-01

    Interstitial Laser Photocoagulation (ILP) is a method of destroying lesions in the center of solid organs without the need for open surgery. Under image guidance, up to four needles are inserted percutaneously into the tumor through which thin optic fibers are passed into the target lesion. Low power laser light from a semiconductor laser is delivered to gently coagulate the tissue. This dead tissue is subsequently resorbed by the body's normal healing processes. Follow up is achieved with ultrasound imaging. One study is described for assessing ILP for benign fibroadenomas. Fibroadenomas were treated to assess how laser treated breast tissue healed in the long term and we have shown that the necrosed tissue is resorbed without complications over a period of months. Nevertheless, by following treated fibroadenomas (up to 35mm diameter) with ultrasound measurement at 3, 6 and 12 months, in 14 patients, only one lesion was still detectable 12 months after ILP. In appropriate cases, ILP could be an attractive option, as it leaves no scars and should not change the shape or size of the breast. If the present studies are successful, the plan is for a multi-center trial of minimally invasive, thermal ablation of breast cancers.

  18. Core Needle Biopsy of Breast Cancer Tumors Increases Distant Metastases in a Mouse Model12

    PubMed Central

    Mathenge, Edward Gitau; Dean, Cheryl Ann; Clements, Derek; Vaghar-Kashani, Ahmad; Photopoulos, Steffany; Coyle, Krysta Mila; Giacomantonio, Michael; Malueth, Benjamin; Nunokawa, Anna; Jordan, Julie; Lewis, John D.; Gujar, Shashi Ashok; Marcato, Paola; Lee, Patrick W.K.; Giacomantonio, Carman Anthony

    2014-01-01

    INTRODUCTION: Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely performed before surgical excision of breast cancer tumors are hypothesized to increase the risk of metastatic disease. In this study, we experimentally determined whether CNB of breast cancer tumors results in increased distant metastases and examine important resultant changes in the primary tumor and tumor microenvironment associated with this outcome. METHOD: To evaluate the effect of CNB on metastasis development, we implanted murine mammary 4T1 tumor cells in BALB/c mice and performed CNB on palpable tumors in half the mice. Subsequently, emulating the human scenario, all mice underwent complete tumor excision and were allowed to recover, with attendant metastasis development. Tumor growth, lung metastasis, circulating tumor cell (CTC) levels, variation in gene expression, composition of the tumor microenvironment, and changes in immunologic markers were compared in biopsied and non-biopsied mice. RESULTS: Mice with biopsied tumors developed significantly more lung metastases compared to non-biopsied mice. Tumors from biopsied mice contained a higher frequency of myeloid-derived suppressor cells (MDSCs) accompanied by reduced CD4 + T cells, CD8 + T cells, and macrophages, suggesting biopsy-mediated development of an increasingly immunosuppressive tumor microenvironment. We also observed a CNB-dependent up-regulation in the expression of SOX4, Ezh2, and other key epithelial-mesenchymal transition (EMT) genes, as well as increased CTC levels among the biopsy group. CONCLUSION: CNB creates an immunosuppressive tumor microenvironment, increases EMT, and facilitates release of CTCs, all of which likely contribute to the observed increase in development of distant metastases. PMID:25425969

  19. Axillary Dissection in Breast Cancer Patients with Metastatic Sentinel Node: To Do or Not to Do? Suggestions from Our Series

    PubMed Central

    Bortolini, M.; Genta, F.; Biacchiardi, Chiara Perono; Zanon, E.; Camanni, M.; Deltetto, F.

    2011-01-01

    Several studies have put to question and evaluated the indication and prognosis of sentinel lymph node biopsy (SNLB) as sole treatment in human breast cancer. We reviewed 1588 patients who underwent axillary surgery. In 239 patients, axillary lymph node dissection (ALND) was performed following positive fine needle aspiration cytology (FNAC), and, in 299 cases, ALND was executed after positive SNLB. The most dramatic result from our data is that patients with either micrometastasis of the sentinel lymph node (SLN) or only metastatic SLN have, respectively, an 84.5% and a 75.0% chance of having no other nodal involvement. We believe a more refined patient selection is neccessary when considering ALND. Where the primary tumor is larger than 5 cm, where radio or adjuvant therapies are not indicated, in cases of FNAC+ nodes, and in cases presenting more than one metastatic sentinel node, we prefer to carry out ALND. Having thus said, however, our data suggests that it is wise not to perform ALND in almost all cases presenting positive SLNs. PMID:22084733

  20. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.

    PubMed

    Ibrahim, Safaa A; Katara, Gajendra K; Kulshrestha, Arpita; Jaiswal, Mukesh K; Amin, Magdy A; Beaman, Kenneth D

    2015-10-20

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy.

  1. Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis

    PubMed Central

    Habibi, Mehran; Kmieciak, Maciej; Graham, Laura; Morales, Johanna K; Bear, Harry D; Manjili, Masoud H

    2008-01-01

    Tumor development or recurrence is always a matter of concern following radiofrequency thermal ablation (RFA) of tumors. To determine whether combining RFA with immunologically active cytokines might induce tumor-specific immune responses against mammary carcinoma and inhibit tumor development or metastasis, we evaluated intralesional injection of IL-7 and IL-15 in RFA-treated murine tumors. We used two different breast carcinoma models: neu-overexpressing mouse mammary carcinoma (MMC) in FVBN202 transgenic mouse and 4T1 tumors in Balb/c mouse. MMC tend to relapse even in the presence of neu-specific immune responses, and 4T1 is a weakly immunogenic, aggressive and highly metastatic transplantable tumor. In vivo growth of both of these tumors is also associated with increased numbers of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC). We showed for the first time that unlike RFA alone, RFA combined with the administration of intralesional IL-7 and IL-15 (after RFA), induced immune responses to tumors, inhibited tumor development and lung metastasis, and reduced MDSC. PMID:18425677

  2. Metastatic breast cancer presenting as a primary hindgut neuroendocrine tumour.

    PubMed

    Okines, Alicia F C; Hawkes, Eliza A; Rao, Sheela; VAN As, Nicholas; Marsh, Henry; Riddell, Angela; Wilson, Philip O G; Osin, Peter; Wotherspoon, Andrew C; Wetherspoon, Andrew C

    2010-07-01

    The examination of limited, potentially non-representative fragments of tumour tissue from a core biopsy can be misleading and misdirect subsequent treatment, especially in cases where a primary tumour has not been identified. This case report is of a 65-year-old woman presenting with a destructive sacral mass, diagnosed on radiological imaging and core biopsy as a hindgut neuroendocrine tumour, which on histopathological review of the subsequently resected tumour was found instead to represent a metastasis from an occult hormone-positive breast cancer with neuroendocrine features.

  3. Identification of genomic signatures in circulating tumor cells from breast cancer.

    PubMed

    Kanwar, Nisha; Hu, Pingzhao; Bedard, Philippe; Clemons, Mark; McCready, David; Done, Susan J

    2015-07-15

    Levels of circulating tumor cells (CTCs) in blood have prognostic value in early and metastatic breast cancer. CTCs also show varying degrees of concordance with molecular markers of primary tumors they originate from. It is expected that individual cells reflect the heterogeneity and evolution of tumor cells as they acquire new functions and differential responses to chemotherapy. However, a degree of commonality is also plausible, highlighting alterations that allow tumor cells to perform CTC-defining activities such as invasion and intravasation. Using a matched tumor-normal approach, we performed high-resolution copy number profiling of CTCs from breast cancer to identify occult changes occurring during progression to metastasis. We identified a signature of recurrent gain in CTCs, consisting of 90 minimal common regions (MCRs) of copy number gain. These were predominantly found across chromosome 19 and were identified at low frequencies (3-4%) in 787 primary breast carcinomas examined. CTC genomic signatures clustered into two groups independent of subtype: a dormancy-related signature with 16 MCRs (AKT2, PTEN, CADM2); and a tumor-aggressiveness related signature with 358 MCRs (ANGPTL4, BSG, MIR-373). There were two MCRs in common between the groups on 19q13 and 21q21, containing genes involved in resistance to anoikis, TGFβ-signaling and metastasis (TFF3, LTBP4, NUMBL). Furthermore, a region harboring the ERBB2 gene was gained in a majority of patients. Regions 20q13 and 15q24 were associated with distant metastasis. The distinctiveness of CTC signatures highlights cell populations with different functional or metastatic potential. Such novel targets could help to specifically identify and block dissemination.

  4. Passive Entrapment of Tumor Cells Determines Metastatic Dissemination to Spinal Bone and Other Osseous Tissues

    PubMed Central

    Piffko, Andras; Hoffmann, Christian J.; Harms, Christoph; Vajkoczy, Peter; Czabanka, Marcus

    2016-01-01

    During the metastatic process tumor cells circulate in the blood stream and are carried to various organs. In order to spread to different organs tumor cell—endothelial cell interactions are crucial for extravasation mechanisms. It remains unclear if tumor cell dissemination to the spinal bone occurs by passive entrapment of circulating tumor cells or by active cellular mechanisms mediated by cell surface molecules or secreted factors. We investigated the seeding of three different tumor cell lines (melanoma, lung and prostate carcinoma) to the microvasculature of different organs. Their dissemination was compared to biologically passive microbeads. The spine and other organs were resected three hours after intraarterial injection of tumor cells or microbeads. Ex vivo homogenization and fluorescence analysis allowed quantification of tumor cells or microbeads in different organs. Interestingly, tumor cell distribution to the spinal bone was comparable to dissemination of microbeads independent of the tumor cell type (melanoma: 5.646% ± 7.614%, lung: 6.007% ± 1.785%, prostate: 3.469% ± 0.602%, 7 μm beads: 9.884% ± 7.379%, 16 μm beads: 7.23% ± 1.488%). Tumor cell seeding differed significantly between tumor cells and microbeads in all soft tissue organs. Moreover, there were significant differences between the different tumor cell lines in their dissemination behaviour to soft tissue organs only. These findings demonstrate that metastatic dissemination of tumor cells to spinal bone and other osseous organs is mediated by passive entrapment of tumor cells similar to passive plugging of microvasculature observed after intraarterial microbeads injection. PMID:27603673

  5. Passive Entrapment of Tumor Cells Determines Metastatic Dissemination to Spinal Bone and Other Osseous Tissues.

    PubMed

    Broggini, Thomas; Piffko, Andras; Hoffmann, Christian J; Harms, Christoph; Vajkoczy, Peter; Czabanka, Marcus

    2016-01-01

    During the metastatic process tumor cells circulate in the blood stream and are carried to various organs. In order to spread to different organs tumor cell-endothelial cell interactions are crucial for extravasation mechanisms. It remains unclear if tumor cell dissemination to the spinal bone occurs by passive entrapment of circulating tumor cells or by active cellular mechanisms mediated by cell surface molecules or secreted factors. We investigated the seeding of three different tumor cell lines (melanoma, lung and prostate carcinoma) to the microvasculature of different organs. Their dissemination was compared to biologically passive microbeads. The spine and other organs were resected three hours after intraarterial injection of tumor cells or microbeads. Ex vivo homogenization and fluorescence analysis allowed quantification of tumor cells or microbeads in different organs. Interestingly, tumor cell distribution to the spinal bone was comparable to dissemination of microbeads independent of the tumor cell type (melanoma: 5.646% ± 7.614%, lung: 6.007% ± 1.785%, prostate: 3.469% ± 0.602%, 7 μm beads: 9.884% ± 7.379%, 16 μm beads: 7.23% ± 1.488%). Tumor cell seeding differed significantly between tumor cells and microbeads in all soft tissue organs. Moreover, there were significant differences between the different tumor cell lines in their dissemination behaviour to soft tissue organs only. These findings demonstrate that metastatic dissemination of tumor cells to spinal bone and other osseous organs is mediated by passive entrapment of tumor cells similar to passive plugging of microvasculature observed after intraarterial microbeads injection. PMID:27603673

  6. Ductal Breast Carcinoma Metastatic to the Stomach Resembling Primary Linitis Plastica in a Male Patient

    PubMed Central

    Leonardi, Giulia Costanza; Ravaioli, Noemi; De Giglio, Andrea; Brambilla, Marta; Prosperi, Enrico; Ribacchi, Franca; Meacci, Marialuisa; Crinò, Lucio; Maiettini, Daniele; Chiari, Rita; Metro, Giulio

    2016-01-01

    Breast cancer metastases to the gastrointestinal tract are very rare occurrences. Among the histological subtypes of breast cancer, invasive lobular carcinomas have a high capacity of metastasis to uncommon sites including the stomach. Conversely, there has not been sufficient evidence supporting the gastric metastasis of invasive ductal carcinoma. Herein, we report a unique case of metastatic ductal breast carcinoma mimicking primary linitis plastica in a male patient, particularly focusing on the clinical and pathological features of presentation. Moreover, we propose a immunohistochemical panel of selected antibodies including those for cytokeratin 20, cytokeratin 7, estrogen receptor, progesterone receptor, E-cadherin, gross cystic disease fluid protein 15, and GATA binding protein 3 for an accurate differential diagnosis. PMID:27721883

  7. Anorectal melanoma metastatic to the breast: a case report and review of the literature

    PubMed Central

    Feng, Liang; Qi, Dian-Jun; Zhang, Qing-Fu

    2016-01-01

    Melanoma develops from melanocytes and typically occurs on the skin and mucosa with a high degree of malignancy. Intensive local invasion and distant metastasis of melanoma result in poor patient prognosis, owing to frequent metastases to the lungs, bones, brains, and other parts of the body. In the present study, we report a case of anorectal melanoma in a 56-year-old woman who was admitted to our hospital because of local recurrence 9 months after local resection. She subsequently underwent radical surgery. Metastasis to the left breast occurred within 4 months after radical surgery. Metastasis of anorectal melanoma to the breast is very rare. In the present case report and literature review, we analyzed the clinical manifestation, diagnosis, and treatment of anorectal melanoma metastatic to the breast. PMID:27563250

  8. Diabetes insipidus and adrenal insufficiency in a patient with metastatic breast cancer.

    PubMed

    Netelenbos, T; Nooij, M A; Nortier, J W R

    2006-09-01

    A patient previously treated for bilateral breast cancer with mastectomy, radiation therapy and in remission on hormonal therapy for more than five years presented with abdominal symptoms from breast cancer relapse. She developed inappropriate polyuria and hypernatraemia, which responded to desmopressin. In combination with the absence of a high signal from the posterior lobe of the pituitary on MRI , these data indicated the presence of partial central diabetes insipidus. The anterior pituitary showed partial failure (low follicle-stimulating hormone, luteinising hormone and insulin-like growth factor-1 levels). Furthermore, primary adrenal insufficiency had developed, ascribed to bilateral tumour invasion of the adrenals. This rare combination of endocrinological failures in a patient with metastatic breast cancer is discussed.

  9. Steroid Tumor Environment in Male and Female Mice Model of Canine and Human Inflammatory Breast Cancer

    PubMed Central

    Caceres, Sara; Peña, Laura; Silvan, Gema; Illera, Maria J.; Woodward, Wendy A.; Reuben, James M.; Illera, Juan C.

    2016-01-01

    Canine inflammatory mammary cancer (IMC) shares clinical and histopathological characteristics with human inflammatory breast cancer (IBC) and has been proposed as a good model for studying the human disease. The aim of this study was to evaluate the capacity of female and male mice to reproduce IMC and IBC tumors and identify the hormonal tumor environment. To perform the study sixty 6–8-week-old male and female mice were inoculated subcutaneously with a suspension of 106IPC-366 and SUM149 cells. Tumors and serum were collected and used for hormonal analysis. Results revealed that IPC-366 reproduced tumors in 90% of males inoculated after 2 weeks compared with 100% of females that reproduced tumor at the same time. SUM149 reproduced tumors in 40% of males instead of 80% of females that reproduced tumors after 4 weeks. Both cell lines produce distant metastasis in lungs being higher than the metastatic rates in females. EIA analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors. Serum steroid levels were lower than those found in tumors. In conclusion, IBC and IMC male mouse model is useful as a tool for IBC research and those circulating estrogens and intratumoral hormonal levels are crucial in the development and progression of tumors. PMID:27195300

  10. Metastatic Breast Cancer in Medication-Related Osteonecrosis Around Mandibular Implants

    PubMed Central

    Favia, Gianfranco; Tempesta, Angela; Limongelli, Luisa; Crincoli, Vito; Piattelli, Adriano; Maiorano, Eugenio

    2015-01-01

    Patient: Female, 66 Final Diagnosis: Breast cancer metastasis in medication-related osteonecrosis of the jaw Symptoms: — Medication: — Clinical Procedure: Clinical and radiological examination • surgical treatment Specialty: Dentistry Objective: Rare co-existance of disease or pathology Background: Many authors have considered dental implants to be unrelated to increased risk of medication-related osteonecrosis of the jaw (MRONJ). Nevertheless, more recently, more cases of peri-implant MRONJ (PI-MRONJ) have been described, thus becoming a challenging health problem. Also, metastatic cancer deposits are not infrequently found at peri-implant sites and this may represent an additional complication for such treatments. We present the case of a breast cancer patient with PI-MRONJ, presenting a clinically and radiologically undetected metastasis within the necrotic bone, and highlight the necessity of an accurate histopathological analysis. Case Report: A 66-year-old female patient, who had received intravenous bisphosphonates for bone breast cancer metastases, came to our attention for a non-implant surgery-triggered PI-MRONJ. After surgical resection of the necrotic bone, conventional and immunohistochemical examinations were performed, which showed breast cancer deposits within the necrotic bone. Conclusions: Cancer patients with metastatic disease, who are undergoing bisphosphonate treatment, may develop unusual complications, including MRONJ, which is a site at risk for hosting additional metastatic deposits that may be clinically and radiologically overlooked. Such risk is increased by previous or concomitant implant procedures. Consequently, clinicians should be prudent when performing implant surgery in cancer patients with advanced-stage disease and consider the possible occurrence of peri-implant metastases while planning adequate treatments in such patients. PMID:26371774

  11. Concerns about Breast Cancer, Pain, and Fatigue in Non-Metastatic Breast Cancer Patients Undergoing Primary Treatment.

    PubMed

    Amiel, Chelsea R; Fisher, Hannah M; Antoni, Michael H

    2016-01-01

    Women diagnosed with breast cancer often endorse psychosocial concerns prior to treatment, which may influence symptom experiences. Among these, low perceived social support relates to elevated fatigue. Those with low social support perceptions may also experience a greater sense of rejection. We sought to determine if social rejection concerns post-surgery predict fatigue interference 12 months later in women with non-metastatic breast cancer. Depressive symptoms and pain severity after completion of adjuvant therapy (six months post-surgery) were examined as potential mediators. Women (N = 240) with non-metastatic breast cancer were recruited 2-10 weeks post-surgery. Multiple regression analyses examined relationships among variables adjusting for relevant covariates. Greater rejection concerns at study entry predicted greater fatigue interference 12 months later (p < 0.01). Pain severity after adjuvant therapy partially mediated the relationship between social rejection concerns and fatigue interference, with significant indirect (β = 0.06, 95% CI (0.009, 0.176)) and direct effects (β = 0.18, SE = 0.07, t(146) = 2.78, p < 0.01, 95% CI (0.053, 0.311)). Therefore, pain levels post-treatment may affect how concerns of social rejection relate to subsequent fatigue interference. Interventions targeting fears of social rejection and interpersonal skills early in treatment may reduce physical symptom burden during treatment and into survivorship. PMID:27571115

  12. Concerns about Breast Cancer, Pain, and Fatigue in Non-Metastatic Breast Cancer Patients Undergoing Primary Treatment

    PubMed Central

    Amiel, Chelsea R.; Fisher, Hannah M.; Antoni, Michael H.

    2016-01-01

    Women diagnosed with breast cancer often endorse psychosocial concerns prior to treatment, which may influence symptom experiences. Among these, low perceived social support relates to elevated fatigue. Those with low social support perceptions may also experience a greater sense of rejection. We sought to determine if social rejection concerns post-surgery predict fatigue interference 12 months later in women with non-metastatic breast cancer. Depressive symptoms and pain severity after completion of adjuvant therapy (six months post-surgery) were examined as potential mediators. Women (N = 240) with non-metastatic breast cancer were recruited 2–10 weeks post-surgery. Multiple regression analyses examined relationships among variables adjusting for relevant covariates. Greater rejection concerns at study entry predicted greater fatigue interference 12 months later (p < 0.01). Pain severity after adjuvant therapy partially mediated the relationship between social rejection concerns and fatigue interference, with significant indirect (β = 0.06, 95% CI (0.009, 0.176)) and direct effects (β = 0.18, SE = 0.07, t(146) = 2.78, p < 0.01, 95% CI (0.053, 0.311)). Therefore, pain levels post-treatment may affect how concerns of social rejection relate to subsequent fatigue interference. Interventions targeting fears of social rejection and interpersonal skills early in treatment may reduce physical symptom burden during treatment and into survivorship. PMID:27571115

  13. Biological Therapy in Treating Patients With Metastatic Cancer

    ClinicalTrials.gov

    2013-02-21

    Breast Cancer; Colorectal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastric Cancer; Head and Neck Cancer; Liver Cancer; Lung Cancer; Metastatic Cancer; Ovarian Cancer; Pancreatic Cancer; Testicular Germ Cell Tumor

  14. Combination of anti-angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis.

    PubMed

    Bachelier, Richard; Confavreux, Cyrille B; Peyruchaud, Olivier; Croset, Martine; Goehrig, Delphine; van der Pluijm, Gabri; Clézardin, Philippe

    2014-09-15

    The clinical efficacy of anti-angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti-angiogenic therapies is. Here, we examined the impact of neutralizing tumor-derived vascular endothelial growth factor (VEGF) in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh-VEGF) in osteotropic human MDA-MB-231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh-VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock-transfected (Sc-VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor-derived VEGF or the use of a VEGF-neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti-angiogenic monotherapies in metastatic breast cancer is relatively modest. PMID:24615579

  15. Effect of Lapatinib on the Outgrowth of Metastatic Breast Cancer Cells to the Brain

    PubMed Central

    Gril, Brunilde; Palmieri, Diane; Bronder, Julie L.; Herring, Jeanne M.; Vega-Valle, Eleazar; Feigenbaum, Lionel; Liewehr, David J.; Steinberg, Seth M.; Merino, Maria J.; Rubin, Stephen D.

    2008-01-01

    Background The brain is increasingly being recognized as a sanctuary site for metastatic tumor cells in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy, and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis. Methods EGFR-overexpressing MDA-MB-231-BR (231-BR) brain-seeking breast cancer cells were transfected with an expression vector that contained or lacked the HER2 cDNA and used to examine the effect of lapatinib on the activation (ie, phosphorylation) of cell signaling proteins by immunoblotting, on cell growth by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and on cell migration using a Boyden chamber assay. The outgrowth of large (ie, >50 μm2) and micrometastases was counted in brain sections from nude mice that had been injected into the left cardiac ventricle with 231-BR cells and, beginning 5 days later, treated by oral gavage with lapatinib or vehicle (n = 22–26 mice per treatment group). All statistical tests were two-sided. Results In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream signaling proteins; cell proliferation; and migration in 231-BR cells (both with and without HER2). Among mice injected with 231-BR-vector cells, those treated with 100 mg lapatinib/kg body weight had 54% fewer large metastases 24 days after starting treatment than those treated with vehicle (mean number of large metastases per brain section: 1.56 vs 3.36, difference = 1.80, 95% confidence interval [CI] = 0.92 to 2.68, P < .001), whereas treatment with 30 mg lapatinib/kg body weight had no effect. Among mice injected with 231-BR-HER2 cells, those treated with

  16. Imaging characteristic analysis of metastatic spine lesions from breast, prostate, lung, and renal cell carcinomas for surgical planning: Osteolytic versus osteoblastic

    PubMed Central

    Reddington, Justin A.; Mendez, Gustavo A.; Ching, Alex; Kubicky, Charlotte Dai; Klimo, Paul; Ragel, Brian T.

    2016-01-01

    Background: Surgeons treating metastatic spine disease can use computed tomography (CT) imaging to determine whether lesions are osteolytic, osteoblastic, or mixed. This enables treatment that considers the structural integrity of the vertebral body (VB), which is impaired with lytic lesions but not blastic lesions. The authors analyzed CT imaging characteristics of spine metastasis from breast, lung, prostate, and renal cell carcinomas (RCCs) to determine the metastasis patterns of each of these common tumors. Methods: The authors identified patients with metastatic spine disease treated during a 3-year period. Variables studied included age, sex, and cancer type. Lesions from breast, lung, prostate, and RCC primary lesions were selected for imaging analysis. Results: Sixty-six patients were identified: 17 had breast metastasis, 14 prostate, 18 lung, and 17 RCC. Breast cancer metastasis involved 33% of VBs with 56%, 20%, and 24% osteolytic, osteoblastic, and mixed, respectively. Prostate cancer metastasis involved 35% of VBs with 14%, 62%, and 24% osteolytic, osteoblastic, and mixed, respectively. Lung cancer metastasis involved 13% of VBs with 64%, 33%, and 3% osteolytic, osteoblastic, and mixed, respectively. RCC metastasis involved 11% of VBs with 91%, 7%, and 2% osteolytic, osteoblastic, and mixed lesions, respectively. Conclusions: To improve surgical planning, we advocate the use of CT prior to surgery to evaluate whether spine metastases are osteolytic or osteoblastic. In cases of osteolytic lesions, the concern is of segmental instability requiring reconstruction and the risk for screw pull out should instrumentation be considered. In cases of osteoblastic lesions, surgeons should consider debulking dense bone. PMID:27274410

  17. Endosalpingiosis in axillary lymph nodes simulating metastatic breast carcinoma: a potential diagnostic pitfall.

    PubMed

    Salehi, Amir H; Omeroglu, Gulbeyaz; Kanber, Yonca; Omeroglu, Atilla

    2013-12-01

    Intraoperative assessment of sentinel lymph nodes at time of surgical excision of primary breast carcinoma is a crucial step in the determination of cancer extent and the need for further axillary dissection. Benign epithelial inclusions in axillary lymph nodes can mimic metastatic carcinoma and are a well-known pitfall during examination of these nodes in frozen or permanent sections. Most often, these inclusions consists of heterotopic mammary glands and are familiar to the practicing pathologist. Here, however, we present a rare case of endosalpingiosis in the axillary lymph nodes of a breast cancer patient and describe our experience and effort to characterize the lesion. Simulating a metastatic focus of invasive ductal carcinoma, the glandular inclusions lacked myoepithelial cells and failed to stain with myoepithelial markers. However, consistent with a Mullerian origin, the inclusions demonstrated strong staining with PAX-8 and WT-1. Although endosalpingiotic inclusions are not uncommonly encountered in subdiaphragmatic lymph nodes, they are an extremely rare finding above the diaphragm. Pathologists must be aware of these lesions and their ability to imitate metastatic gland-forming carcinoma during frozen section or permanent examination of axillary lymph nodes.

  18. [Pertuzumab (Perjeta®) approval in HER2-positive metastatic breast cancers].

    PubMed

    Sabatier, Renaud; Gonçalves, Anthony

    2014-01-01

    Fifteen to 20% of breast cancers display HER2 amplification. Many therapeutic successes have been obtained for this subtype in the last decade since trastuzumab approval for metastatic and localized diseases. Pertuzumab, a new anti-HER2 antibody, has been approved in 2013 by the European Medicine Agency. This drug can be used in combination with trastuzumab and docetaxel for the first line treatment of metastatic or locally recurrent non resecable HER2-positive breast cancers not previously treated by chemotherapy or HER2-inhibitors in the metastatic setting. This approval has been done after the CLEOPATRA trial results. This was a randomized, double-blind, multicentre, phase III trial evaluating the standard treatment (trastuzumab plus docetaxel) associated to pertuzumab or placebo. The authors have reported a statistically significant and clinically relevant benefit for the pertuzumab-based treatment. Median progression-free survival was 18.4 for the pertuzumab arm versus 12.5 months for the control group (p<0.001). They also observed benefits concerning the secondary endpoints: overall response rate and overall survival. Patients receiving pertuzumab presented more frequent diarrhea and febrile neutropenia but no increase in cardiac events. This drug has already been evaluated in the neoadjuvant setting with a FDA approval recently obtained. Its use in the adjuvant setting is under evaluation.

  19. Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

    ClinicalTrials.gov

    2016-01-12

    Estrogen Receptor-positive Breast Cancer; Gastrinoma; Glucagonoma; HER2-negative Breast Cancer; Insulinoma; Mucositis; Oral Complications; Pancreatic Polypeptide Tumor; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Islet Cell Carcinoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Renal Cell Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Renal Cell Cancer

  20. Benign mixed tumors (pleomorphic adenomas) of the breast.

    PubMed

    Moran, C A; Suster, S; Carter, D

    1990-10-01

    Six cases of benign mixed tumors of the female breast are described. The tumors were found in three settings: (a) as a de-novo lesion arising from breast parenchyma, (b) as single or multiple nodules arising in a background of benign proliferative epithelial elements, and (c) in association with breast carcinoma. The tumors ranged from 1 to 4 cm in diameter, and were histologically characterized by the admixture in various proportions of benign glandular epithelial and myoepithelial elements and cartilaginous or myxoid components. Immunohistochemical staining supported this interpretation. One of the cases was remarkable for the presence of abundant tyrosine-like crystals, a feature described in benign mixed tumors of salivary glands. None of the tumors has recurred during a follow-up period of 1-7 years. Mixed tumors of the breast are considered to be similar to their dermal and salivary gland counterparts.

  1. Polyphenols from Artemisia annua L Inhibit Adhesion and EMT of Highly Metastatic Breast Cancer Cells MDA-MB-231.

    PubMed

    Ko, Young Shin; Lee, Won Sup; Panchanathan, Radha; Joo, Young Nak; Choi, Yung Hyun; Kim, Gon Sup; Jung, Jin-Myung; Ryu, Chung Ho; Shin, Sung Chul; Kim, Hye Jung

    2016-07-01

    Recent evidence suggests that polyphenolic compounds from plants have anti-invasion and anti-metastasis capabilities. The Korean annual weed, Artemisia annua L., has been used as a folk medicine for treatment of various diseases. Here, we isolated and characterized polyphenols from Korean A. annua L (pKAL). We investigated anti-metastatic effects of pKAL on the highly metastatic MDA-MB-231 breast cancer cells especially focusing on cancer cell adhesion to the endothelial cell and epithelial-mesenchymal transition (EMT). Firstly, pKAL inhibited cell viability of MDA-MB-231 cells in a dose-dependent manner, but not that of human umbilical vein endothelial cells (ECs). Polyphenols from Korean A. annua L inhibited the adhesion of MDA-MB-231 cells to ECs through reducing vascular cell adhesion molecule-1 expression of MDA-MB-231 and ECs, but not intracellular adhesion molecule-1 at the concentrations where pKAL did not influence the cell viability of either MDA-MB-231 cells nor EC. Further, pKAL inhibited tumor necrosis factor-activated MDA-MB-231 breast cancer cell invasion through inhibition of matrix metalloproteinase-2 and matrix metalloproteinase-9 and EMT. Moreover, pKAL inhibited phosphorylation of Akt, but not that of protein kinase C. These results suggest that pKAL may serve as a therapeutic agent against cancer metastasis at least in part by inhibiting the cancer cell adhesion to ECs through suppression of vascular cell adhesion molecule-1 and invasion through suppression of EMT. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27151203

  2. Metastatic testicular tumor presenting as a scrotal hydrocele: An initial manifestation of pancreatic adenocarcinoma

    PubMed Central

    KIM, YEON WOOK; KIM, JIN WON; KIM, JEE-HYUN; LEE, JUNGSIL; LEE, EUIJAE; KIM, MOON YOUNG; YANG, HYUN KYUNG; CHANG, HYUN

    2014-01-01

    Metastatic pancreatic adenocarcinoma involving the testis is a rare condition with a poor prognosis. The current study describes the case of a 69-year-old male who presented with a painful swelling of the left scrotum. Scrotal ultrasonography revealed hydroceles in the scrotal sacs, with the left one being larger in size. The patient underwent left hydrocelectomy and was eventually diagnosed with metastatic adenocarcinoma. Abdominal computed tomography, which was performed to detect the primary cancer, showed a pancreatic tail carcinoma with liver and multiple lymph node metastases, and peritoneal carcinomatosis. The patient received gemcitabine-based chemotherapy but resulted in progressive disease. This case shows that in a patient in whom a primary testicular tumor is unusual due to their age, a testicular mass or hydrocele should be a suspect for possible metastatic disease. PMID:24932235

  3. Metastatic solitary fibrous tumor of the meninges. Case report.

    PubMed

    Ng, H K; Choi, P C; Wong, C W; To, K F; Poon, W S

    2000-09-01

    Solitary fibrous tumor (SFT) is a unique tumor composed of interstitial dendritic cells that was first described in the thorax and subsequently reported in diverse organs. Extrathoracic SFTs are predominantly benign but rare malignant cases have been documented. In the nervous system, SFT has been described as a meningeal lesion although all 14 previously reported cases were benign. The authors report the first case of a meningeal SFT occurring in a 55-year-old woman. The tumor first presented as a meningeal lesion that after three recurrences over a 10-year period metastasized to the soft tissues and lungs. The potentially malignant nature of cranial SFTs, especially those with atypical histological features and high mitotic counts, should be recognized.

  4. Thermal detection of a prevascular tumor embedded in breast tissue.

    PubMed

    Agyingi, Ephraim; Wiandt, Tamas; Maggelakis, Sophia A

    2015-10-01

    This paper presents a mathematical model of heat transfer in a prevascular breast tumor. The model uses the steady state temperature of the breast at the skin surface to determine whether there is an underlying tumor and if so, verifies whether the tumor is growing or dormant. The model is governed by the Pennes equations and we present numerical simulations for versions of the model in two and three dimensions.

  5. Selective photothermal laser-tissue interaction with augmentation of immunoadjuvants in treatment of DMBA-4 metastatic mammary tumors in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Liu, Hong; Wolf, Roman F.; Lucroy, Michael D.; Nordquist, Robert E.

    2002-09-01

    Induced anti-tumor immunity can be the most effective and long-term cure for cancers, particularly for metastatic tumors. Laser immunotherapy has been developed to induce such immunological responses in rats bearing DMBA-4 metastatic mammary tumors. It involves an intratumoral administration of a laser-absorbing dye (indocyanine green) and a specially formulated immunoadjuvant (glycated chitosan), followed by an irradiation of a near-infrared laser (805-nm diode laser). To understand the immunity induced in this tumor model, immunization using freeze-thaw cell lysates against the DMBA-4 tumors was performed, followed by the tumor challenge twenty-one days later. Also performed is the surgical removal of the primary tumors of the rats before the observation of metastatic tumors. The immunization only delayed the emergence of the primary and metastases in the rats but did not provide immunity against the tumor challenge. After surgical removal of the primary tumors, the tumors re-emerged at the primary sites and the metastases developed at multiple remote sites. In contrast, laser immunotherapy cured rats experienced tumor regression and eradication. Our research has provided strong support for the working mechanism of laser immunotherapy. The experimental results showed that selective photothermal laser-tissue interaction with a complementary use of immunoadjuvant could be a potential therapy for treatment of metastatic tumors by inducing a tumor-specific, long-lasting immunity.

  6. Metastatic Breast Cancer Cells Collectively Invade Collagen by Following a Glucose Gradient

    NASA Astrophysics Data System (ADS)

    Sun, Bo; Austin, Robert; Liu, Liyu; Duclos, Guillaume; Lee, Jeongseog; Wu, Amy; Kam, Yooseok; Sontag, Eduardo; Stone, Howard; Sturm, James; Gatenby, Robert

    2013-03-01

    We show that MDA-MB-231 metastatic breast cancer cells collectively invade a three dimensional collagen matrix by following a glucose gradient. We observe that due to the 3D physical deformation of the matrix, as measured by the displacement of reporter beads within the matrix, there exists a long range deformation mechanical field inside the matrix which serves to couple the motions of the invading metastatic cell. The invasion front of the cells is a dynamic one, with different cells assuming the lead on a time scale of 24 hours due to certain cells having higher speeds of penetration, which are not sustained. The front cell leadership is dynamic presumably due to metabolic costs associated with the long range strain field which proceeds the invading cell front, which we have imaged using confocal imaging and marker beads imbedded in the collagen matrix. Sponsored by the NCI/NIH Physical Sciences Oncology Centers

  7. Ablation techniques for primary and metastatic liver tumors

    PubMed Central

    Ryan, Michael J; Willatt, Jonathon; Majdalany, Bill S; Kielar, Ania Z; Chong, Suzanne; Ruma, Julie A; Pandya, Amit

    2016-01-01

    Ablative treatment methods have emerged as safe and effective therapies for patients with primary and secondary liver tumors who are not surgical candidates at the time of diagnosis. This article reviews the current literature and describes the techniques, complications and results for radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation. PMID:26839642

  8. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF).

    PubMed

    Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki; Ushijima, Naofumi

    2008-01-15

    Serum vitamin D3-binding protein (Gc protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of breast cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Patient serum Nagalase activity is proportional to tumor burden. The deglycosylated Gc protein cannot be converted to MAF, resulting in no macrophage activation and immunosuppression. Stepwise incubation of purified Gc protein with immobilized beta-galactosidase and sialidase generated probably the most potent macrophage activating factor (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages treated in vitro with GcMAF (100 pg/ml) are highly tumoricidal to mammary adenocarcinomas. Efficacy of GcMAF for treatment of metastatic breast cancer was investigated with 16 nonanemic patients who received weekly administration of GcMAF (100 ng). As GcMAF therapy progresses, the MAF precursor activity of patient Gc protein increased with a concomitant decrease in serum Nagalase. Because of proportionality of serum Nagalase activity to tumor burden, the time course progress of GcMAF therapy was assessed by serum Nagalase activity as a prognostic index. These patients had the initial Nagalase activities ranging from 2.32 to 6.28 nmole/min/mg protein. After about 16-22 administrations (approximately 3.5-5 months) of GcMAF, these patients had insignificantly low serum enzyme levels equivalent to healthy control enzyme levels, ranging from 0.38 to 0.63 nmole/min/mg protein, indicating eradication of the tumors. This therapeutic procedure resulted in no recurrence for more than 4 years. PMID:17935130

  9. Regulation of vimentin by SIP1 in human epithelial breast tumor cells.

    PubMed

    Bindels, S; Mestdagt, M; Vandewalle, C; Jacobs, N; Volders, L; Noël, A; van Roy, F; Berx, G; Foidart, J-M; Gilles, C

    2006-08-17

    The expression of Smad interacting protein-1 (SIP1; ZEB2) and the de novo expression of vimentin are frequently involved in epithelial-to-mesenchymal transitions (EMTs) under both normal and pathological conditions. In the present study, we investigated the potential role of SIP1 in the regulation of vimentin during the EMT associated with breast tumor cell migration and invasion. Examining several breast tumor cell lines displaying various degrees of invasiveness, we found SIP1 and vimentin expression only in invasive cell lines. Also, using a model of cell migration with human mammary MCF10A cells, we showed that SIP1 is induced specifically in vimentin-positive migratory cells. Furthermore, transfection of SIP1 cDNA in MCF10A cells increased their vimentin expression both at the mRNA and protein levels and enhanced their migratory abilities in Boyden Chamber assays. Inversely, inhibition of SIP1 expression by RNAi strategies in BT-549 cells and MCF10A cells decreased vimentin expression. We also showed that SIP1 transfection did not activate the TOP-FLASH reporter system, suggesting that the beta-catenin/TCF pathway is not implicated in the regulation of vimentin by SIP1. Our results therefore implicate SIP1 in the regulation of vimentin observed in the EMT associated with breast tumor cell migration, a pathway that may contribute to the metastatic progression of breast cancer.

  10. Drug withdrawal in women with progressive metastatic breast cancer while on aromatase inhibitor therapy

    PubMed Central

    Chavarri-Guerra, Y; Higgins, M J; Szymonifka, J; Cigler, T; Liedke, P; Partridge, A; Ligibel, J; Come, S E; Finkelstein, D; Ryan, P D; Goss, P E

    2014-01-01

    Background: Acquiring resistance to endocrine therapy is common in metastatic hormone-receptor-positive breast cancer (MBC). These patients most often transition either to next-line endocrine therapy or to systemic chemotherapy. However, withdrawal of endocrine therapy and observation as is selectively practiced in prostate cancer is another potential strategy for breast cancer patients. Methods: A prospective, single-arm phase II trial of aromatase inhibitor (AI) withdrawal was performed in women with MBC, who had disease progression on AI therapy. The primary objective was to estimate the clinical benefit rate (defined as complete or partial response, or stable disease for at least 24 weeks, by RECIST criteria). Participants were monitored clinically and radiographically off all therapy at 8, 16 and 24 weeks after treatment and every 12 weeks thereafter until disease progression. Results: Twenty-four patients (of 40 intended) were enrolled when the study was closed due to slow accrual. Clinical benefit rate overall was 46% (95% CI 26% to 67%). Median progression-free survival from time of AI withdrawal was 4 months. Two patients have remained progression free, off all treatment, for over 60 months. Conclusions: Despite suboptimal patient accrual, our results suggest that selected patients with metastatic breast cancer progressing on AI therapy can experience disease stabilisation and a period of observation after AI withdrawal. A randomised phase II trial is planned. PMID:25233398

  11. Vaginal Dryness and Beyond: The Sexual Health Needs of Women Diagnosed With Metastatic Breast Cancer.

    PubMed

    McClelland, Sara I; Holland, Kathryn J; Griggs, Jennifer J

    2015-01-01

    While research on the sexual health of women with early stage cancer has grown extensively over the past decade, markedly less information is available to support the sexual health needs of women diagnosed with advanced breast cancer. Semistructured interviews were conducted with 32 women diagnosed with metastatic breast cancer (ages 35 to 77) about questions they had concerning their sexual health and intimate relationships. All participants were recruited from a comprehensive cancer center at a large Midwestern university. Three themes were examined: the role of sexual activity and intimate touch in participants' lives, unmet information needs about sexual health, and communication with medical providers about sexual concerns. Findings indicated that sexual activities with partners were important; however, participants worried about their own physical limitations and reported frequent physical (e.g., bone pains) and vaginal pain associated with intercourse. When women raised concerns about these issues in clinical settings, medical providers often focused exclusively on vaginal lubricants, which did not address the entirety of women's problems or concerns. In addition, women diagnosed with metastatic breast cancer reported needing additional resources about specialized vaginal lubricants, nonpenetrative and nongenitally focused sex, and sexual positions that did not compromise their physical health yet still provided pleasure.

  12. Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential

    SciTech Connect

    Kim, Yoo-Shin; Lee, Tae Hoon; O'Neill, Brian E.

    2015-08-14

    Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors. In this study, we elucidate a third possibility, that hyperthermia alters cellular adhesion and mechanotransduction, with particular impact on the cancer stem cell population. We demonstrate that cell heating results in a robust but temporary loss of cancer cell aggressiveness and metastatic potential in mouse models. In vitro, this heating results in a temporary loss in cell mobility, adhesion, and proliferation. Our hypothesis is that the loss of cellular adhesion results in suppression of cancer stem cells and loss of tumor virulence and metastatic potential. Our study suggests that the metastatic potential of cancer is particularly reduced by the effects of heat on cellular adhesion and mechanotransduction. If true, this could help explain both the successes and failures of clinical hyperthermia, and suggest ways to target treatments to those who would most benefit. - Highlights: • Non-lethal hyperthermia treatment of cancer cells is shown to cause a reduction in rates of tumor initiation and metastasis. • Dynamic imaging of cells during heat treatment shows temporary changes in cell shape, cell migration, and cell proliferation. • Loss of adhesion may lead to the observed effect, which may disproportionately impact the tumor initiating cell fraction. • Loss or suppression of the tumor initiating cell fraction results in the observed loss of metastatic potential in vivo. • This result may lead to new approaches to synergizing hyperthermia with surgery, radiation, and chemotherapy.

  13. Clinical and cytopathological aspects in phyllodes tumors of the breast.

    PubMed

    Pătraşcu, Anca; Popescu, Carmen Florina; Pleşea, I E; Bădulescu, Adriana; Tănase, Florentina; Mateescu, Garofiţa

    2009-01-01

    The frequency of mesenchymal breast tumors is very low, being represented mostly by tumors with biphasic proliferation (phyllodes tumors) and less by other types of non-epithelial tumors. From clinical point of view, phyllodes tumors (PT) can mimic a breast carcinoma. Therefore, the preoperative diagnosis by cytological examination on material obtained by fine needle aspiration (FNA) is very important for adequate treatment of these tumors. In current study, we assessed clinical aspects of 79 phyllodes tumors regarding patient's age and localization of the tumors. In 17 out of 79 cases, it has been performed FNA within the tumors with further cytological examination on the smears obtained. The median age of the patients was 46.07-year-old, being progressively higher with grade of the tumors with significant values between benign and borderline tumors (p=0.04954) and between benign and malignant ones (p=0.02890). The distinguish on the smears of stromal fragments and naked stromal nuclei with variable grade of atypia regarding the tumoral type, in detriment of epithelial elements have been conclusive for fibroepithelial lesion as cytopathological diagnosis. The preoperative differentiation between a breast phyllodes tumor and a breast carcinoma is extremely important for avoiding of a useless radical surgery for the patient. If the fine needle aspiration was correctly performed, the accuracy of the cytodiagnosis has been 82% in current study. PMID:19942954

  14. [Mucin-like carcinoma-associated antigen: sensitivity and specificity in metastatic breast cancer].

    PubMed

    Ammon, A; Eiffert, H; Alhusen, R; Weber, M; Rümelin, B; Groh, E; Bartsch, H; Marschner, N; Nagel, G A; Krieger, G

    1990-06-01

    The clinical usefulness of a tumor marker essentially depends on its sensitivity and specificity for a certain tumor. To prove, wheather the new tumor marker 'mucin-like carcinoma-associated antigen' could be used for the management of breast cancer patients, we determined its serum concentration in 50 healthy blood donors, 130 patients with various non-malignant diseases, 138 patients with different metastazised tumors and 137 breast cancer patients. 78 of the breast cancer patients had known metastases while 59 had no evidence of disease after initial surgical and adjuvant therapy. Only 2% of the blood donors and 3% of the patients with non-malignant diseases exceeded the cut-off level of 15 U/ml. In contrast to these findings, 28% of patients with various metastazised tumors and 77% of patients with metastazised breast cancer had serum levels above 15 U/ml. Breast cancer patients without evidence of disease had elevated marker values in only 3%. In breast cancer the serum levels of this antigen depends on the type of metastases. Maximal concentrations were found in mixed metastases while cutaneous or lymph-node metastases showed the lowest rate of positivity. Furthermore a good correlation of serial determined marker levels with the course of the disease was observed, so that we conclude, that mucin-like carcinoma-associated antigen can be used in follow-up of patients with metastazised breast cancer. Because of its high sensitivity and specificity it provides some advantage over other markers used in this disease. PMID:2204009

  15. Metastatic patterns of breast cancer subtypes: what radiologists should know in the era of personalized cancer medicine.

    PubMed

    Chikarmane, S A; Tirumani, S H; Howard, S A; Jagannathan, J P; DiPiro, P J

    2015-01-01

    There is accumulating evidence that molecular phenotyping of breast cancer determines the timing, pattern, and outcome of metastatic disease. The most clinically relevant subtypes are hormonal-positive [oestrogen and progesterone receptor (ER/PR) positive], HER2 expressing, and triple-negative breast cancers (TNBCs). ER/PR-positive breast cancers demonstrate the best prognosis; however, metastases, in particular osseous disease, may develop much later. HER2-expressing breast cancers, although aggressive, have improved outcomes due to the advent of HER2-targeted therapies, with increased risk of central nervous system (CNS) relapses later. Finally, TNBCs present in younger women, BRCA1 mutations carriers, and carry the worst overall prognosis, with high incidence of CNS metastases, especially during the first 5 years of diagnosis. It is important for radiologists to understand the nuances of these breast cancer subtypes to predict metastatic behaviours and guide possible imaging surveillance.

  16. Biomechanics of vertebral level, geometry, and transcortical tumors in the metastatic spine.

    PubMed

    Tschirhart, Craig E; Finkelstein, Joel A; Whyne, Cari M

    2007-01-01

    Metastatic involvement can disrupt the mechanical integrity of the spine, rendering vertebrae susceptible to burst fracture and neurologic damage. Fracture risk assessment for patients with spinal metastases is important in considering prophylactic treatment options. Stability of thoracic vertebrae affected by metastatic disease has been shown to be dependent on tumor size and bone density, but additional structural and geometric factors may also play a role in fracture risk assessment. The objective of this study was to use parametric finite element modeling to determine the effects of vertebral level, geometry, and metastatic compromise to the cortical shell on the risk of burst fracture in the thoracic spine. Analysis of vertebral level and geometry was assessed by investigation of seven scenarios ranging in geometry from T2-T4 to T10-T12. The effects of cortical shell compromised were assessed by comparison of four transcortical scenarios to a fully contained central vertebral body tumor scenario. Results demonstrated that upper thoracic vertebrae are at greater risk of burst fracture and that kyphotic motion segments are at decreased risk of burst fracture. Vertebrae with transcortical lesions are up to 30% less likely to lead to burst fracture initiation. The findings of this study are important for improving the understanding of burst fracture mechanics in metastatically involved vertebrae and guiding future modeling efforts.

  17. Oral fluoropyrimidines among the new drugs for patients with metastatic breast cancer

    PubMed Central

    Leonard, R C F

    2001-01-01

    Although drugs such as the taxoids and vinorelbine have increased the options available for anthracycline-resistant metastatic breast cancer, new therapeutic options are needed, particularly for taxoid-refractory tumours. Increasing emphasis is being placed on the development of oral agents, which many patients prefer provided efficacy is not compromised, particularly if the oral agents are less toxic than current intravenous agents. Capecitabine, a new, oral fluoropyrimidine, mimics continuous infusion 5-FU and is activated preferentially at the tumour site. Phase II studies of capecitabine have demonstrated encouraging response rates in patients with few further treatment options (20% response with an additional 43% achieving stable disease in paclitaxel-refractory patients; 36% response with a further 23% achieving stable disease in anthracycline-refractory patients). In addition, a randomized, phase II trial demonstrated a response rate of 30% (95% Cl: 19–43%) with capecitabine as first-line treatment for metastatic breast cancer, compared with 16% (95% Cl: 5–33%) in patients receiving low-dose CMF. These trials also showed that capecitabine has a favourable safety profile typical of infused fluoropyrimidines. Both alopecia and myelosuppression were rare. Capecitabine may therefore provide an effective, well-tolerated and convenient alternative to intravenous cytotoxic agents, not only in taxoid-resistant patients, but also in anthracycline-resistant metastatic breast cancer or as first-line therapy. Furthermore, the low incidence of myelosuppression makes capecitabine an attractive agent for incorporation into combination regimens with agents such as epirubicin/doxorubicin, the taxoids and vinorelbine. © 2001 Cancer ResearchCampaign http://www.bjcancer.com PMID:11384089

  18. Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [68Ga]ABY-025 Affibody PET/CT

    PubMed Central

    Sörensen, Jens; Velikyan, Irina; Sandberg, Dan; Wennborg, Anders; Feldwisch, Joachim; Tolmachev, Vladimir; Orlova, Anna; Sandström, Mattias; Lubberink, Mark; Olofsson, Helena; Carlsson, Jörgen; Lindman, Henrik

    2016-01-01

    Purpose: Positron Emission Tomography (PET) imaging of HER2 expression could potentially be used to select patients for HER2-targed therapy, predict response based on uptake and be used for monitoring. In this phase I/II study the HER2-binding Affibody molecule ABY-025 was labeled with 68Ga-gallium ([68Ga]ABY-025) for PET to study effect of peptide mass, test-retest variability and correlation of quantified uptake in tumors to histopathology. Experimental design: Sixteen women with known metastatic breast cancer and on-going treatment were included and underwent FDG PET/CT to identify viable metastases. After iv injection of 212±46 MBq [68Ga]ABY-025 whole-body PET was performed at 1, 2 and 4 h. In the first 10 patients (6 with HER2-positive and 4 with HER2-negative primary tumors), [68Ga]ABY-025 PET/CT with two different doses of injected peptide was performed one week apart. In the last six patients (5 HER2-positive and 1 HER2-negative primary tumors), repeated [68Ga]ABY-025 PET were performed one week apart as a test-retest of uptake in individual lesions. Biopsies from 16 metastases in 12 patients were collected for verification of HER2 expression by immunohistochemistry and in-situ hybridization. Results: Imaging 4h after injection with high peptide content discriminated HER2-positive metastases best (p<0.01). PET SUV correlated with biopsy HER2-scores (r=0.91, p<0.001). Uptake was five times higher in HER2-positive than in HER2-negative lesions with no overlap (p=0.005). The test-retest intra-class correlation was r=0.996. [68Ga]ABY-025 PET correctly identified conversion and mixed expression of HER2 and targeted treatment was changed in 3 of the 16 patients. Conclusion: [68Ga]ABY-025 PET accurately quantifies whole-body HER2-receptor status in metastatic breast cancer. PMID:26877784

  19. LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers.

    PubMed

    Prunier, Chloé; Josserand, Véronique; Vollaire, Julien; Beerling, Evelyne; Petropoulos, Christos; Destaing, Olivier; Montemagno, Christopher; Hurbin, Amandine; Prudent, Renaud; de Koning, Leanne; Kapur, Reuben; Cohen, Pascale A; Albiges-Rizo, Corinne; Coll, Jean-Luc; van Rheenen, Jacco; Billaud, Marc; Lafanechère, Laurence

    2016-06-15

    LIM kinases (LIMK) are emerging targets for cancer therapy, and they function as network hubs to coordinate actin and microtubule dynamics. When LIMKs are inhibited, actin microfilaments are disorganized and microtubules are stabilized. Owing to their stabilizing effect on microtubules, LIMK inhibitors may provide a therapeutic strategy to treat taxane-resistant cancers. In this study, we investigated the effect of LIMK inhibition on breast tumor development and on paclitaxel-resistant tumors, using a novel selective LIMK inhibitor termed Pyr1. Treatment of breast cancer cells, including paclitaxel-resistant cells, blocked their invasion and proliferation in vitro and their growth in vivo in tumor xenograft assays. The tumor-invasive properties of Pyr1 were investigated in vivo by intravital microscopy of tumor xenografts. A striking change of cell morphology was observed with a rounded phenotype arising in a subpopulation of cells, while other cells remained elongated. Notably, although Pyr1 decreased the motility of elongated cells, it increased the motility of rounded cells in the tumor. Pyr1 administration prevented the growth of metastasis but not their spread. Overall, our results provided a preclinical proof of concept concerning how a small-molecule inhibitor of LIMK may offer a strategy to treat taxane-resistant breast tumors and metastases. Cancer Res; 76(12); 3541-52. ©2016 AACR.

  20. [Metastatic cancer of the breast treated by polychemotherapy: a new prognostic approach].

    PubMed

    Nadal, J M; Jouve, M; Mosseri, V; Asselain, B; Pouillart, P

    1988-01-01

    The series consisted of 759 patients with metastatic breast cancer entered into randomized clinical trials at the Curie Institute. Twenty factors were found to be significant by univariate analysis. The current report gives a detailed analysis of prognostic factors using a new method of multivariate analysis for survival data, the recursive partition. This method was based on the construction of a regression scheme consisting of eight variables and four prognostic groups. A test sample procedure was used to validate our results and a regression scheme with three variables was constructed (LDH, adjuvant chemotherapy and the Karnofsky scale). The results were compared to the stepwise Cox regression. PMID:3179512

  1. Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors

    PubMed Central

    Schwab, Richard; Harismendy, Olivier; Pu, Minya; Crain, Brian; Yost, Shawn; Frazer, Kelly A.; Rana, Brinda; Hasteh, Farnaz; Wallace, Anne; Parker, Barbara A.

    2015-01-01

    Background Synchronous tumors can be independent primary tumors or a primary-metastatic (clonal) pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC) mutations/ # total HC mutations). Methods Statistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas. Results We validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48) and 283 known tumor clonal pairs (minimum CLS 13%, maximum p-value <0.01), across renal cell, testicular, and colorectal cancer. The CLS test correctly classified all validation samples but one, which it appears may have been incorrectly classified in the published data. As proof-of-concept we then applied the CLS test to two new cases of invasive synchronous bilateral breast cancer at our institution, each with one hormone receptor positive (ER+/PR+/HER2-) lobular and one triple negative ductal carcinoma. High confidence mutations were identified by exome sequencing and results were validated using deep targeted sequencing. The first tumor pair had CLS of 81% (p-value < 10–15), supporting clonality. In the second pair, no common mutations of 184 variants were validated (p-value >0.99), supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the

  2. Vorinostat in Combination With Paclitaxel and Carboplatin in Treating Patients With Metastatic or Recurrent Solid Tumors and HIV Infection

    ClinicalTrials.gov

    2016-10-11

    HIV Infection; Recurrent Anal Cancer; Recurrent Breast Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Anal Cancer; Stage IV Breast Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Unspecified Adult Solid Tumor, Protocol Specific

  3. Metastatic extra-abdominal presentation of gastrointestinal stromal tumors in a young Hispanic male: a case presentation and literature review.

    PubMed

    Di Marco, Anna; Paulo-Malave, Liza; Alayon-Laguer, Diogenes; Baez, Luis; Conde, Daniel; William, Caceres

    2012-01-01

    This article presents the medical history and management of a 44-year-old Hispanic male with metastatic extra-abdominal gastrointestinal stromal tumor including a literature review on this rare clinical presentation.

  4. An unusual case of metastatic male breast cancer to the nasopharynx-review of literature.

    PubMed

    Agrawal, Swati; Jayant, Kumar; Agarwal, Rajendra Kumar; Dayama, Kalyan G; Arora, Seema

    2015-10-01

    Metastatic breast carcinoma has been described to the various areas in the head and neck region. However, these metastases are rarely found in nasopharynx. Herein we are presenting the first case of male breast carcinoma with the longest survival secondary to distant metastases in right maxillary sinus and extending to the nasopharynx with extensive skeletal & lung metastases. Here we present a case of 65-year-old male with past medical history of right breast carcinoma, presented clinically with symptoms of recurrent sinusitis. Physical examination revealed a mass in the nasopharynx, which subsequently proved to be hormonal receptor positive high-grade adenocarcinoma secondary to metastasis of primary breast cancer on biopsy. The patient received three cycles of palliative chemotherapy based on Doxorubicin with Paclitaxel weekly. In spite of that, he developed pulmonary, liver and bone metastases. Later, treatment regimen was changed to Gemcitabine, Paclitaxel and injectable Zolendronate with calcium and vitamin D supplementation. Still he didn't show any improvement and later, he developed febrile neutropenia. Then, he refused further chemotherapy and died after 12 months of receiving the best hospice care. Breast cancer is one of the most common cancers in terms of incidence and mortality; breast cancer deserves extensive studies and research in different aspects. Breast cancer metastasizing to nasopharynx would be the last diagnosis that comes to mind for a male patient presenting with clinical features suggestive of recurrent sinusitis infection. As recurrent sinusitis is a very common ailment affecting human kind and is mostly due to benign causes. Metastasis, although rare, should be included in the differential diagnosis of nasopharyngeal lesion since it may clinically mimic a benign neoplasm or primary carcinoma. Based on our clinical experience and review of literature, although it is a very rare possibility in a patient with sinusitis, still we advise

  5. TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer.

    PubMed

    May, Felicity E B; Westley, Bruce R

    2015-06-01

    The stratification of breast cancer patients for endocrine therapies by oestrogen or progesterone receptor expression is effective but imperfect. The present study aims were to validate microarray studies that demonstrate TFF3 regulation by oestrogen and its association with oestrogen receptors in breast cancer, to evaluate TFF3 as a biomarker of endocrine response, and to investigate TFF3 function. Microarray data were validated by quantitative RT-PCR and northern and western transfer analyses. TFF3 was induced by oestrogen, and its induction was inhibited by antioestrogens, tamoxifen, 4-hydroxytamoxifen and fulvestrant in oestrogen-responsive breast cancer cells. The expression of TFF3 mRNA was associated with oestrogen receptor mRNA in breast tumours (Pearson's coefficient=0.762, P=0.000). Monoclonal antibodies raised against the TFF3 protein detected TFF3 by immunohistochemistry in oesophageal submucosal glands, intestinal goblet and neuroendocrine cells, Barrett's metaplasia and intestinal metaplasia. TFF3 protein expression was associated with oestrogen receptor, progesterone receptor and TFF1 expression in malignant breast cells. TFF3 is a specific and sensitive predictive biomarker of response to endocrine therapy, degree of response and duration of response in unstratified metastatic breast cancer patients (P=0.000, P=0.002 and P=0.002 respectively). Multivariate binary logistic regression analysis demonstrated that TFF3 is an independent biomarker of endocrine response and degree of response, and this was confirmed in a validation cohort. TFF3 stimulated migration and invasion of breast cancer cells. In conclusion, TFF3 expression is associated with response to endocrine therapy, and outperforms oestrogen receptor, progesterone receptor and TFF1 as an independent biomarker, possibly because it mediates the malign effects of oestrogen on invasion and metastasis.

  6. TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer

    PubMed Central

    May, Felicity E B; Westley, Bruce R

    2015-01-01

    The stratification of breast cancer patients for endocrine therapies by oestrogen or progesterone receptor expression is effective but imperfect. The present study aims were to validate microarray studies that demonstrate TFF3 regulation by oestrogen and its association with oestrogen receptors in breast cancer, to evaluate TFF3 as a biomarker of endocrine response, and to investigate TFF3 function. Microarray data were validated by quantitative RT-PCR and northern and western transfer analyses. TFF3 was induced by oestrogen, and its induction was inhibited by antioestrogens, tamoxifen, 4-hydroxytamoxifen and fulvestrant in oestrogen-responsive breast cancer cells. The expression of TFF3 mRNA was associated with oestrogen receptor mRNA in breast tumours (Pearson's coefficient=0.762, P=0.000). Monoclonal antibodies raised against the TFF3 protein detected TFF3 by immunohistochemistry in oesophageal submucosal glands, intestinal goblet and neuroendocrine cells, Barrett's metaplasia and intestinal metaplasia. TFF3 protein expression was associated with oestrogen receptor, progesterone receptor and TFF1 expression in malignant breast cells. TFF3 is a specific and sensitive predictive biomarker of response to endocrine therapy, degree of response and duration of response in unstratified metastatic breast cancer patients (P=0.000, P=0.002 and P=0.002 respectively). Multivariate binary logistic regression analysis demonstrated that TFF3 is an independent biomarker of endocrine response and degree of response, and this was confirmed in a validation cohort. TFF3 stimulated migration and invasion of breast cancer cells. In conclusion, TFF3 expression is associated with response to endocrine therapy, and outperforms oestrogen receptor, progesterone receptor and TFF1 as an independent biomarker, possibly because it mediates the malign effects of oestrogen on invasion and metastasis. PMID:25900183

  7. Induction of the metastatic phenotype in a mouse tumor model by 5-azacytidine, and characterization of an antigen associated with metastatic activity.

    PubMed Central

    Olsson, L; Forchhammer, J

    1984-01-01

    The murine Lewis lung carcinoma is a long-term grafted tumor that, after subcutaneous inoculation, forms metastases to the lungs. Forty-two cell lines were established from a primary tumor site and 40 were established from lung metastatic foci. Cloned sublines were established from the original 82 lines, and 2 sublines among 405 were found to be tumorigenic but not metastatic (T+/M-), whereas the remaining 403 sublines were both tumorigenic and metastatic (T+/M+). The T+/M- phenotype was shown to be stable for greater than 2 yr. However, treatment of the T+/M- cell lines for 3 days with 3 microM 5-azacytidine resulted in reexpression of the metastatic phenotype in otherwise stable T+/M- lines. Also, 5-azacytidine treatment could result in loss of the metastatic phenotype in lines that had been stable T+/M+. The changes in tumorigenic and metastatic phenotypes were not associated with altered immunogenicity of the cells. Monoclonal antibodies were generated against T+/M+ cells, and one antibody ( M36D3 ) was found to bind only to T+/M+ cells. Reactivity of the antibody was found to co-vary with expression of the metastatic phenotype. The antigen recognized by M36D3 antibody thus seems to be associated with metastatic capability. The antigen was found by two-dimensional gel electrophoretic analysis to be a cellular protein of Mr approximately equal to 45,000 and pI approximately equal to 6.7. Images PMID:6203119

  8. Economic evaluation of eribulin as second-line treatment for metastatic breast cancer in South Korea

    PubMed Central

    Tremblay, Gabriel; Majethia, Unnati; Breeze, Janis L; Kontoudis, Ilias; Park, Jeongae

    2016-01-01

    Background Metastatic breast cancer (MBC) is associated with poor prognosis, particularly for those patients with human epidermal growth factor receptor (HER2)-negative tumor. Similar to the rest of the world, treatment options are limited in South Korea following first-line chemotherapy with anthracyclines and/or taxanes. This study examined the cost-effectiveness and cost-utility of eribulin in South Korean patients with HER2-negative MBC who have progressed after usage of at least one chemotherapeutic regimen for advanced disease (second-line therapy). Methods A partition survival model was developed from the perspective of the South Korean health care system. The economic impact of introducing eribulin as second-line therapy for HER2-negative MBC was compared to that of capecitabine and vinorelbine. The analysis estimated incremental cost per life-year (LY), that is, cost-effectiveness, and cost per quality-adjusted life-year (QALY), that is, cost-utility, of eribulin for management of HER2-negative MBC in South Korea. The model accounted for overall survival, progression-free survival, drug costs, grade 3/4 adverse events, and health care utilization. Deterministic and probabilistic sensitivity analyses were performed to identify uncertainty in the results of the economic evaluation. Results Second-line eribulin was associated with greater benefits in terms of LY and QALY, compared to capecitabine and vinorelbine. The incremental cost-effectiveness ratio was ₩10.5M (approximately USD 9,200) per LY, and the incremental cost-utility ratio was ₩17M (approximately USD 14,800) per QALY in the basecase analysis. The incremental cost-utility ratio ranged from ₩12M (USD 10,461) to ₩27M (USD 23,538) per QALY in the deterministic sensitivity analysis. In the probabilistic sensitivity analysis, >99% of the simulations were below ₩50M (USD 42,300), and the lower and upper 95% confidence intervals were ₩3M (USD 2,600) and ₩24M (USD 20,900) per QALY

  9. Economic evaluation of eribulin as second-line treatment for metastatic breast cancer in South Korea

    PubMed Central

    Tremblay, Gabriel; Majethia, Unnati; Breeze, Janis L; Kontoudis, Ilias; Park, Jeongae

    2016-01-01

    Background Metastatic breast cancer (MBC) is associated with poor prognosis, particularly for those patients with human epidermal growth factor receptor (HER2)-negative tumor. Similar to the rest of the world, treatment options are limited in South Korea following first-line chemotherapy with anthracyclines and/or taxanes. This study examined the cost-effectiveness and cost-utility of eribulin in South Korean patients with HER2-negative MBC who have progressed after usage of at least one chemotherapeutic regimen for advanced disease (second-line therapy). Methods A partition survival model was developed from the perspective of the South Korean health care system. The economic impact of introducing eribulin as second-line therapy for HER2-negative MBC was compared to that of capecitabine and vinorelbine. The analysis estimated incremental cost per life-year (LY), that is, cost-effectiveness, and cost per quality-adjusted life-year (QALY), that is, cost-utility, of eribulin for management of HER2-negative MBC in South Korea. The model accounted for overall survival, progression-free survival, drug costs, grade 3/4 adverse events, and health care utilization. Deterministic and probabilistic sensitivity analyses were performed to identify uncertainty in the results of the economic evaluation. Results Second-line eribulin was associated with greater benefits in terms of LY and QALY, compared to capecitabine and vinorelbine. The incremental cost-effectiveness ratio was ₩10.5M (approximately USD 9,200) per LY, and the incremental cost-utility ratio was ₩17M (approximately USD 14,800) per QALY in the basecase analysis. The incremental cost-utility ratio ranged from ₩12M (USD 10,461) to ₩27M (USD 23,538) per QALY in the deterministic sensitivity analysis. In the probabilistic sensitivity analysis, >99% of the simulations were below ₩50M (USD 42,300), and the lower and upper 95% confidence intervals were ₩3M (USD 2,600) and ₩24M (USD 20,900) per QALY

  10. Huge malignant phyllodes breast tumor: a real entity in a new era of early breast cancer.

    PubMed

    Testori, Alberto; Meroni, Stefano; Errico, Valentina; Travaglini, Roberto; Voulaz, Emanuele; Alloisio, Marco

    2015-01-01

    Phyllodes tumor is an extremely rare tumor of the breast. It occurs in females in the third and fourth decades. The difficulty in distinguishing between phyllodes tumors and benign fibroadenoma may lead to misdiagnosis. Lymph node involvement is rarely described in phyllodes tumors; for this reason, sentinel node biopsy may be warranted. We present a case of a 33-year-old woman affected by huge tumor of the right breast with ulceration in the skin with a rapid tumor growth and with omolateral axillary metastasis. PMID:25880837

  11. Patient-Derived Tumor Xenograft Models of Breast Cancer.

    PubMed

    Suarez, Christopher D; Littlepage, Laurie E

    2016-01-01

    The need for model systems that more accurately predict patient outcome has led to a renewed interest and a rapid development of orthotopic transplantation models designed to grow, expand, and study patient-derived human breast tumor tissue in mice. After implanting a human breast tumor piece into a mouse mammary fat pad and allowing the tumor to grow in vivo, the tumor tissue can be either harvested and immediately implanted into mice or can be stored as tissue pieces in liquid nitrogen for surgical implantation at a later time. Here, we describe the process of surgically implanting patient-derived breast tumor tissue into the mammary gland of nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice and harvesting tumor tissue for long-term storage in liquid nitrogen.

  12. Assessment of Tumor Radioresponsiveness and Metastatic Potential by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

    SciTech Connect

    Ovrebo, Kirsti Marie; Gulliksrud, Kristine; Mathiesen, Berit; Rofstad, Einar K.

    2011-09-01

    Purpose: It has been suggested that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide clinically useful biomarkers for personalized cancer treatment. In this preclinical study, we investigated the potential of DCE-MRI as a noninvasive method for assessing the radioresponsiveness and metastatic potential of tumors. Methods and Materials: R-18 melanoma xenografts growing in BALB/c nu/nu mice were used as experimental tumor models. Fifty tumors were subjected to DCE-MRI, and parametric images of K{sup trans} (the volume transfer constant of Gd-DTPA) and v{sub e} (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The tumors were irradiated after the DCE-MRI, either with a single dose of 10 Gy for detection of radiobiological hypoxia (30 tumors) or with five fractions of 4 Gy in 48 h for assessment of radioresponsiveness (20 tumors). The host mice were then euthanized and examined for lymph node metastases, and the primary tumors were resected for measurement of cell survival in vitro. Results: Tumors with hypoxic cells showed significantly lower K{sup trans} values than tumors without significant hypoxia (p < 0.0001, n = 30), and K{sup trans} decreased with increasing cell surviving fraction for tumors given fractionated radiation treatment (p < 0.0001, n = 20). Tumors in metastasis-positive mice had significantly lower K{sup trans} values than tumors in metastasis-negative mice (p < 0.0001, n = 50). Significant correlations between v{sub e} and tumor hypoxia, radioresponsiveness, or metastatic potential could not be detected. Conclusions: R-18 tumors with low K{sup trans} values are likely to be resistant to radiation treatment and have a high probability of developing lymph node metastases. The general validity of these observations should be investigated further by studying preclinical tumor models with biological

  13. Loss of monomorphic and polymorphic HLA antigens in metastatic breast and colon carcinoma.

    PubMed Central

    Goepel, J. R.; Rees, R. C.; Rogers, K.; Stoddard, C. J.; Thomas, W. E.; Shepherd, L.

    1991-01-01

    MHC class I antigens are intimately involved in intercellular communication, and recognition by cytotoxic T cells. Thus tumour cells that fail to express them may be at a growth or metastatic advantage. A series of ten colorectal and ten breast carcinomas, and their respective lymph node metastases, were examined immunohistologically using monoclonal antibodies (mAb) against both monomorphic and A2 polymorphic determinants, and beta-2-microglobulin (beta 2m). Four colon polypoid adenomas stained positively throughout, but 6/10 primary tumours had partial or complete loss of expression of monomorphic determinants using mAb W6/32: two node and the liver metastasis showed less, four more expression. Similar results were seen for beta 2m. HLA-A2 expression was absent or reduced in 4/4 colon tumours and all their metastases. Among the breast tumours, W6/32 staining was absent or reduced in 2/10, and node deposits showed two with less reactivity than their primary. Beta 2m staining was reduced or absent in 8/10 primaries and all the node metastases; in every case in which beta 2m was detected in the primary tumour their corresponding lymph node metastasis showed a decreased expression. HLA-A2 expression was absent or reduced in 3/4 primary breast carcinomas, and all their metastases. These results show that individual human colon and breast carcinomas often have a reduced HLA class I antigen expression, which apparently confers a metastatic advantage. Images Figure 1 Figure 2 Figure 3 PMID:1718386

  14. Targeting of miR9/NOTCH1 interaction reduces metastatic behavior in triple-negative breast cancer.

    PubMed

    Mohammadi-Yeganeh, Samira; Mansouri, Ardalan; Paryan, Mahdi

    2015-11-01

    Many reports have indicated deregulation of a variety of microRNAs (miRNAs) in human cancers. In this study, we appraised miR-9 correlation with NOTCH1 involved in Notch signaling in metastatic breast cancer. The Notch signaling pathway has been approved to be associated with the development and progression of many human cancers, including breast cancer, but the precise mechanism has remained unknown. To the best of our knowledge, this is the first study that introduces miR-9 and NOTCH1 correlation as an effective factor in breast cancer. We found that miR-9 expression was decreased in MDA-MB-231 breast cancer cells compared with MCF-10A normal breast cell line. However, NOTCH1 was upregulated in the metastatic breast cancer cells. Furthermore, luciferase assay revealed a significant inverse correlation between miR-9 and NOTCH1. Overexpression of Notch signaling via Notch1 intracellular domain in MDA-MB-231 cell line was suppressed by lentiviruses expressing miR-9. Taken together, the results obtained by MTT, flow cytometry, migration, and wound healing assays showed that it is possible to inhibit metastasis and induce pro-apoptotic state by induction of miR-9 expression in MDA-MB-231 cells but with no effect on cell proliferation. These results shows that miR-9, by direct targeting of NOTCH1, can reveal a suppressor-like activity in metastatic breast cancer cells.

  15. Retroperitoneal metastatic germ cell tumor presenting as a psoas abscess: a diagnostic pitfall.

    PubMed

    Dieker, Carrie A; De Las Casas, Luis E; Davis, Brian R

    2013-07-01

    Most testicular neoplasms are germ cell tumors, the vast majority of which represent seminomas. Most seminomas present localized to the testis, whereas nonseminomatous germ cell tumors more often present with lymph node metastases. Psoas abscesses generally arise from a contiguous intra-abdominal or pelvic infectious process, an adjacent focus of osteomyelitis or septic emboli from distant infectious foci. In this study, the case of a 24-year-old man who presented with a right psoas mass presumptively diagnosed as an abscess secondary to fever and leukocytosis is presented. The patient had a history of right testicular seminoma, and normal serum levels of alpha-fetoprotein and human chorionic gonadotropin. Surgical exploration and biopsy demonstrated seminoma metastasis. This case represents an extremely unusual clinical presentation of metastatic germ cell tumor presenting as a psoas abscess. This unique case represents an unusual presentation of a recurrent germ cell tumor mimicking a psoas abscess. Awareness of possible metastatic testicular germ cell neoplasm as a psoas abscess could prevent diagnosis delay before retroperitoneal tumor debulking. PMID:23360792

  16. Recovery from Choriocarcinoma Syndrome Associated with a Metastatic Extragonadal Germ Cell Tumor Hemorrhage

    PubMed Central

    Komori, Koji; Takahari, Daisuke; Kimura, Kenya; Kinoshita, Takashi; Ito, Seiji; Abe, Tetsuya; Senda, Yoshiki; Misawa, Kazunari; Ito, Yuichi; Uemura, Norihisa; Natsume, Seiji; Kawakami, Jiro; Iwata, Yoshinori; Tsutsuyama, Masayuki; Shigeyoshi, Itaru; Akazawa, Tomoyuki; Hayashi, Daisuke; Ouchi, Akira; Shimizu, Yasuhiro

    2016-01-01

    A germ cell tumor is the most common form of malignancy in early male life, and can be classified as either seminomatous or nonseminomatous. Choriocarcinoma, comprised of nonseminomatous germ cells, is the most aggressive type of germ cell tumor and characteristically metastasizes to the retroperitoneal lymph nodes and less frequently to the lungs, liver, bone or brain [Shibuya et al., 2009;48: 551–554]. A 56-year-old man was admitted to another hospital complaining of abdominal distension. Symptoms included anorexia, vomiting, and diarrhea. The patient was diagnosed with an extragonadal germ cell tumor and referred to our hospital to receive chemotherapy. The day after admission, the patient's abdominal distension gradually worsened. An emergency operation revealed venous hemorrhage from the surface of a metastatic extragonadal germ cell tumor between the ligament of Treitz and the inferior mesenteric vein in a horizontal position. Hemostatic treatment was performed with 4-0 proline thread attached to a medicated cotton sponge, rather than using a simple proline thread, and the closure area was manually compressed. Chemotherapy was initiated on postoperative day 10. A metastatic extragonadal germ cell tumor that causes massive hemorrhage and gastrointestinal hemorrhage is very rare, and represents a life-threatening emergency. If the patient's condition carries a substantial risk of bleeding to death, it may be worthwhile to attempt abdominal operations. PMID:27403124

  17. Recovery from Choriocarcinoma Syndrome Associated with a Metastatic Extragonadal Germ Cell Tumor Hemorrhage.

    PubMed

    Komori, Koji; Takahari, Daisuke; Kimura, Kenya; Kinoshita, Takashi; Ito, Seiji; Abe, Tetsuya; Senda, Yoshiki; Misawa, Kazunari; Ito, Yuichi; Uemura, Norihisa; Natsume, Seiji; Kawakami, Jiro; Iwata, Yoshinori; Tsutsuyama, Masayuki; Shigeyoshi, Itaru; Akazawa, Tomoyuki; Hayashi, Daisuke; Ouchi, Akira; Shimizu, Yasuhiro

    2016-01-01

    A germ cell tumor is the most common form of malignancy in early male life, and can be classified as either seminomatous or nonseminomatous. Choriocarcinoma, comprised of nonseminomatous germ cells, is the most aggressive type of germ cell tumor and characteristically metastasizes to the retroperitoneal lymph nodes and less frequently to the lungs, liver, bone or brain [Shibuya et al., 2009;48: 551-554]. A 56-year-old man was admitted to another hospital complaining of abdominal distension. Symptoms included anorexia, vomiting, and diarrhea. The patient was diagnosed with an extragonadal germ cell tumor and referred to our hospital to receive chemotherapy. The day after admission, the patient's abdominal distension gradually worsened. An emergency operation revealed venous hemorrhage from the surface of a metastatic extragonadal germ cell tumor between the ligament of Treitz and the inferior mesenteric vein in a horizontal position. Hemostatic treatment was performed with 4-0 proline thread attached to a medicated cotton sponge, rather than using a simple proline thread, and the closure area was manually compressed. Chemotherapy was initiated on postoperative day 10. A metastatic extragonadal germ cell tumor that causes massive hemorrhage and gastrointestinal hemorrhage is very rare, and represents a life-threatening emergency. If the patient's condition carries a substantial risk of bleeding to death, it may be worthwhile to attempt abdominal operations. PMID:27403124

  18. Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer

    PubMed Central

    2012-01-01

    Introduction The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and breast cancer-related death (BRD) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether the presence of CTC at the time of diagnosis was associated with recurrence-free survival (RFS) and BRD. Methods In a prospective single center study, CTC were enumerated with the CellSearch system in 30 ml of peripheral blood of 602 patients before undergoing surgery for breast cancer. There were 97 patients with a benign tumor, 101 did not meet the inclusion criteria of which there were 48 patients with DCIS, leaving 404 stage I to III patients. Patients were stratified into unfavorable (CTC ≥1) and favorable (CTC = 0) prognostic groups. Results ≥1 CTC in 30 ml blood was detected in 15 (15%) benign tumors, in 9 DCIS (19%), in 28 (16%) stage I, 32 (18%) stage II and in 16 (31%) patients with stage III. In stage I to III patients 76 (19%) had ≥1 CTC of whom 16 (21.1%) developed a recurrence. In 328 patients with 0 CTC 38 (11.6%) developed a recurrence. Four-year RFS was 88.4% for favorable CTC and 78.9% for unfavorable CTC (P = 0.038). A total of 25 patients died of breast cancer-related causes and 11 (44%) had ≥1 CTC. BRD was 4.3% for favorable and 14.5% for unfavorable CTC (P = 0.001). In multivariate analysis ≥1 CTC was associated with distant disease-free survival, but not for overall recurrence-free survival. CTC, progesterone receptor and N-stage were independent predictors of BRD in multivariate analysis. Conclusions Presence of CTC in breast cancer patients before undergoing surgery with curative intent is associated with an increased risk for breast cancer-related death. PMID:23088337

  19. NGlycolylGM3/VSSP Vaccine in Metastatic Breast Cancer Patients: Results of Phase I/IIa Clinical Trial

    PubMed Central

    de la Torre, Ana; Hernandez, Julio; Ortiz, Ramón; Cepeda, Meylán; Perez, Kirenia; Car, Adriana; Viada, Carmen; Toledo, Darién; Guerra, Pedro Pablo; García, Elena; Arboláez, Migdacelys; Fernandez, Luis E

    2012-01-01

    Patients treated with vaccines based on NGlycolil gangliosides have showed benefit in progression free survival and overall survival. These molecules, which have been observed in breast cancer cells, are minimally or not expressed in normal human tissue and have been considered as antigen tumor-specific. For this reason they are very attractive to immunotherapy. A phase I/II clinical trial was carried out in metastatic breast cancer patients with the NGlycolylGM3/VSSP vaccine administered by subcutaneous route. Selecting the optimal biological doses of the vaccine in these patients was the principal objective based on the immunogenicity, efficacy and safety results. Six levels of doses of vaccine were studied. Treatment schedule consisted of five doses every two weeks and then monthly until reaching a fifteenth doses. Doses levels studied were 150, 300, 600, 900, 1200 and 1500 μg. Five patients in each level were included except at the 900 μg dose, in which ten patients were included. Immunogenicity was determined by levels of antibodies generated in patients after vaccination. The response criteria of evaluation in solid tumors (RECIST) was used to evaluate antitumoral effect. Safety was evaluated by Common Toxicity Criteria of Adverse Event (CTCAE). The vaccine administration was safe and immunogenic in all does levels. Most frequent adverse events related to vaccination were mild or moderate and were related to injection site reactions and “flu-like” symptoms. Vaccination induced specific anti-NeuGcGM3 IgM and IgG antibodies responses in all patients. Disease control (objective response or stable disease) was obtained in 72.7% of evaluated patients. Median overall survival was 15.9 months. Two patients of two different dose levels achieved overall survival values of about six years. The dose of 900 μg was selected as biological optimal dose in which overall survival was 28.5 months. PMID:23055739

  20. Bilateral desmoid tumor of the breast: case seriesand literature review

    PubMed Central

    Wongmaneerung, Phanchaporn; Somwangprasert, Areewan; Watcharachan, Kirati; Ditsatham, Chagkrit

    2016-01-01

    Background Desmoid tumor of the breast is very rare and locally aggressive but has no distant metastasis. Bilateral lesions are extremely rare, found in only 4% of patients. Two cases of bilateral desmoid tumor of the breast are reported. The clinical presentation, diagnosis, imaging, treatment, and follow-up outcomes of recurrence as well as a brief literature review are provided. Case reports Case 1 is a 31-year-old woman who presented with nipple retraction. An ultrasound revealed BIRAD V in both breasts. She underwent a bilateral excisional biopsy under ultrasound mark with the pathology result of extra-abdominal desmoid tumor in both breasts. The patient had a bilateral mastectomy with silicone implantation due to the involved margins by excision. She remained tumor free after 7-year follow-up. Case 2 is a 28-year-old woman who presented with a lump on her right breast that she had discovered ~2 months earlier. An ultrasound showed a spiculated mass in the right breast and some circumscribed hypoechoic masses in both breasts. A bilateral breast excision was done. The pathology result was an extra-abdominal desmoid tumor. She had recurrence on both sides and underwent a mastectomy and silicone implantation. The tumor has not recurred after 1-year follow-up. Conclusion Imaging cannot distinguish between benign breast lesions and malignancy. Pathology results are helpful in making a definitive diagnosis. Given that the desmoid tumor is locally aggressive, a local excision with clear margins is recommended. Chemotherapy and hormonal treatment are controversial. PMID:27578999

  1. miR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors.

    PubMed

    Gong, Chang; Nie, Yan; Qu, Shaohua; Liao, Jian-You; Cui, Xiuying; Yao, Herui; Zeng, Yunjie; Su, Fengxi; Song, Erwei; Liu, Qiang

    2014-08-15

    Phyllodes tumors of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of phyllodes tumors. It remains unknown what drives the malignant progression of phyllodes tumors. We found that the expression of myofibroblast markers, α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), and stromal cell-derived factor-1 (SDF-1), is progressively increased in the malignant progression of phyllodes tumors. Microarray showed that miR-21 was one of the most significantly upregulated microRNAs in malignant phyllodes tumors compared with benign phyllodes tumors. In addition, increased miR-21 expression was primarily localized to α-SMA-positive myofibroblasts. More importantly, α-SMA and miR-21 are independent predictors of recurrence and metastasis, with their predictive value of recurrence better than histologic grading. Furthermore, miR-21 mimics promoted, whereas miR-21 antisense oligos inhibited, the expression of α-SMA, FAP, and SDF-1, as well as the proliferation and invasion of primary stromal cells of phyllodes tumors. The ability of miR-21 to induce myofibroblast differentiation was mediated by its regulation on Smad7 and PTEN, which regulate the migration and proliferation, respectively. In breast phyllodes tumor xenografts, miR-21 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. This study suggests an important role of myofibroblast differentiation in the malignant progression of phyllodes tumors that is driven by increased miR-21.

  2. Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer.

    PubMed

    Kim, Min Soo; Lee, Won Sung; Jeong, Joon; Kim, Seong-Jin; Jin, Wook

    2015-11-24

    In metastatic breast cancers, the acquisition of metastatic ability, which leads to clinically incurable disease and poor survival, has been associated with acquisition of epithelial-mesenchymal transition (EMT) program and self-renewing trait (CSCs) via activation of PI3K/AKT and IL6/JAK2/STAT3 signaling pathways. We found that TrkB is a key regulator of PI3K/AKT and JAK/STAT signal pathway-mediated tumor metastasis and EMT program. Here, we demonstrated that TrkB activates AKT by directly binding to c-Src, leading to increased proliferation. Also, TrkB increases Twist-1 and Twist-2 expression through activation of JAK2/STAT3 by inducing c-Src-JAK2 complex formation. Furthermore, TrkB in the absence of c-Src binds directly to JAK2 and inhibits SOCS3-mediated JAK2 degradation, resulting in increased total JAK2 and STAT3 levels, which subsequently leads to JAK2/STAT3 activation and Twist-1 upregulation. Additionally, activation of the JAK2/STAT3 pathway via induction of IL-6 secretion by TrkB enables induction of activation of the EMT program via induction of STAT3 nuclear translocation. These observations suggest that TrkB is a promising target for future intervention strategies to prevent tumor metastasis, EMT program and self-renewing trait in breast cancer. PMID:26515594

  3. Extremely rare borderline phyllodes tumor in the male breast: a case report.

    PubMed

    Kim, Jung Gyu; Kim, Shin Young; Jung, Hae Yoen; Lee, Deuk Young; Lee, Jong Eun

    2015-01-01

    Phyllodes tumor of the male breast is an extremely rare disease, and far fewer cases of borderline phyllodes tumors than benign or malignant tumors in the male breast have been reported. We report a case of borderline phyllodes tumor in the male breast with imaging findings of the tumor and pathologic correlation. PMID:26316459

  4. Perceptions and needs of women with metastatic breast cancer: A focus on clinical trials

    PubMed Central

    Nahleh, Zeina A.; Lin, Nancy U.; Wolff, Antonio C.; Cardoso, Fatima

    2014-01-01

    Many patients are living longer with Metastatic Breast Cancer (MBC) than ever before. However, complete responses remain uncommon, and progression of disease is often inevitable. The experience of living with MBC exposes patients to a wide variety of clinical, psychological, social and spiritual issues. Although much research effort has focused on decision-making and coping strategies among women with early breast cancer, relatively little attention has been given to the needs, experiences, and perceptions of women living with MBC. Furthermore, there are major research gaps in understanding and prioritizing the types of psycho-social interventions that would make the most difference in the lives of these patients. Fortunately, the tide is turning. This communication represents a joint effort of the Breast International Group and the National Cancer Institute (NCI)-sponsored North American Breast Cancer Group (BIG-NABCG) to highlight perceptions and needs of patients living with MBC and current obstacles facing them, and recommends strategies for better addressing some of these unmet needs. PMID:23535510

  5. Gene expression profile in breast cancer comprising predictive markers for metastatic risk.

    PubMed

    Sirirattanakul, S; Wannakrairot, P; Tencomnao, T; Santiyanont, R

    2015-01-01

    Quantitative multiplex reverse transcriptase-polymerase chain reaction was developed for the simultaneous detection of multiple-gene expression levels of formalin-fixed, paraffin-embedded breast cancer samples. Candidate genes were selected from previous microarray data relevant to breast cancer markers that had the potential to serve as predictive markers for metastatic risk. This multiplex gene set included 11 candidate and 3 housekeeping genes, and the aim was to predict breast cancer progression based on lymph node involvement status. Our study demonstrated that the system generated a good standard curve fit (R(2) = 0.9901-0.9998) correlated with RNA concentration. The multiplex gene expression profile indicated significantly downregulated levels of G protein-coupled receptor kinase interacting ArfGAP 2 (GIT2) and mitochondrial transcription termination factor (MTERF) genes in a lymph node-positive group of patients, with P values of 0.004 and 0.038, respectively. Therefore, this in-house method using multiple genes of interest might be an alternative tool for prediction of breast cancer metastasis. PMID:26400320

  6. Local microRNA delivery targets Palladin and prevents metastatic breast cancer.

    PubMed

    Gilam, Avital; Conde, João; Weissglas-Volkov, Daphna; Oliva, Nuria; Friedman, Eitan; Artzi, Natalie; Shomron, Noam

    2016-01-01

    Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3'-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug. PMID:27641360

  7. Cushing's storm secondary to a rare case of ectopic ACTH secreting metastatic breast cancer

    PubMed Central

    Bucciarelli, Maura; Lee, Ya-Yu

    2015-01-01

    Summary Ectopic ACTH secretion from breast cancer is extremely rare. We report a case of a 30-year-old woman with a history of breast cancer, who presented with psychosis and paranoid behaviour. CT of the head showed white matter disease consistent with posterior reversible encephalopathy syndrome (PRES). Despite using mifepristone with multiple antihypertensives including lisinopril, spironolactone and metoprolol, she was hypertensive. Transaminitis did not allow mifepristone dose escalation and ketoconazole utilization. Etomidate infusion at a non-sedating dose in the intensive care unit controlled her hypertension and cortisol levels. She was transitioned to metyrapone and spironolactone. She was discharged from the hospital on metyrapone with spironolactone and underwent chemotherapy. She died 9 months later after she rapidly redeveloped Cushing's syndrome and had progressive metastatic breast cancer involving multiple bones, liver and lungs causing respiratory failure. Learning points Cushing's syndrome from ectopic ACTH secreting breast cancer is extremely rare.Cushing's syndrome causing psychosis could be multifactorial including hypercortisolism and PRES.Etomidate at non-sedating doses in intensive care setting can be effective to reduce cortisol production followed by transition to oral metyrapone. PMID:26525183

  8. Local microRNA delivery targets Palladin and prevents metastatic breast cancer

    PubMed Central

    Gilam, Avital; Conde, João; Weissglas-Volkov, Daphna; Oliva, Nuria; Friedman, Eitan; Artzi, Natalie; Shomron, Noam

    2016-01-01

    Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3′-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug. PMID:27641360

  9. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers.

    PubMed

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis. PMID:27625789

  10. Korean medicine therapy as a substitute for chemotherapy for metastatic breast cancer: a case report.

    PubMed

    Lee, Dong-Hyun; Kim, Sung-Su; Seong, Shin; Kim, Nari; Han, Jae-Bok

    2015-01-01

    A 46-year-old Korean woman was diagnosed with stage III breast cancer and underwent 8 cycles of neoadjuvant chemotherapy, breast conservation surgery and adjuvant radiotherapy. However, the cancer recurred in the right upper lung (RUL) and the right pulmonary hilum after 8 months. The RUL nodule was removed through a wedge resection, and the pathologic finding was revealed as a metastatic adenocarcinoma. Adjuvant chemotherapy was recommended, but she refused it because she feared adverse reactions to chemotherapy. Instead, Korean Medicine Therapy with intravenous wild ginseng pharmacopuncture (WGP), Cordyceps sinensis pharmacopuncture, Trichosanthes kirilowii pharmacopuncture, Euonymus alatus pharmacopuncture (EAP) and Astragalus membranaceus pharmacopuncture was started. After a month, the disease looked stable, but findings of newly occurring metastatic lymphadenopathies appeared on CT after 6 months. Salvage chemotherapy was recommended, but she also refused it. At this time, Prunella vulgaris pharmacopuncture was started. Finally, a complete resolution was confirmed on PET-CT after 5 months, and she has remained in stable condition for more than 6 months with WGP, EAP, a Soram nebulizer solution inhalation and the oral intake of Soramdan S and Hangamdan S.

  11. Korean Medicine Therapy as a Substitute for Chemotherapy for Metastatic Breast Cancer: A Case Report

    PubMed Central

    Lee, Dong-Hyun; Kim, Sung-Su; Seong, Shin; Kim, Nari; Han, Jae-Bok

    2015-01-01

    A 46-year-old Korean woman was diagnosed with stage III breast cancer and underwent 8 cycles of neoadjuvant chemotherapy, breast conservation surgery and adjuvant radiotherapy. However, the cancer recurred in the right upper lung (RUL) and the right pulmonary hilum after 8 months. The RUL nodule was removed through a wedge resection, and the pathologic finding was revealed as a metastatic adenocarcinoma. Adjuvant chemotherapy was recommended, but she refused it because she feared adverse reactions to chemotherapy. Instead, Korean Medicine Therapy with intravenous wild ginseng pharmacopuncture (WGP), Cordyceps sinensis pharmacopuncture, Trichosanthes kirilowii pharmacopuncture, Euonymus alatus pharmacopuncture (EAP) and Astragalus membranaceus pharmacopuncture was started. After a month, the disease looked stable, but findings of newly occurring metastatic lymphadenopathies appeared on CT after 6 months. Salvage chemotherapy was recommended, but she also refused it. At this time, Prunella vulgaris pharmacopuncture was started. Finally, a complete resolution was confirmed on PET-CT after 5 months, and she has remained in stable condition for more than 6 months with WGP, EAP, a Soram nebulizer solution inhalation and the oral intake of Soramdan S and Hangamdan S. PMID:25848354

  12. A phase II and pharmacokinetic study with oral piritrexim for metastatic breast cancer.

    PubMed Central

    de Vries, E. G.; Gietema, J. A.; Workman, P.; Scott, J. E.; Crawshaw, A.; Dobbs, H. J.; Dennis, I.; Mulder, N. H.; Sleijfer, D. T.; Willemse, P. H.

    1993-01-01

    Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase II study with piritrexim in patients with locally advanced or metastatic breast cancer. Twenty-four patients of which sixteen had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated weekly, with provision for dose escalation or reduction according to observed toxicity. Of twenty-one patients evaluable for tumour response, one patient achieved a partial response which lasted for 24 weeks. Three patients had stable disease during 12 weeks of treatment, seventeen had progressive disease. Pirtrexim was generally well tolerated, in eighteen patients the dose could be escalated. Myelotoxicity was the most frequent observed toxicity of this piritrexim regimen. Leucopenia and thrombocytopenia grade 3/4 occurred in 38% of the patients sometime during treatment. Pharmacokinetic analysis of piritrexim in three patients during the first treatment cycle, revealed peak levels 1 to 2 h after an oral dose, with a trend towards a higher peak plasma levels and AUCs on the fourth dosing day compared with the first dosing day. In conclusion, orally administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic breast carcinoma. PMID:8353055

  13. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers

    PubMed Central

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis.

  14. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers

    PubMed Central

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis. PMID:27625789

  15. A bioimage informatics based reconstruction of breast tumor microvasculature with computational blood flow predictions.

    PubMed

    Stamatelos, Spyros K; Kim, Eugene; Pathak, Arvind P; Popel, Aleksander S

    2014-01-01

    Induction of tumor angiogenesis is among the hallmarks of cancer and a driver of metastatic cascade initiation. Recent advances in high-resolution imaging enable highly detailed three-dimensional geometrical representation of the whole-tumor microvascular architecture. This enormous increase in complexity of image-based data necessitates the application of informatics methods for the analysis, mining and reconstruction of these spatial graph data structures. We present a novel methodology that combines ex-vivo high-resolution micro-computed tomography imaging data with a bioimage informatics algorithm to track and reconstruct the whole-tumor vasculature of a human breast cancer model. The reconstructed tumor vascular network is used as an input of a computational model that estimates blood flow in each segment of the tumor microvascular network. This formulation involves a well-established biophysical model and an optimization algorithm that ensures mass balance and detailed monitoring of all the vessels that feed and drain blood from the tumor microvascular network. Perfusion maps for the whole-tumor microvascular network are computed. Morphological and hemodynamic indices from different regions are compared to infer their role in overall tumor perfusion. PMID:24342178

  16. Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens

    PubMed Central

    Baine, Marina K.; Turcu, Gabriela; Zito, Christopher R.; Adeniran, Adebowale J.; Camp, Robert L.; Chen, Lieping

    2015-01-01

    Renal cell carcinoma (RCC) is one of the most chemo- and radio-resistant malignancies, with poor associated patient survival if the disease metastasizes. With recent advances in immunotherapy, particularly with PD-1/PD-L1 blockade, outcomes are improving, but a substantial subset of patients does not respond to the new agents. Identifying such patients and improving the therapeutic ratio has been a challenge, although much effort has been made to study PD-1/PD-L1 status in pre-treatment tumor. However, tumor infiltrating lymphocyte (TIL) content might also be predictive of response, and our goal was to characterize TIL content and PD-L1 expression in RCC tumors from various anatomic sites. Utilizing a quantitative immunofluorescence technique, TIL subsets were examined in matched primary and metastatic specimens. In metastatic specimens, we found an association between low CD8+ to Foxp3+ T-cell ratios and high levels of PD-L1. High PD-L1-expressing metastases were also found to be associated with tumors that were high in both CD4+ and Foxp3+ T-cell content. Taken together these results provide the basis for combining agents that target the PD-1/PD-L1 pathway with agonist of immune activation, particularly in treating RCC metastases with unfavorable tumor characteristics and microenvironment. In addition, CD8+ TIL density and CD8:Foxp3 T-cell ratio were higher in primary than metastatic specimens, supporting the need to assess distant sites for predictive biomarkers when treating disseminated disease. PMID:26317902

  17. A Rare Case of Breast Malignant Phyllodes Tumor With Metastases to the Kidney

    PubMed Central

    Karczmarek-Borowska, Bożenna; Bukala, Agnieszka; Syrek-Kaplita, Karolina; Ksiazek, Mariusz; Filipowska, Justyna; Gradalska-Lampart, Monika

    2015-01-01

    Abstract Phyllodes tumors are rare breast neoplasms. Surgery is the treatment of choice. The role of postoperative radiotherapy and chemotherapy is still under dispute, as there are no equivocal prognostic factors. Treatment failure results in the occurrence of distant metastasis—mainly to the lungs, bones, liver, and brain. We have described the case of a woman with a malignant phyllodes tumor of the breast that was surgically treated. She did not receive adjuvant therapy because there is no consensus on the role of postoperative chemotherapy and radiotherapy. One year following the surgery, the patient had left-sided nephrectomy performed because of a rapidly growing tumor of the kidney. Renal cancer was suspected; however, a histopathological examination revealed that it was a metastatic phyllodes tumor. At the same time, the patient was diagnosed as having metastases in the other kidney, the lungs, liver, and bones. Our case report describes not only an unusual localization of the metastases (in the kidneys), but also failure of the chemotherapy and the aggressive course of malignant phyllodes tumor. Identification of patients with high risk for distant metastasis and the introduction of uniform rules for the management of adjuvant chemotherapy and radiotherapy would make planning treatment as efficacious as possible. PMID:26287414

  18. Nerve Fibers in Breast Cancer Tissues Indicate Aggressive Tumor Progression

    PubMed Central

    Huang, Di; Su, Shicheng; Cui, Xiuying; Shen, Ximing; Zeng, Yunjie; Wu, Wei; Chen, Jianing; Chen, Fei; He, Chonghua; Liu, Jiang; Huang, Wei; Liu, Qiang; Su, Fengxi; Song, Erwei; Ouyang, Nengtai

    2014-01-01

    Abstract Emerging evidence has indicated nerve fibers as a marker in the progression of various types of cancers, such as pancreatic cancer and prostate cancer. However, whether nerve fibers are associated with breast cancer progression remains unclear. In this study, we evaluated the presence of nerve fibers in 352 breast cancer specimens and 83 benign breast tissue specimens including 43 cases of cystic fibrosis and 40 cases of fibroadenoma from 2 independent breast tumor center using immunohistochemical staining for specific peripheral nerve fiber markers. In all, nerve fibers were present in 130 out of 352 breast cancer tissue specimens, while none were detected in normal breast tissue specimens. Among 352 cases, we defined 239 cases from Sun Yat-Sen Memorial Hospital, Guangzhou, China, as the training set, and 113 cases from the First Affiliated Hospital of Shantou University, Guangdong, China, as the validation set. The thickness of tumor-involving nerve fibers is significantly correlated with poor differentiation, lymph node metastasis, high clinical staging, and triple negative subtype in breast cancer. More importantly, Cox multifactor analysis indicates that the thickness of tumor-involving nerve fibers is a previously unappreciated independent prognostic factors associated with shorter disease-free survival of breast cancer patients. Our findings are further validated by online Oncomine database. In conclusion, our results show that nerve fiber involvement in breast cancer is associated with progression of the malignancy and warrant further studies in the future. PMID:25501061

  19. Breast metastases from a malignant peripheral nerve sheath tumor of the kidney: An unusual presentation.

    PubMed

    Koppisetty, Shalini; Alessio, Ricardo C; Rajpurkar, Atul

    2016-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare soft tissue sarcomas of ectomesenchymal origin. They are commonly seen in association with neurofibromatosis type 1 (NF-1), but can also occur without a history of NF (isolated MPNST). MPNSTs are most commonly located on the extremities (brachial and sacral plexus), head and neck, and trunk regions and are rarely reported in genitourinary organs. These tumors are aggressive, with a high recurrence rate and distant metastases. MPNST involving the kidney is extremely rare, and review of the literature using PubMed from 2001 to 2014 revealed eight cases of MPNST involving the kidney (seven, primarily involving the kidney and one metastatic MPNST of the kidney). Herein, we describe a case of breast metastases from an MPNST of the kidney without a history of NF-1. The patient was initially diagnosed with a spindle cell neoplasm of the kidney with peripheral nerve sheath differentiation. Eventually, the patient developed a right breast mass that was diagnosed as metastatic MPNST. The patient refused any kind of treatment and died 6 months later in hospice care. PMID:27453670

  20. Breast metastases from a malignant peripheral nerve sheath tumor of the kidney: An unusual presentation

    PubMed Central

    Koppisetty, Shalini; Alessio, Ricardo C.; Rajpurkar, Atul

    2016-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare soft tissue sarcomas of ectomesenchymal origin. They are commonly seen in association with neurofibromatosis type 1 (NF-1), but can also occur without a history of NF (isolated MPNST). MPNSTs are most commonly located on the extremities (brachial and sacral plexus), head and neck, and trunk regions and are rarely reported in genitourinary organs. These tumors are aggressive, with a high recurrence rate and distant metastases. MPNST involving the kidney is extremely rare, and review of the literature using PubMed from 2001 to 2014 revealed eight cases of MPNST involving the kidney (seven, primarily involving the kidney and one metastatic MPNST of the kidney). Herein, we describe a case of breast metastases from an MPNST of the kidney without a history of NF-1. The patient was initially diagnosed with a spindle cell neoplasm of the kidney with peripheral nerve sheath differentiation. Eventually, the patient developed a right breast mass that was diagnosed as metastatic MPNST. The patient refused any kind of treatment and died 6 months later in hospice care. PMID:27453670

  1. Health-related Quality of Life in Metastatic and Adjuvant Breast Cancer Patients

    PubMed Central

    Wallwiener, M.; Simoes, E.; Sokolov, A. N.; Brucker, S. Y.; Fasching, P. A.; Graf, J.

    2016-01-01

    Introduction: When cancer patients have advanced disease and a primary cure is no longer possible, the focus is on maintaining the patientʼs quality of life. Recent therapeutic advances in breast cancer treatment mean that even patients with metastatic disease can remain stable for long periods of time. The aim of this study was to look at the health-related quality of life (HRQL) of these patients and compare it with data for the general population and to show the differences in outcomes for different survey instruments used to measure quality of life. Material and Methods: A total of 96 breast cancer patients with metastatic disesae or receiving adjuvant therapy were questioned about their quality of life. Patients were investigated using the established survey instruments EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L and EQ VAS. All patients filled out questionnaires. Statistical analysis was done using MS Excel and SPSS. Results: Although the questionnaires were completed at the same time, the different questionnaires showed significant differences with regard to the level of stress experienced by the patient. When the EQ VAS questionnaire was used, the patientʼs current state of health was assessed as significantly better than with the EORTC QLQ-C30. Overall, all aspects of patientsʼ quality of life were found to be in need of optimization and HRQL of patients was significantly poorer in all areas compared to the reference population. Conclusion: To improve the quality of life of patients with metastatic disease, it is necessary to continuously monitor the success of therapy. The choice of survey tools is highly relevant as assessments differ considerably depending on the choice of questionnaire. PMID:27761027

  2. Recurrent angio-fibroma of breast masquerading as phyllodes tumor.

    PubMed

    Chaurasia, Jai K; Alam, Feroz; Shadan, Mariam; Naim, Mohammed

    2015-01-01

    A young Indian female presented with a recurring tumor in the right breast masquerading as phyllodes tumor. Patient had history of five times excision and recurrences of the tumor, diagnosed as fibrous phyllodes of the breast. Presently, a well-circumscribed tumor of about 10 cm size, comprising of benign fibrous-angiomatous tissue with evidence of foci of pyogenic vasculitis was observed. Immuno-histochemical markers for the myo-epithelial and epithelial elements excluded the possibility of fibrous phyllodes, inflammatory myofibroblastic tumor, desmoid fibromatosis, and metaplastic carcinoma. The present findings were diagnostic of an inflammatory angio-fibroma of the right breast, not reported in the earlier literature. The observations indicated that the female breast may be susceptible to spontaneous productive and common-antibiotic-resistant focal septic vascular inflammation giving rise to angio-fibromatous proliferation producing a well-defined tumor mass in the breast, distinguishable from the other breast lesions by the connective tissue stains and immuno-histochemical markers. PMID:26458623

  3. Photothermal and immunological reactions against metastatic tumors using laser photosensitizer immunoadjuvant

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; El-Samad, Ahmad; Nordquist, Robert E.

    1999-06-01

    Photothermal tissue interaction is the most common phenomenon when laser energy is deposited in tissue. Because of the sensitivity of cancer cells to temperature increase, photothermal reaction can be an effective mechanism of direct cancer destruction using lasers. Tumor-specific immune response is crucial in achieving systemic and long-term cures for cancers, particularly for metastatic cancers. Can photothermal interaction induce sufficient immunological reaction when the local destruction of tumor cells occurs? To achieve selective photothermal destruction, indocyanine green as a photosensitizer was directly injected into rat mammary tumors, followed by irradiation of 805 nm laser light. Although extensive photothermal tumor killing was achieved and tumor growth was slowed down immediately following the treatment, photothermal reaction alone was shown not sufficient in controlling the treated primary tumors and their metastases. When an immunoadjuvant was used with the indocyanine green, however, the same laser treatment not only could eventually eradicate the treated primary tumors but also eradicate the untreated metastases at remote sites. The tumor eradication went through a growth-regression process over a period of six to nine weeks post-treatment, indicating an induced immune response. The Western Blot analysis using the serum from a laser-immunotherapy cured rat showed that the tumor-specific antibody induced by the treatment had a long- lasting effect. Our experimental data indicated that photothermal interaction alone was not sufficient to slow and eventually reverse tumor growth. However, it can reduce the tumor burden and at the same time release tumor antigens to be recognized by the host immune system. Therefore, in conjunction with specific immunological stimulation using in situ immunoadjuvants, the selective thermal injury to tumors plays an important and a direct role in this laser immunotherapy.

  4. Coexistence of malignant phyllodes tumor and her2-positive locally advanced breast cancer in distinct breasts: A case report

    PubMed Central

    Sato, Tomoi; Muto, Ichiro; Sakai, Takeshi

    2016-01-01

    Introduction Phyllodes tumor of the breast is a rare biphasic neoplasm, accounting for less than 1% of all breast tumors. Coexistence of phyllodes tumor and breast cancer in distinct breasts is extremely rare. Case presentation A 47-year-old Japanese woman presented with bilateral breast lumps. A HER2-positive, unresectable invasive carcinoma in the right breast and fibroadenoma in the left were diagnosed via core needle biopsy. During chemotherapy with anti-HER2 therapy, the breast cancer shrank quickly, while the left breast lump suddenly enlarged. Under a diagnosis of malignant neoplasm of the breast, left mastectomy was performed. Malignant phyllodes tumor was diagnosed by postoperative histological examination and recurred in multiple areas as early as 2 months after surgery. Discussion Only 10 cases of coexisting phyllodes tumor and breast cancer in distinct breasts have been reported in the English literature. Phyllodes tumor associated with breast cancer in distinct breasts tends to be malignant. This is the first case of phyllodes tumor rapidly enlarging during anti-HER2 chemotherapy for locally advanced HER2-positive breast cancer. Conclusion Even during effective treatment of advanced or recurrent breast cancer, attention should also be paid to the contralateral breast for the possible association of a second malignancy such as phyllodes tumor. PMID:26773878

  5. Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

    PubMed Central

    Patel, Shyam A.; Dave, Meneka A.; Murthy, Raghav G.; Helmy, Karim Y.

    2011-01-01

    Among all cancers, malignancies of the breast are the second leading cause of cancer death in the United States after carcinoma of the lung. One of the major factors considered when assessing the prognosis of breast cancer patients is whether the tumor has metastasized to distant organs. Although the exact phenotype of the malignant cells responsible for metastasis and dormancy is still unknown, growing evidence has revealed that they may have stem cell-like properties that may account for resistance to chemotherapy and radiation. One process that has been attributed to primary tumor metastasis is the epithelial-to-mesenchymal transition. In this review, we specifically discuss breast cancer dissemination to the bone marrow and factors that ultimately serve to shelter and promote tumor growth, including the complex relationship between mesenchymal stem cells (MSCs) and various aspects of the immune system, carcinoma-associated fibroblasts, and the diverse components of the tumor microenvironment. A better understanding of the journey from the primary tumor site to the bone marrow and subsequently the oncoprotective role of MSCs and other factors within that microenvironment can potentially lead to development of novel therapeutic targets. PMID:21776337

  6. Occult breast tumor reservoir: biological properties and clinical significance.

    PubMed

    Santen, Richard J; Yue, Wei; Heitjan, Daniel F

    2013-08-01

    Small, occult, undiagnosed breast cancers are found at autopsy in up to 15.6 % of women dying from unrelated causes with an average of 7 % from eight separate studies. The mammographic detection threshold of breast tumors ranges from 0.88 to 1.66 cm in diameter based on the patient's age. Tumor growth rates, expressed as "effective doubling times," vary from 10 to >700 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. Our models facilitate interpretation of the Women's Health Initiative (WHI) and antiestrogen breast cancer prevention studies. A nude mouse xenograft model was used to validate our assumption that breast tumors grow in a log-linear fashion. We then used our previously reported occult tumor growth (OTG) and computer-simulated tumor growth models to analyze various clinical trial data. Parameters used in the OTG model included a 200-day effective doubling time, 7 % prevalence of occult tumors, and 1.16 cm detection threshold. These models had been validated by comparing predicted with observed incidence of breast cancer in eight different populations of women. Our model suggests that menopausal hormone therapy with estrogens plus a progestogen (E + P) in the WHI trial primarily promoted the growth of pre-existing, occult lesions and minimally initiated de novo tumors. We provide a potential explanation for the lack of an increase in breast cancer incidence in the subgroup of women in the WHI who had not received E + P prior to randomization. This result may have reflected a leftward skew in the distribution of occult tumor doublings and insufficient time for stimulated tumors to reach the detection threshold. Our model predicted that estrogen alone reduced the incidence of breast cancer as a result of apoptosis. Understanding of the biology of occult tumors suggests that breast cancer "prevention" with antiestrogens or aromatase

  7. Lymphatic endothelial cells support tumor growth in breast cancer

    PubMed Central

    Lee, Esak; Pandey, Niranjan B.; Popel, Aleksander S.

    2014-01-01

    Tumor lymphatic vessels (LV) serve as a conduit of tumor cell dissemination, due to their leaky nature and secretion of tumor-recruiting factors. Though lymphatic endothelial cells (LEC) lining the LV express distinct factors (also called lymphangiocrine factors), these factors and their roles in the tumor microenvironment are not well understood. Here we employ LEC, microvascular endothelial cells (MEC), and human umbilical vein endothelial cells (HUVEC) cultured in triple-negative MDA-MB-231 tumor-conditioned media (TCM) to determine the factors that may be secreted by various EC in the MDA-MB-231 breast tumor. These factors will serve as endothelium derived signaling molecules in the tumor microenvironment. We co-injected these EC with MDA-MB-231 breast cancer cells into animals and showed that LEC support tumor growth, HUVEC have no significant effect on tumor growth, whereas MEC suppress it. Focusing on LEC-mediated tumor growth, we discovered that TCM-treated LEC (‘tumor-educated LEC') secrete high amounts of EGF and PDGF-BB, compared to normal LEC. LEC-secreted EGF promotes tumor cell proliferation. LEC-secreted PDGF-BB induces pericyte infiltration and angiogenesis. These lymphangiocrine factors may support tumor growth in the tumor microenvironment. This study shows that LV serve a novel role in the tumor microenvironment apart from their classical role as conduits of metastasis. PMID:25068296

  8. Breast tumor kinase (protein tyrosine kinase 6) regulates heregulin-induced activation of ERK5 and p38 MAP kinases in breast cancer cells.

    PubMed

    Ostrander, Julie Hanson; Daniel, Andrea R; Lofgren, Kristopher; Kleer, Celina G; Lange, Carol A

    2007-05-01

    Total tyrosine kinase activity is often elevated in both cytosolic and membrane fractions of malignant breast tissue and correlates with a decrease in disease-free survival. Breast tumor kinase (Brk; protein tyrosine kinase 6) is a soluble tyrosine kinase that was cloned from a metastatic breast tumor and found to be overexpressed in a majority of breast tumors. Herein, we show that Brk is overexpressed in 86% of invasive ductal breast tumors and coexpressed with ErbB family members in breast cancer cell lines. Additionally, the ErbB ligand, heregulin, activates Brk kinase activity. Knockdown of Brk by stable expression of short hairpin RNA (shRNA) in T47D breast cancer cells decreases proliferation and blocks epidermal growth factor (EGF)- and heregulin-induced activation of Rac GTPase, extracellular signal-regulated kinase (ERK) 5, and p38 mitogen-activated protein kinase (MAPK) but not Akt, ERK1/2, or c-Jun NH(2)-terminal kinase. Furthermore, EGF- and heregulin-induced cyclin D1 expression is dependent on p38 signaling and inhibited by Brk shRNA knockdown. The myocyte enhancer factor 2 transcription factor target of p38 MAPK and ERK5 signaling is also sensitive to altered Brk expression. Finally, heregulin-induced migration of T47D cells requires p38 MAPK activity and is blocked by Brk knockdown. These results place Brk in a novel signaling pathway downstream of ErbB receptors and upstream of Rac, p38 MAPK, and ERK5 and establish the ErbB-Brk-Rac-p38 MAPK pathway as a critical mediator of breast cancer cell migration.

  9. Circulating Tumor Cells from Patients with Advanced Prostate and Breast Cancer Display Both Epithelial and Mesenchymal Markers

    PubMed Central

    Armstrong, Andrew J.; Marengo, Matthew S.; Oltean, Sebastian; Kemeny, Gabor; Bitting, Rhonda L.; Turnbull, James; Herold, Christina I.; Marcom, Paul K.; George, Daniel; Garcia-Blanco, Mariano A.

    2011-01-01

    During cancer progression malignant cells undergo epithelial-mesenchymal transitions (EMTs) and mesenchymal-epithelial transitions (METs) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTCs) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer (BC). We show that the majority (>80%) of these CTCs in patients with metastatic CRPC co-express epithelial proteins such as EpCAM, CK, and E-cadherin, mesenchymal proteins, including vimentin, N-cadherin, and O-cadherin, and the stem cell marker CD133. Equally, we find that over 75% of CTCs from women with metastatic BC co-express cytokeratin, vimentin, and N-cadherin. The existence and high frequency of these CTCs co-expressing epithelial, mesenchymal, and stem-cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs. PMID:21665936

  10. Reassessing the need for primary tumor surgery in unresectable metastatic colorectal cancer: overview and perspective.

    PubMed

    Poultsides, George A; Paty, Phillip B

    2011-01-01

    In the absence of symptoms, primary tumor resection in patients who present with unresectable metastatic colorectal cancer is of uncertain benefit. Prophylactic surgery has been traditionally considered in this setting in order to prevent subsequent complications of perforation, obstruction, or bleeding later during the treatment course, which may require urgent surgery associated with higher mortality. However, recent data have called into question the efficacy of this upfront surgical strategy. We provide a brief overview of how current combinations of systemic chemotherapy including fluorouracil, oxaliplatin, irinotecan, and targeted biologic agents have allowed improved local (in addition to distant) tumor control, significantly decreasing the incidence of late primary-related complications requiring surgery from roughly 20% in the era of single-agent fluoropyrimidine chemotherapy to almost 7% in the era of modern triple-drug chemotherapy. In addition, we attempt to highlight those factors most associated with subsequent primary tumor-related complications in an effort to identify the subset of patients with synchronous metastatic colorectal cancer who might benefit from a surgery-first approach. Finally, we discuss modern nonsurgical options available for palliation of the primary colorectal tumor and review the outcome of patients for which emergent surgery is eventually required to address primary-related symptoms. PMID:21789154

  11. Optically measured microvascular blood flow contrast of malignant breast tumors.

    PubMed

    Choe, Regine; Putt, Mary E; Carlile, Peter M; Durduran, Turgut; Giammarco, Joseph M; Busch, David R; Jung, Ki Won; Czerniecki, Brian J; Tchou, Julia; Feldman, Michael D; Mies, Carolyn; Rosen, Mark A; Schnall, Mitchell D; DeMichele, Angela; Yodh, Arjun G

    2014-01-01

    Microvascular blood flow contrast is an important hemodynamic and metabolic parameter with potential to enhance in vivo breast cancer detection and therapy monitoring. Here we report on non-invasive line-scan measurements of malignant breast tumors with a hand-held optical probe in the remission geometry. The probe employs diffuse correlation spectroscopy (DCS), a near-infrared optical method that quantifies deep tissue microvascular blood flow. Tumor-to-normal perfusion ratios are derived from thirty-two human subjects. Mean (95% confidence interval) tumor-to-normal ratio using surrounding normal tissue was 2.25 (1.92-2.63); tumor-to-normal ratio using normal tissues at the corresponding tumor location in the contralateral breast was 2.27 (1.94-2.66), and using normal tissue in the contralateral breast was 2.27 (1.90-2.70). Thus, the mean tumor-to-normal ratios were significantly different from unity irrespective of the normal tissue chosen, implying that tumors have significantly higher blood flow than normal tissues. Therefore, the study demonstrates existence of breast cancer contrast in blood flow measured by DCS. The new, optically accessible cancer contrast holds potential for cancer detection and therapy monitoring applications, and it is likely to be especially useful when combined with diffuse optical spectroscopy/tomography. PMID:24967878

  12. Malignant solitary fibrous tumor of breast: a rare case report.

    PubMed

    Yang, Lian-He; Dai, Shun-Dong; Li, Qing-Chang; Xu, Hong-Tao; Jiang, Gui-Yang; Zhang, Yong; Wang, Liang; Fan, Chui-Feng; Wang, En-Hua

    2014-01-01

    Solitary fibrous tumor (SFT) is rare mesenchymal neoplasm that has been originally and most often documented in the pleura. Recently, the ubiquitous nature of the SFT has been recognized with reports of involvement of numerous sites all over the body such as: upper respiratory tract, somatic tissue, mediastinum, head, and neck. Less than 10 cases SFT of breast have been reported. Herein, we presented a 52-year-old Asian female with SFT of breast, this tumor showed predominant malignant features. To our knowledge, SFT of breast with such malignant evidence is extremely rare.

  13. The Impacts of Inclusion in Clinical Trials on Outcomes among Patients with Metastatic Breast Cancer (MBC)

    PubMed Central

    Lee, Ji Yun; Lim, Sung Hee; Lee, Min-Young; Kim, Hae Su; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2016-01-01

    Background Metastatic breast cancer (MBC) remains a devastating and incurable disease. Over the past decade, the implementation of clinical trials both with and without molecular targeted therapeutics has impacted the daily clinical treatment of patients with MBC. In this study, we determine whether including MBC patients in clinical trials affects clinical outcomes. Methods We retrospectively reviewed data for a total of 863 patients diagnosed with initial or recurrent (after receiving adjuvant systemic treatments following surgery) metastatic disease between January 2000 and December 2013. Data were obtained from the breast cancer database of Samsung Medical Center. Results Among the 806 patients selected for inclusion, 188 (23%) had participated in clinical trials. A total of 185 clinical trials were conducted from 2000 to 2014. When compared with earlier periods (n = 10 for 2000–2004), clinical trial enrollment significantly increased over time (n = 103 for 2005–2009, P = 0.024; n = 110 for 2010–2014, P = 0.046). Multivariate analyses revealed that biologic subtype, distant recurrence free interval (DRFI), and clinical trial enrollment were independent predictors of overall survival. Patients who participated in clinical trials showed improved survival, with a hazard ratio of 0.75 (95% CI, 0.59–0.95), which was associated with a 25% reduction in the risk of death. However, subgroup analysis showed that this improved survival benefit was not maintained in patients with triple negative breast cancer (TNBC). Conclusions Although not conclusive, we could speculate that there were differences in the use of newer agents or regimens over time, and these differences appear to be associated with improved survival. PMID:26901062

  14. Integrated Multimodal Imaging of Dynamic Bone-Tumor Alterations Associated with Metastatic Prostate Cancer

    PubMed Central

    Chenevert, Thomas L.; Jacobson, Jon A.; Boes, Jennifer L.; Galbán, Stefanie; Rehemtulla, Alnawaz; Johnson, Timothy D.; Pienta, Kenneth J.; Galbán, Craig J.; Meyer, Charles R.; Schakel, Timothy; Nicolay, Klaas; Alva, Ajjai S.; Hussain, Maha; Ross, Brian D.

    2015-01-01

    Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment limit current treatment options thus prostate to bone metastases remains incurable. This study uses voxel-based analysis of diffusion-weighted MRI and CT scans to simultaneously evaluate temporal changes in normal bone homeostasis along with prostate bone metatastsis to deliver an improved understanding of the spatiotemporal local microenvironment. Dynamic tumor-stromal interactions were assessed during treatment in mouse models along with a pilot prospective clinical trial with metastatic hormone sensitive and castration resistant prostate cancer patients with bone metastases. Longitudinal changes in tumor and bone imaging metrics during delivery of therapy were quantified. Studies revealed that voxel-based parametric response maps (PRM) of DW-MRI and CT scans could be used to quantify and spatially visualize dynamic changes during prostate tumor growth and in response to treatment thereby distinguishing patients with stable disease from those with progressive disease (p<0.05). These studies suggest that PRM imaging biomarkers are useful for detection of the impact of prostate tumor-stromal responses to therapies thus demonstrating the potential of multi-modal PRM image-based biomarkers as a novel means for assessing dynamic alterations associated with metastatic prostate cancer. These results establish an integrated and clinically translatable approach which can be readily implemented for improving the clinical management of patients with metastatic bone disease. Trial Registration ClinicalTrials.gov NCT02064283 PMID:25859981

  15. Hepatic Arterial Chemoembolization Using Drug-Eluting Beads in Gastrointestinal Neuroendocrine Tumor Metastatic to the Liver

    SciTech Connect

    Gaur, Shantanu K.; Friese, Jeremy L.; Sadow, Cheryl A.; Ayyagari, Rajasekhara; Binkert, Christoph A.; Schenker, Matthew P.; Kulke, Matthew; Baum, Richard

    2011-06-15

    Purpose: This study was designed to evaluate short (<3 months) and intermediate-term (>3 months) follow-up in patients with metastatic neuroendocrine tumor to the liver who underwent hepatic arterial chemoembolization with drug-eluting beads at a single institution. Methods: Institutional review board approval was obtained for this retrospective review. All patients who were treated with 100-300 or 300-500 {mu}m drug-eluting LC Beads (Biocompatibles, UK) preloaded with doxorubicin (range, 50-100 mg) for GI neuroendocrine tumor metastatic to the liver from June 2004 to June 2009 were included. CT and MRI were evaluated for progression using Response Evaluation Criteria In Solid Tumors (RECIST) or European Association for the Study of the Liver (EASL) criteria. Short-term (<3 months) and intermediate-term (>3 months) imaging response was determined and Kaplan-Meier survival curves were plotted. Results: Thirty-eight drug-eluting bead chemoembolization procedures were performed on 32 hepatic lobes, comprising 21 treatment cycles in 18 patients. All procedures were technically successful with two major complications (biliary injuries). At short-term follow-up (<3 months), 22 of 38 (58%) procedures and 10 of 21 (48%) treatment cycles produced an objective response (OR) with the remainder having stable disease (SD). At intermediate-term follow-up (mean, 445 days; range, 163-1247), 17 of 26 (65%) procedures and 8 of 14 (57%) treatment cycles produced an OR. Probability of progressing was approximately 52% at 1 year with a median time to progression of 419 days. Conclusions: Drug-eluting bead chemoembolization is a reasonable alternative to hepatic arterial embolization and chemoembolization for the treatment of metastatic neuroendocrine tumor to the liver.

  16. TLR8 Agonist VTX-2337 and Cyclophosphamide in Treating Patients With Metastatic, Persistent, Recurrent, or Progressive Solid Tumors

    ClinicalTrials.gov

    2016-06-15

    Colorectal Adenocarcinoma; Metastatic Pancreatic Adenocarcinoma; Recurrent Breast Carcinoma; Recurrent Colorectal Carcinoma; Recurrent Melanoma of the Skin; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Pancreatic Carcinoma; Recurrent Renal Cell Carcinoma; Solid Neoplasm; Stage IV Breast Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma; Stage IVA Colorectal Cancer; Stage IVA Pancreatic Cancer; Stage IVB Colorectal Cancer; Stage IVB Pancreatic Cancer

  17. Mitochondrial Bioenergetics of Metastatic Breast Cancer Cells in Response to Dynamic Changes in Oxygen Tension: Effects of HIF-1α

    PubMed Central

    Oliva, Claudia R.; Griguer, Corinne E.; Darley-Usmar, Victor; Hurst, Douglas R.; Welch, Danny R.; Landar, Aimee

    2013-01-01

    Solid tumors are characterized by regions of low oxygen tension (OT), which play a central role in tumor progression and resistance to therapy. Low OT affects mitochondrial function and for the cells to survive, mitochondria must functionally adapt to low OT to maintain the cellular bioenergetics. In this study, a novel experimental approach was developed to examine the real-time bioenergetic changes in breast cancer cells (BCCs) during adaptation to OT (from 20% to <1% oxygen) using sensitive extracellular flux technology. Oxygen was gradually removed from the medium, and the bioenergetics of metastatic BCCs (MDA-MB-231 and MCF10CA clones) was compared with non-tumorigenic (MCF10A) cells. BCCs, but not MCF10A, rapidly responded to low OT by stabilizing HIF-1α and increasing HIF-1α responsive gene expression and glucose uptake. BCCs also increased extracellular acidification rate (ECAR), which was markedly lower in MCF10A. Interestingly, BCCs exhibited a biphasic response in basal respiration as the OT was reduced from 20% to <1%. The initial stimulation of oxygen consumption is found to be due to increased mitochondrial respiration. This effect was HIF-1α-dependent, as silencing HIF-1α abolished the biphasic response. During hypoxia and reoxygenation, BCCs also maintained oxygen consumption rates at specific OT; however, HIF-1α silenced BCC were less responsive to changes in OT. Our results suggest that HIF-1α provides a high degree of bioenergetic flexibility under different OT which may confer an adaptive advantage for BCC survival in the tumor microenvironment and during invasion and metastasis. This study thus provides direct evidence for the cross-talk between HIF-1α and mitochondria during adaptation to low OT by BCCs and may be useful in identifying novel therapeutic agents that target the bioenergetics of BCCs in response to low OT. PMID:23840849

  18. Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases

    PubMed Central

    Gil, Margaret; Seshadri, Mukund; Komorowski, Marcin P.; Abrams, Scott I.; Kozbor, Danuta

    2013-01-01

    Oncolytic viruses hold promise for the treatment of cancer, but their interaction with the tumor microenvironment needs to be elucidated for optimal tumor cell killing. Because the CXCR4 receptor for the stromal cell-derived factor-1 (SDF-1/CXCL12) chemokine is one of the key stimuli involved in signaling interactions between tumor cells and their stromal microenvironment, we used oncolytic virotherapy with a CXCR4 antagonist to target the CXCL12/CXCR4 signaling axis in a triple-negative 4T1 breast carcinoma in syngeneic mice. We show here that CXCR4 antagonist expression from an oncolytic vaccinia virus delivered intravenously to mice with orthotopic tumors attains higher intratumoral concentration than its soluble counterpart and exhibits increased efficacy over that mediated by oncolysis alone. A systemic delivery of the armed virus after resection of the primary tumor was efficacious in inhibiting the development of spontaneous metastasis and increased overall tumor-free survival. Inhibition of tumor growth with the armed virus was associated with destruction of tumor vasculature, reductions in expression of CXCL12 and VEGF, and decrease in intratumoral numbers of bone marrow-derived endothelial and myeloid cells. These changes led to induction of antitumor antibody responses and resistance to tumor rechallenge. Engineering an oncolytic virus armed with a CXCR4 antagonist represents an innovative strategy that targets multiple elements within the tumor microenvironment. As such, this approach could have a significant therapeutic impact against primary and metastatic breast cancer. PMID:23509246

  19. Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-alpha in a model of metastatic breast cancer.

    PubMed

    Sabel, Michael S; Su, Gang; Griffith, Kent A; Chang, Alfred E

    2010-07-01

    Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-alpha PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-alpha-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-alpha PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-alpha in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-alpha was superior to sequential delivery of IL-12 followed by TNF-alpha, but not TNF-alpha followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-alpha is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-alpha results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-alpha resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-alpha PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy. PMID:19802695

  20. AFP464 in Treating Patients With Metastatic or Refractory Solid Tumors That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2014-02-21

    Male Breast Cancer; Recurrent Breast Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Primary Peritoneal Cavity Cancer; Recurrent Renal Cell Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Primary Peritoneal Cavity Cancer; Stage IV Renal Cell Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  1. International study on inter-reader variability for circulating tumor cells in breast cancer

    PubMed Central

    2014-01-01

    Introduction Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch® system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement. Methods CellSearch® images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (κ) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test. Results For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median κ of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and ≥3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median κ of 0.74 (range 0.25 to 0.90). Conclusions The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are required. PMID:24758318

  2. Hypercalcemia from metastatic pancreatic neuroendocrine tumor secreting 1,25-dihydroxyvitamin D

    PubMed Central

    Zhu, Viola; de las Morenas, Antonio; Janicek, Milos

    2014-01-01

    Malignant hypercalcemia occurs in about 20-30% of patients with cancer, both solid tumors and hematologic malignancies. The secretion of parathyroid hormone-related protein (PTH-rP) is the most common cause and has been shown to be the etiology of hypercalcemia associated with neuroendocrine tumors. Here we report the case of a patient with metastatic pancreatic neuroendocrine tumor who developed hypercalcemia more than 4 years after the initial diagnosis as a result of secretion of 1,25-dihydroxyvitamin D, a mechanism only commonly seen in lymphomas. The successful control of the patient’s disease with capecitabine and temozolomide led to the alleviation of this paraneoplastic syndrome. PMID:25083313

  3. Tumor suppressive function of mir-205 in breast cancer is linked to HMGB3 regulation.

    PubMed

    Elgamal, Ola A; Park, Jong-Kook; Gusev, Yuriy; Azevedo-Pouly, Ana Clara P; Jiang, Jinmai; Roopra, Avtar; Schmittgen, Thomas D

    2013-01-01

    Identifying targets of dysregulated microRNAs (miRNAs) will enhance our understanding of how altered miRNA expression contributes to the malignant phenotype of breast cancer. The expression of miR-205 was reduced in four breast cancer cell lines compared to the normal-like epithelial cell line MCF10A and in tumor and metastatic tissues compared to adjacent benign breast tissue. Two predicted binding sites for miR-205 were identified in the 3' untranslated region of the high mobility group box 3 gene, HMGB3. Both dual-luciferase reporter assay and Western blotting confirmed that miR-205 binds to and regulates HMGB3. To further explore miR-205 targeting of HMGB3, WST-1 proliferation and in vitro invasion assays were performed in MDA-MB-231 and BT549 cells transiently transfected with precursor miR-205 oligonucleotide or HMGB3 small interfering RNA (siRNA). Both treatments reduced the proliferation and invasion of the cancer cells. The mRNA and protein levels of HMGB3 were higher in the tumor compared to adjacent benign specimens and there was an indirect correlation between the expression of HMGB3 mRNA and patient survival. Treatment of breast cancer cells with 5-Aza/TSA derepressed miR-205 and reduced HMGB3 mRNA while knockdown of the transcriptional repressor NRSF/REST, reduced miR-205 and increased HMGB3. In conclusion, regulation of HMGB3 by miR-205 reduced both proliferation and invasion of breast cancer cells. Our findings suggest that modulating miR-205 and/or targeting HMGB3 are potential therapies for advanced breast cancer. PMID:24098490

  4. Role of bone and liver scans in surveying patients with breast cancer for metastatic disease

    SciTech Connect

    Evans, D.M.; Wright, D.J.

    1987-10-01

    The objective of this study is to correlate the presence of bone and liver metastases in patients with breast cancer with respect to the results of bone and liver scans, axillary nodal status, and serum alkaline phosphatase levels. One hundred ninety-seven patients with breast cancer treated by modified radical mastectomy between the years 1978 and 1981 were studied. Fifty-nine (30%) of the total group had distant metastases during the course of observation of 60 to 96 months; of 35 patients in whom bone metastases developed, 30 had normal preoperative bone scan results. Of 21 patients who had liver metastases, 19 had normal preoperative liver scans. Nineteen (70%) of the 27 patients with abnormal bone scans had normal alkaline phosphatase levels. Seven (63%) of the 11 patients who had abnormal liver scans had a normal alkaline phosphatase. The study supports the concept that preoperative bone and liver scans are ineffective indicators of metastatic involvement. Selection of patients for screening by bone and liver scans according to alkaline phosphatase determinations was not supported by this study. The appropriate use of bone scans for screening in patients with breast carcinoma is suggested as a follow-up device in patients with positive lymph nodes.

  5. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer.

    PubMed

    Taube, T; Elomaa, I; Blomqvist, C; Beneton, M N; Kanis, J A

    1994-01-01

    We studied bone biopsies from 65 normocalcaemic women with breast cancer and predominantly osteolytic bone metastases in order to examine the pathophysiology of bone destruction in metastatic bone disease. Quantitative histomorphometric measurements were made at sites of tumour involvement, at sites adjacent to tumour tissue and at sites distant from tumour tissue. There were no significant differences in bone volume or in indices of bone resorption or formation between biopsies taken from sites distant from tumour and the controls. Bone resorption, as judged by eroded surface, increased progressively from bone distant from tumour to tumour-laden bone. The number of osteoclasts was significantly increased in bone immediately adjacent to tumour and within metastases. There was no decrease in the ratio of osteoclast to eroded surface in breast cancer compared to controls suggesting that increased resorption in breast cancer was mainly osteoclast mediated and locally activated by the tumour. Two thirds of the biopsies taken from tumour involved regions showed osteosclerosis with woven bone formation. The volume of the pre-existing lamellar trabecular bone was lower than normal in 75% of these biopsies, suggesting that bone resorption must have been increased before the onset of woven bone formation. Since all patients were receiving hormonal treatment or chemotherapy, it is likely that osteosclerosis at sites of previous resorption mainly resulted from the basic cancer treatment as a sign of response to treatment. Osteoclastic bone resorption was, however, not completely inhibited by the active cancer treatment.

  6. Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile.

    PubMed

    González-Martín, Antonio; Alba, Emilio; Ciruelos, Eva; Cortés, Javier; Llombart, Antonio; Lluch, Ana; Andrés, Raquel; Álvarez, Isabel; Aramendía, José Manuel; de la Peña, Francisco Ayala; Barnadas, Agustí; Batista, Norberto; Calvo, Lourdes; Galve, Elena; García-Palomo, Andrés; García-Sáenz, José Ángel; de la Haba, Juan; López, Rafael; López-Vivanco, Guillermo; Martínez-Jáñez, Noelia; de Dueñas, Eduardo Martínez; Plazaola, Arrate; Rodríguez-Lescure, Álvaro; Ruiz, Manuel; Sánchez-Rovira, Pedro; Santaballa, Ana; Seguí, Miguel Ángel; Tusquets, Ignasi; Zamora, Pilar; Martín, Miguel

    2016-01-01

    Around 40% of patients with breast cancer will present with a recurrence of the disease. Chemotherapy is recommended for patients with recurrent hormone-independent or hormone-refractory breast cancer and almost all patients with metastatic breast cancer (MBC) receive chemotherapy during their medical history. Nanoparticle albuminbound (nab)-paclitaxel is a solvent-free, 130-nanometer particle formulation of paclitaxel. Nab-paclitaxel can be administered to all patients for whom the treatment choice is a taxane. In this review, 6 patient profiles for which nabpaclitaxel may be particularly useful are described and analyzed: (i) as first-line treatment of MBC, (ii) as second-line treatment of MBC after oral chemotherapy, (iii) after a standard taxane, (iv) as third-line treatment after a standard taxane and oral chemotherapy, (v) for patients with HER2-positive MBC and (vi) for patients with intolerance to standard taxanes. Nab-paclitaxel is a rational treatment choice for patients with MBC in different settings, as well as for those with prior exposure to a standard taxane. PMID:26278712

  7. Low-temperature plasma needle effects on cultured metastatic breast cancer cells

    NASA Astrophysics Data System (ADS)

    Knecht, Sean; Bilen, Sven; Micci, Michael; Brubaker, Timothy; Wilson, Michael; Cook, Ian; Czesak, Nicholas; Hipkins, Garret

    2015-11-01

    The Penn State Low-Temperature Plasma group is presently investigating the applications of low-temperature plasma for biomedical applications, including the effects on MDA-MB-231 metastatic breast cancer cells. A plasma needle system has been designed and constructed that consists of a 22-gauge stainless steel syringe needle, which acts as the high-voltage electrode, covered with PEEK tubing as the dielectric with a ring ground electrode on the outside. The system is driven by a low-frequency AC voltage amplifier, with typical operating conditions of 2-5 kV peak voltage at 5 kHz. Helium is used as the working fluid and produces a plasma jet with ~ cm's visible extent. Cultured breast cancer cells were provided by our collaborator and exposed to the plasma needle for varying doses and detachment of cells was observed. The effects are attributed to reactive oxygen and nitrogen species generation and transport through the cell culture medium. Plasma needle characterization and the results of the breast cancer experiments will be presented.

  8. Distinct tumor protein p53 mutants in breast cancer subgroups.

    PubMed

    Dumay, Anne; Feugeas, Jean-Paul; Wittmer, Evelyne; Lehmann-Che, Jacqueline; Bertheau, Philippe; Espié, Marc; Plassa, Louis-François; Cottu, Paul; Marty, Michel; André, Fabrice; Sotiriou, Christos; Pusztai, Lajos; de Thé, Hugues

    2013-03-01