Metastatic Organotropism: An Intrinsic Property of Breast Cancer Molecular Subtypes.

PubMed

Wei, Shi; Siegal, Gene P

2017-03-01

It has long been known that some cancers have the propensity to metastasize to certain organs thus creating a nonrandom distribution of sites for distant relapse, a phenomenon known as "metastatic organotropism." Some of these examples include ovary primary to abdominal cavity, prostate primary to bone, and pancreas primary to liver. In contrast, other tumor types, such as mammary and renal cell carcinoma, can relapse in multiple organs although approximately half of advanced breast cancers metastasize to bone. On the other hand gene expression profiling studies have identified various breast cancer classes with prognostic significance. Recent studies have revealed that breast cancer subtypes differ not only in primary tumor characteristics but also in their metastatic behavior. In particular, the luminal tumors are remarkable for their significant bone-seeking phenotype; the HER2 subtype demonstrates a significant liver-homing characteristic; whereas so-called triple-negative breast cancers predispose to lung metastases. These findings suggest that this knowledge could potentially be utilized in the development of effective disease surveillance strategies in the pursuit of precision medicine, thus necessitating further investigation.

An evaluation of bone scans as screening procedures for occult metastases in primary breast cancer.

PubMed Central

Baker, R R; Holmes, E R; Alderson, P O; Khouri, N F; Wagner, H N

1977-01-01

Preoperative bone scans were obtained in 104 patients with operable breast cancer. Areas of increased radioactivity detected by the bone scan were correlated with appropriate radiographs. One of 64 patients (1.5%) with clinical Stage I and Stage II breast cancer had a metastatic lesion detected by the preoperative bone scan. In contrast, 10 of 41 patients (24%) with Stage III breast cancer had occult metastatic lesions detected by the preoperative bone scan. The majority of patients with abnormal bone scans and no radiographic evidence of a benign lesion to explain the cause of the increased radioactivity proved to have metastatic breast cancer on follow-examination. Even though 20% of patients with operable breast cancer will eventually develop bone metastases, our results indicate that preoperative bone scans are not an effective means of predicting which patients with Stage I and Stage II disease will develop metastatic breast cancer. Because of the considerably increased frequency of detection of occult metastases in patients with Stage III breast cancer, bone scans should be obtained routinely in the preoperative assessment of these patients. Images Figs. 1a and b. Figs. 2a and b. Figs. 3a-d. PMID:889378

Sirolimus, Docetaxel, and Carboplatin in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

ClinicalTrials.gov

2018-05-25

Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Prostate Carcinoma Metastatic in the Bone; PSA Level Greater Than or Equal to Two; PSA Progression; Stage IV Prostate Cancer AJCC v7

Gastric carcinoma metastatic to the bone marrow: immunoperoxidase identification of KMO-1 antigen in MGG-destained aspirate.

PubMed

Kobayashi, T K; Yakushiji, M

1991-01-01

A case is presented that illustrates the application of the immunoperoxidase technique to the May-Grünwald-Giemsa (MGG)-destained bone marrow aspirate. The cytologic findings in a MGG-stained smear of the bone marrow suggested a metastatic epithelial tumor. Subsequently, a positive reaction to KMO-1, a monoclonal antibody raised against a colon carcinoma cell line, was demonstrated in tumor cells in the MGG-destained smear sample as well as in the paraffin-embedded section of the primary gastric cancer. The demonstration of the cancer-associated antigen in the MGG-destained material may be useful in establishing the diagnosis of metastatic tumor in the bone marrow.

AR Expression in Breast Cancer CTCs Associates with Bone Metastases.

PubMed

Aceto, Nicola; Bardia, Aditya; Wittner, Ben S; Donaldson, Maria C; O'Keefe, Ryan; Engstrom, Amanda; Bersani, Francesca; Zheng, Yu; Comaills, Valentine; Niederhoffer, Kira; Zhu, Huili; Mackenzie, Olivia; Shioda, Toshi; Sgroi, Dennis; Kapur, Ravi; Ting, David T; Moy, Beverly; Ramaswamy, Sridhar; Toner, Mehmet; Haber, Daniel A; Maheswaran, Shyamala

2018-04-01

Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing was performed of circulating tumor cells (CTC) isolated from blood samples of women with metastatic estrogen receptor (ER) + breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it contributes to acquired resistance to endocrine therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER + breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients. Implications: This study highlights a role for the AR in breast cancer bone metastasis, and suggests that therapeutic targeting of the AR may benefit patients with metastatic breast cancer. Mol Cancer Res; 16(4); 720-7. ©2018 AACR . ©2018 American Association for Cancer Research.

A Spontaneous 3D Bone-On-a-Chip for Bone Metastasis Study of Breast Cancer Cells.

PubMed

Hao, Sijie; Ha, Laura; Cheng, Gong; Wan, Yuan; Xia, Yiqiu; Sosnoski, Donna M; Mastro, Andrea M; Zheng, Si-Yang

2018-03-01

Bone metastasis occurs at ≈70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone-on-a-chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co-culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone-on-a-chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Isolation and characterization of a metastatic hybrid cell line generated by ER negative and ER positive breast cancer cells in mouse bone marrow.

PubMed

Mukhopadhyay, Keya De; Bandyopadhyay, Abhik; Chang, Ting-Tung A; Elkahloun, Abdel G; Cornell, John E; Yang, Junhua; Goins, Beth A; Yeh, I-Tien; Sun, Lu-Zhe

2011-01-01

The origin and the contribution of breast tumor heterogeneity to its progression are not clear. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other's metastatic behavior. ER positive ZR-75-1/GFP/puro cells, resistant to puromycin and non-tumorigenic/non-metastatic without exogenous estrogen supplementation, were injected intracardiacally into mice bearing growing orthotopic tumors, formed by ER negative MDA-MB-231/GFP/Neo cells resistant to G418. A variant cell line B6, containing both estrogen-dependent and -independent cells, were isolated from GFP expressing cells in the bone marrow and re-inoculated in nude mice to generate an estrogen-independent cell line B6TC. The presence of ER negative orthotopic tumors resulted in bone metastasis of ZR-75-1 without estrogen supplementation. The newly established B6TC cell line was tumorigenic without estrogen supplementation and resistant to both puromycin and G418 suggesting its origin from the fusion of MDA-MB-231/GFP/Neo and ZR-75-1/GFP/puro in the mouse bone marrow. Compared to parental cells, B6TC cells were more metastatic to lung and bone after intracardiac inoculation. More significantly, B6TC mice also developed brain metastasis, which was not observed in the MDA-MB-231/GFP/Neo cell-inoculated mice. Low expression of ERα and CD24, and high expression of EMT-related markers such as Vimentin, CXCR4, and Integrin-β1 along with high CD44 and ALDH expression indicated stem cell-like characteristics of B6TC. Gene microarray analysis demonstrated a significantly different gene expression profile of B6TC in comparison to those of parental cell lines. Spontaneous generation of the novel hybrid cell line B6TC, in a metastatic site with stem cell-like properties

PKCε Is an Essential Mediator of Prostate Cancer Bone Metastasis.

PubMed

Gutierrez-Uzquiza, Alvaro; Lopez-Haber, Cynthia; Jernigan, Danielle L; Fatatis, Alessandro; Kazanietz, Marcelo G

2015-09-01

The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCε), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCε expression was silenced using shRNA. Interestingly, while PKCε depletion had only marginal effects on the proliferative, adhesive, and migratory capacities of PC3-ML cells in vitro or in the growth of xenografts upon s.c. inoculation, it caused a significant reduction in cell invasiveness. Notably, PKCε was required for transendothelial cell migration (TEM) as well as for the growth of PC3-ML cells in a bone biomimetic environment. At a mechanistic level, PKCε depletion abrogates the expression of IL1β, a cytokine implicated in skeletal metastasis. Taken together, PKCε is a key factor for driving the formation of bone metastasis by prostate cancer cells and is a potential therapeutic target for advanced stages of the disease. This study uncovers an important new function of PKCε in the dissemination of cancer cells to the bone; thus, highlighting the promising potential of this oncogenic kinase as a therapeutic target for skeletal metastasis. ©2015 American Association for Cancer Research.

Expression of Lipid Metabolism-Related Proteins in Metastatic Breast Cancer.

PubMed

Jung, Yoon Yang; Kim, Hye Min; Koo, Ja Seung

2015-01-01

The tumor biology of metastatic breast cancers differ according to the metastatic sites, and the features of cancer metabolism may also be different. The aim of this study is to investigate the expression of lipid metabolism-related proteins in metastatic breast cancer according to metastatic site and discuss the clinical significance thereof. Immunohistochemical staining for lipid metabolism-related proteins [fatty acid synthase (FASN), hormone-sensitive lipase (HSL), carnitine palmitoyltransferase IA (CPT-1A), acyl-CoA oxidase 1 (ACOX1), fatty acid binding protein 4 (FABP4,) and perilipin 1 (PLIN1)] was performed using a tissue microarray of 149 cases of metastatic breast cancer (bone metastasis = 39, brain metastasis = 37, liver metastasis = 21, and lung metastasis = 52). The expression levels of ACOX1 (p = 0.009) and FASN (p = 0.007) varied significantly according to metastatic site, with the highest expression in brain metastasis and the lowest expression in liver metastasis. ACOX1 positivity (p = 0.005) and FASN positivity (p = 0.003) correlated with HER-2 positivity. The expression of FASN was significantly higher in HER-2 type breast cancer, and lower in luminal A and TNBC type breast cancer (p<0.001). Among lipid metabolism-related proteins, PLIN1 positivity was found to be an independent poor prognostic factor on multivariate analysis (Hazard ratio: 4.979, 95% CI: 1.054-22.59, p = 0.043). Different expression levels of lipid metabolism-related proteins were observed according to metastatic site. The expression of ACOX1 and FASN was highest in brain metastasis. These results suggest that the metastatic site should be considered when using lipid metabolism inhibitors for targeted therapy.

Prostate Cancer and Bone: The Elective Affinities

PubMed Central

2014-01-01

The onset of metastases dramatically changes the prognosis of prostate cancer patients, determining increased morbidity and a drastic fall in survival expectancy. Bone is a common site of metastases in few types of cancer, and it represents the most frequent metastatic site in prostate cancer. Of note, the prevalence of tumor relapse to the bone appears to be increasing over the years, likely due to a longer overall survival of prostate cancer patients. Bone tropism represents an intriguing challenge for researchers also because the preference of prostate cancer cells for the bone is the result of a sequential series of targetable molecular events. Many factors have been associated with the peculiar ability of prostate cancer cells to migrate in bone marrow and to determine mixed osteoblastic/osteolytic lesions. As anticipated by the success of current targeted therapy aimed to block bone resorption, a better understanding of molecular affinity between prostate cancer and bone microenvironment will permit us to cure bone metastasis and to improve prognosis of prostate cancer patients. PMID:24971315

Selinexor in Treating Patients With Abiraterone Acetate and/or Enzalutamide Refractory Metastatic Castration-Resistant Prostate Cancer

ClinicalTrials.gov

2018-05-29

Castration Levels of Testosterone; Hormone-Resistant Prostate Cancer; Metastatic Prostate Carcinoma in the Soft Tissue; Prostate Carcinoma Metastatic in the Bone; PSA Progression; Stage IV Prostate Adenocarcinoma AJCC v7

Human bone perivascular niche-on-a-chip for studying metastatic colonization.

PubMed

Marturano-Kruik, Alessandro; Nava, Michele Maria; Yeager, Keith; Chramiec, Alan; Hao, Luke; Robinson, Samuel; Guo, Edward; Raimondi, Manuela Teresa; Vunjak-Novakovic, Gordana

2018-02-06

Eight out of 10 breast cancer patients die within 5 years after the primary tumor has spread to the bones. Tumor cells disseminated from the breast roam the vasculature, colonizing perivascular niches around blood capillaries. Slow flows support the niche maintenance by driving the oxygen, nutrients, and signaling factors from the blood into the interstitial tissue, while extracellular matrix, endothelial cells, and mesenchymal stem cells regulate metastatic homing. Here, we show the feasibility of developing a perfused bone perivascular niche-on-a-chip to investigate the progression and drug resistance of breast cancer cells colonizing the bone. The model is a functional human triculture with stable vascular networks within a 3D native bone matrix cultured on a microfluidic chip. Providing the niche-on-a-chip with controlled flow velocities, shear stresses, and oxygen gradients, we established a long-lasting, self-assembled vascular network without supplementation of angiogenic factors. We further show that human bone marrow-derived mesenchymal stem cells, which have undergone phenotypical transition toward perivascular cell lineages, support the formation of capillary-like structures lining the vascular lumen. Finally, breast cancer cells exposed to interstitial flow within the bone perivascular niche-on-a-chip persist in a slow-proliferative state associated with increased drug resistance. We propose that the bone perivascular niche-on-a-chip with interstitial flow promotes the formation of stable vasculature and mediates cancer cell colonization.

Metastatic Cancer

Cancer.gov

Metastatic cancer is cancer that spreads from its site of origin to another part of the body. Learn how cancer spreads, possible symptoms, common sites where cancer spreads, and how to find out about treatment options.

Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice.

PubMed

Campbell, J Preston; Karolak, Matthew R; Ma, Yun; Perrien, Daniel S; Masood-Campbell, S Kathryn; Penner, Niki L; Munoz, Steve A; Zijlstra, Andries; Yang, Xiangli; Sterling, Julie A; Elefteriou, Florent

2012-07-01

Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells.

Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGFβRIII-p38MAPK-pS249/T252RB Pathway.

PubMed

Yu-Lee, Li-Yuan; Yu, Guoyu; Lee, Yu-Chen; Lin, Song-Chang; Pan, Jing; Pan, Tianhong; Yu, Kai-Jie; Liu, Bin; Creighton, Chad J; Rodriguez-Canales, Jaime; Villalobos, Pamela A; Wistuba, Ignacio I; de Nadal, Eulalia; Posas, Francesc; Gallick, Gary E; Lin, Sue-Hwa

2018-06-01

Bone metastasis from prostate cancer can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTCs are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 prostate cancer cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single-cell level revealed that conditioned medium from differentiated, but not undifferentiated, osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to prostate cancer cells. Gene array analyses identified GDF10 and TGFβ2 among osteoblast-secreted proteins that induced quiescence of C4-2B4, C4-2b, and PC3-mm2, but not 22RV1 or BPH-1 cells, indicating prostate cancer tumor cells differ in their dormancy response. TGFβ2 and GDF10 induced dormancy through TGFβRIII to activate phospho-p38MAPK, which phosphorylates retinoblastoma (RB) at the novel N-terminal S249/T252 sites to block prostate cancer cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 prostate cancer cell lines abolished tumor cell dormancy both in vitro and in vivo Lower TGFβRIII expression in patients with prostate cancer correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTCs are induced into a dormant state through TGFβRIII-p38MAPK-pS249/pT252-RB signaling and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone. Significance: These findings provide mechanistic insights into the dormancy of metastatic prostate cancer in the bone and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone. Cancer Res; 78(11); 2911

Collecting and Studying Blood and Tissue Samples From Patients With Locally Recurrent or Metastatic Prostate or Bladder/Urothelial Cancer

ClinicalTrials.gov

2017-12-04

Healthy Control; Localized Urothelial Carcinoma of the Renal Pelvis and Ureter; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Recurrent Bladder Carcinoma; Recurrent Prostate Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage IV Bladder Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Prostate Cancer

PET Tracer 18F-Fluciclovine Can Detect Histologically Proven Bone Metastatic Lesions: A Preclinical Study in Rat Osteolytic and Osteoblastic Bone Metastasis Models.

PubMed

Oka, Shuntaro; Kanagawa, Masaru; Doi, Yoshihiro; Schuster, David M; Goodman, Mark M; Yoshimura, Hirokatsu

2017-01-01

18 F-Fluciclovine ( trans -1-amino-3- 18 F-fluorocyclobutanecarboxylic acid; anti - 18 F-FACBC) is a positron emission tomography (PET) tracer for diagnosing cancers (e.g., prostate and breast cancer). The most frequent metastatic organ of these cancers is bone. Fluciclovine-PET can visualize bony lesions in clinical practice; however, such lesions have not been described histologically. Methods: We investigated the potential of 14 C-fluciclovine in aiding the visualization of osteolytic and osteoblastic bone metastases (with histological analyses), compared with 3 H-2-deoxy-2-fluoro-D-glucose ( 3 H-FDG), 3 H-choline chloride ( 3 H-choline), and 99m Tc-hydroxymethylene diphosphonate ( 99m Tc-HMDP) by using triple-tracer autoradiography in rat breast cancer osteolytic (on day 12 ± 1 postinjection of MRMT-1) and prostate cancer osteoblastic (on day 20 ± 3 postinjection of AT6.1) metastatic models. Results: The distribution patterns of 14 C-fluciclovine, 3 H-FDG, and 3 H-choline, but not 99m Tc-HMDP, were similar in both models, and the lesions where these tracers accumulated were, histologically, typical osteolytic and osteoblastic lesions. 99m Tc-HMDP accumulated mostly in osteoblastic lesions. 14 C-fluciclovine could visualize the osteolytic lesions as early as day 6 postinjection of MRMT-1. However, differential distributions in 14 C-fluciclovine and 3 H-FDG existed, based on histological differences: low 14 C-fluciclovine and high 3 H-FDG accumulation in osteolytic lesions with inflammation. In the osteoblastic metastatic model, visualization of osteoblastic lesions with 14 C-fluciclovine was not clear, yet clearer than with 3 H-FDG. Although half of the osteoblastic lesions with 14 C-fluciclovine accumulation showed negligible 3 H-choline accumulation in comparison, they were histologically similar to lesions with marked 14 C-fluciclovine and 3 H-choline accumulation. Conclusion: These results suggest that fluciclovine-PET can visualize true osteolytic and

PET Tracer 18F-Fluciclovine Can Detect Histologically Proven Bone Metastatic Lesions: A Preclinical Study in Rat Osteolytic and Osteoblastic Bone Metastasis Models

PubMed Central

Oka, Shuntaro; Kanagawa, Masaru; Doi, Yoshihiro; Schuster, David M.; Goodman, Mark M.; Yoshimura, Hirokatsu

2017-01-01

18F-Fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid; anti-18F-FACBC) is a positron emission tomography (PET) tracer for diagnosing cancers (e.g., prostate and breast cancer). The most frequent metastatic organ of these cancers is bone. Fluciclovine-PET can visualize bony lesions in clinical practice; however, such lesions have not been described histologically. Methods: We investigated the potential of 14C-fluciclovine in aiding the visualization of osteolytic and osteoblastic bone metastases (with histological analyses), compared with 3H-2-deoxy-2-fluoro-D-glucose (3H-FDG), 3H-choline chloride (3H-choline), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) by using triple-tracer autoradiography in rat breast cancer osteolytic (on day 12 ± 1 postinjection of MRMT-1) and prostate cancer osteoblastic (on day 20 ± 3 postinjection of AT6.1) metastatic models. Results: The distribution patterns of 14C-fluciclovine, 3H-FDG, and 3H-choline, but not 99mTc-HMDP, were similar in both models, and the lesions where these tracers accumulated were, histologically, typical osteolytic and osteoblastic lesions. 99mTc-HMDP accumulated mostly in osteoblastic lesions. 14C-fluciclovine could visualize the osteolytic lesions as early as day 6 postinjection of MRMT-1. However, differential distributions in 14C-fluciclovine and 3H-FDG existed, based on histological differences: low 14C-fluciclovine and high 3H-FDG accumulation in osteolytic lesions with inflammation. In the osteoblastic metastatic model, visualization of osteoblastic lesions with 14C-fluciclovine was not clear, yet clearer than with 3H-FDG. Although half of the osteoblastic lesions with 14C-fluciclovine accumulation showed negligible 3H-choline accumulation in comparison, they were histologically similar to lesions with marked 14C-fluciclovine and 3H-choline accumulation. Conclusion: These results suggest that fluciclovine-PET can visualize true osteolytic and osteoblastic bone metastatic lesions

Bone metastasis in prostate cancer: Recurring mitochondrial DNA mutation reveals selective pressure exerted by the bone microenvironment.

PubMed

Arnold, Rebecca S; Fedewa, Stacey A; Goodman, Michael; Osunkoya, Adeboye O; Kissick, Haydn T; Morrissey, Colm; True, Lawrence D; Petros, John A

2015-09-01

Cancer progression and metastasis occur such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell's description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis. We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary tumor and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation. Somatic mutations were significantly more numerous in the bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (n.p.) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in the bone. Other notable somatic mutations that occurred in more than one patient

Bone Metastasis in Prostate Cancer: Recurring Mitochondrial DNA Mutation Reveals Selective Pressure Exerted by the Bone Microenvironment

PubMed Central

Arnold, Rebecca S.; Fedewa, Stacey A.; Goodman, Michael; Osunkoya, Adeboye O.; Kissick, Haydn T.; Morrissey, Colm; True, Lawrence D.; Petros, John A.

2015-01-01

Background Cancer progression and metastasis occurs such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell’s description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis. Methods We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation. Results Somatic mutations were significantly more numerous in bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (np) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in bone. Other notable somatic mutations that occurred in more than

Theranostics Targeting Metastatic Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-1-0389 TITLE: Theranostics Targeting Metastatic Breast Cancer PRINCIPAL INVESTIGATOR: Kevin Burgess CONTRACTING...ADDRESS. 1. REPORT DATE October 2017 2. REPORT TYPE Annual 3. DATES COVERED 4. TITLE AND SUBTITLE Theranostics Targeting Metastatic Breast Cancer 5a...safe and effective interventions; (ii) elimination of mortality associated with metastatic breast cancer ; and, (iii) distinguishing aggressive breast

Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells.

PubMed

Li, Qinlong; Yin, Lijuan; Jones, Lawrence W; Chu, Gina C-Y; Wu, Jason B-Y; Huang, Jen-Ming; Li, Quanlin; You, Sungyong; Kim, Jayoung; Lu, Yi-Tsung; Mrdenovic, Stefan; Wang, Ruoxiang; Freeman, Michael R; Garraway, Isla; Lewis, Michael S; Chung, Leland W K; Zhau, Haiyen E

2016-12-20

Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.

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.

Lipid Osteoclastokines Regulate Breast Cancer Bone Metastasis

PubMed Central

Krzeszinski, Jing Y.; Schwaid, Adam G.; Cheng, Wing Yin; Jin, Zixue; Gallegos, Zachary R.; Saghatelian, Alan

2017-01-01

Bone metastasis is a deadly consequence of cancers, in which osteoclast forms a vicious cycle with tumor cells. Bone metastasis attenuation by clinical usage of osteoclast inhibitors and in our osteopetrotic mouse genetic models with β-catenin constitutive activation or peroxisome proliferator-activated receptor γ deficiency fully support the important role of osteoclast in driving the bone metastatic niche. However, the mechanisms for this “partnership in crime” are underexplored. Here we show that osteoclasts reprogram their lipid secretion to support cancer cells. Metabolomic profiling reveals elevated prometastatic arachidonic acid (AA) but reduced antimetastatic lysophosphatidylcholines (LPCs). This shift in lipid osteoclastokines synergistically stimulates tumor cell proliferation, migration, survival, and expression of prometastatic genes. Pharmacologically, combined treatment with LPCs and BW-755C, an inhibitor of AA signaling via blocking lipoxygenase and cyclooxygenase, impedes breast cancer bone metastasis. Our findings elucidate key paracrine mechanisms for the osteoclast-cancer vicious cycle and uncover important therapeutic targets for bone metastasis. PMID:27967239

A radiobiological model of metastatic burden reduction for molecular radiotherapy: application to patients with bone metastases

NASA Astrophysics Data System (ADS)

Denis-Bacelar, Ana M.; Chittenden, Sarah J.; Murray, Iain; Divoli, Antigoni; McCready, V. Ralph; Dearnaley, David P.; O'Sullivan, Joe M.; Johnson, Bernadette; Flux, Glenn D.

2017-04-01

Skeletal tumour burden is a biomarker of prognosis and survival in cancer patients. This study proposes a novel method based on the linear quadratic model to predict the reduction in metastatic tumour burden as a function of the absorbed doses delivered from molecular radiotherapy treatments. The range of absorbed doses necessary to eradicate all the bone lesions and to reduce the metastatic burden was investigated in a cohort of 22 patients with bone metastases from castration-resistant prostate cancer. A metastatic burden reduction curve was generated for each patient, which predicts the reduction in metastatic burden as a function of the patient mean absorbed dose, defined as the mean of all the lesion absorbed doses in any given patient. In the patient cohort studied, the median of the patient mean absorbed dose predicted to reduce the metastatic burden by 50% was 89 Gy (interquartile range: 83-105 Gy), whilst a median of 183 Gy (interquartile range: 107-247 Gy) was found necessary to eradicate all metastases in a given patient. The absorbed dose required to eradicate all the lesions was strongly correlated with the variability of the absorbed doses delivered to multiple lesions in a given patient (r  =  0.98, P  <  0.0001). The metastatic burden reduction curves showed a potential large reduction in metastatic burden for a small increase in absorbed dose in 91% of patients. The results indicate the range of absorbed doses required to potentially obtain a significant survival benefit. The metastatic burden reduction method provides a simple tool that could be used in routine clinical practice for patient selection and to indicate the required administered activity to achieve a predicted patient mean absorbed dose and reduction in metastatic tumour burden.

Actomyosin tension as a determinant of metastatic cancer mechanical tropism

NASA Astrophysics Data System (ADS)

McGrail, Daniel J.; Kieu, Quang Minh N.; Iandoli, Jason A.; Dawson, Michelle R.

2015-04-01

Despite major advances in the characterization of molecular regulators of cancer growth and metastasis, patient survival rates have largely stagnated. Recent studies have shown that mechanical cues from the extracellular matrix can drive the transition to a malignant phenotype. Moreover, it is also known that the metastatic process, which results in over 90% of cancer-related deaths, is governed by intracellular mechanical forces. To better understand these processes, we identified metastatic tumor cells originating from different locations which undergo inverse responses to altered matrix elasticity: MDA-MB-231 breast cancer cells that prefer rigid matrices and SKOV-3 ovarian cancer cells that prefer compliant matrices as characterized by parameters such as tumor cell proliferation, chemoresistance, and migration. Transcriptomic analysis revealed higher expression of genes associated with cytoskeletal tension and contractility in cells that prefer stiff environments, both when comparing MDA-MB-231 to SKOV-3 cells as well as when comparing bone-metastatic to lung-metastatic MDA-MB-231 subclones. Using small molecule inhibitors, we found that blocking the activity of these pathways mitigated rigidity-dependent behavior in both cell lines. Probing the physical forces exerted by cells on the underlying substrates revealed that though force magnitude may not directly correlate with functional outcomes, other parameters such as force polarization do correlate directly with cell motility. Finally, this biophysical analysis demonstrates that intrinsic levels of cell contractility determine the matrix rigidity for maximal cell function, possibly influencing tissue sites for metastatic cancer cell engraftment during dissemination. By increasing our understanding of the physical interactions of cancer cells with their microenvironment, these studies may help develop novel therapeutic strategies.

Clinical characteristics and outcome of bone-only metastasis in inflammatory and noninflammatory breast cancers.

PubMed

Kai, Megumi; Kogawa, Takahiro; Liu, Diane D; Fouad, Tamer M; Kai, Kazuharu; Niikura, Naoki; Hsu, Limin; Willey, Jie S; Theriault, Richard L; Valero, Vicente; Ueno, Naoto T

2015-02-01

Inflammatory breast cancer is a rare and aggressive presentation of breast cancer. Bone is a common metastatic site in breast cancer, and bone-only metastatic disease is clinically considered to have a better prognosis than visceral metastasis. However, bone-only metastasis in IBC (bone-only IBC) has not been compared with bone-only metastasis in non-IBC (bone-only non-IBC) in terms of clinical features and outcome. Because of the intrinsically aggressive nature of IBC, we hypothesized that bone-only IBC has a poorer prognosis than does bone-only non-IBC. We retrospectively identified patients with stage III primary diagnosed breast cancer who, between January 1997 and December 2012, had a first recurrence located only in the bone. Among the 197 patients that we defined as a study cohort, 50 patients had IBC and 147 patients had non-IBC. Progression-free survival (PFS) and overall survival (OS) from the date of recurrence were estimated using the Kaplan-Meier method, and patient characteristic groups were compared using the log-rank test. OS did not differ significantly between the 2 groups (P = .2467), but a shorter PFS was seen in patients with bone-only IBC than in patients with bone-only non-IBC (P = .0357). Among patients with estrogen receptor (ER)-positive disease, a much shorter PFS was seen in bone-only IBC than in bone-only non-IBC (P = .0159). Bone-only IBC has a poorer prognosis than does bone-only non-IBC, particularly in those with ER-positive tumors. We might need to consider more aggressive intervention (e.g., chemotherapy) for IBC patients with ER-positive bone-only metastatic disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Bone Factors Regulating the Osteotropism of Metastatic Breast Cancer

DTIC Science & Technology

1998-10-01

growth factors and rapid angiogenesis occurs in the immediate vicinity of an active osteoclast. 4,5 Osteoblast-derived bone sialoprotein (BSP...Cells Antigenic Marker Cells Cultured Alone Cells Co-Cultured (2d) MCF-7 MC3T3 MCF-7 MC3T3 human cytokeratin-+ -1 bone sialoprotein (BSP...proteins. Osteonectin, osteopontin and bone sialoprotein have been studied in a series of human breast cancers. 3,15-3 0 Immunohistochemical evaluation

Pembrolizumab and Ruxolitinib Phosphate in Treating Patients With Metastatic Stage IV Triple Negative Breast Cancer

ClinicalTrials.gov

2018-03-05

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

Psoralen inhibits bone metastasis of breast cancer in mice.

PubMed

Wu, Chunyu; Sun, Zhenping; Ye, Yiyi; Han, Xianghui; Song, Xiaoyun; Liu, Sheng

2013-12-01

Breast cancer is the most common female malignancy and it frequently metastasizes to bone. Metastatic breast cancer continues to be the primary cause of death for women in East and Southeast Asia. Psoralen is a furocoumarin that can be isolated from the seeds of Psoralea corylifolia L. Psoralen exhibits a wide range of biological properties and has been demonstrated as an antioxidant, antidepressant, anticancer, antibacterial, and antiviral agent. Additionally, it is involved in the formation and regulation of bone. This study investigated whether psoralen can inhibit metastasis of breast cancer to bone in vivo. Histological, molecular biological, and imaging analyses revealed that psoralen inhibits bone metastases in mice. Psoralen may function to inhibit breast cancer cell growth in the bone microenvironment and regulate the function of osteoblasts and osteoclasts in tumor-bearing mice. The results of this study suggest that psoralen is a bone-modifying agent and a potential therapeutic to treat patients with bone metastases. © 2013.

Breast Cancer Cell Colonization of the Human Bone Marrow Adipose Tissue Niche.

PubMed

Templeton, Zach S; Lie, Wen-Rong; Wang, Weiqi; Rosenberg-Hasson, Yael; Alluri, Rajiv V; Tamaresis, John S; Bachmann, Michael H; Lee, Kitty; Maloney, William J; Contag, Christopher H; King, Bonnie L

2015-12-01

Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche. Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry. Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment. Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effective Immunotherapy in Bone Marrow Metastatic Melanoma Presenting with Disseminated Intravascular Coagulopathy.

PubMed

Gbadamosi, Bolanle; Ezekwudo, Daniel; Nayak, Bhadresh; Yu, Zhou; Gjorgova-Gjeorgjievski, Sandra; Xie, Ming; Robert, Colvin; Jaiyesimi, Ishmael; Huben, Marianne

2018-01-01

Malignant melanoma is responsible for the majority of skin cancer deaths and is increasing in prevalence. Bone marrow (BM) involvement by melanoma is rare in the absence of widespread visceral disease. Here, we report the case of a 30-year-old female who presented to the hospital with back pain, low-grade fever, and easy bruising. She was found to be bicytopenic and in disseminated intravascular coagulopathy (DIC). Surprisingly, BM biopsy showed extensive involvement by metastatic malignant melanoma in the absence of visceral or brain metastasis. The unique presentation of this case and the challenge of management of a potentially treatable cancer in a critically ill patient are discussed, alongside a review of published cases of metastatic melanoma in the BM and an exploration of currently available treatment options. The excellent response of our patient to combined immune checkpoint inhibitors has yet to be paralleled in the available literature.

EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer.

PubMed

Poeppel, Thorsten D; Handkiewicz-Junak, Daria; Andreeff, Michael; Becherer, Alexander; Bockisch, Andreas; Fricke, Eva; Geworski, Lilli; Heinzel, Alexander; Krause, Bernd J; Krause, Thomas; Mitterhauser, Markus; Sonnenschein, Wilfried; Bodei, Lisa; Delgado-Bolton, Roberto C; Gabriel, Michael

2018-05-01

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.

ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling

PubMed Central

Masuda, Tetsuro; Endo, Motoyoshi; Yamamoto, Yutaka; Odagiri, Haruki; Kadomatsu, Tsuyoshi; Nakamura, Takayuki; Tanoue, Hironori; Ito, Hitoshi; Yugami, Masaki; Miyata, Keishi; Morinaga, Jun; Horiguchi, Haruki; Motokawa, Ikuyo; Terada, Kazutoyo; Morioka, Masaki Suimye; Manabe, Ichiro; Iwase, Hirotaka; Mizuta, Hiroshi; Oike, Yuichi

2015-01-01

Bone metastasis of breast cancer cells is a major concern, as it causes increased morbidity and mortality in patients. Bone tissue-derived CXCL12 preferentially recruits breast cancer cells expressing CXCR4 to bone metastatic sites. Thus, understanding how CXCR4 expression is regulated in breast cancer cells could suggest approaches to decrease bone metastasis of breast tumor cells. Here, we show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) increases responsiveness of breast cancer cells to CXCL12 by promoting up-regulation of CXCR4 in those cells. In addition, we used a xenograft mouse model established by intracardiac injection of tumor cells to show that ANGPTL2 knockdown in breast cancer cells attenuates tumor cell responsiveness to CXCL12 by decreasing CXCR4 expression in those cells, thereby decreasing bone metastasis. Finally, we found that ANGPTL2 and CXCR4 expression levels within primary tumor tissues from breast cancer patients are positively correlated. We conclude that tumor cell-derived ANGPTL2 may increase bone metastasis by enhancing breast tumor cell responsiveness to CXCL12 signaling through up-regulation of tumor cell CXCR4 expression. These findings may suggest novel therapeutic approaches to treat metastatic breast cancer. PMID:25773070

Cancer and the metastatic substrate

PubMed Central

Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

2016-01-01

Seventy percent of cancer patients have detectable metastases when they receive a diagnosis and 90% of cancer deaths result from metastases. These two facts emphasise the urgency for research to study the mechanisms and processes that enable metastasis. We need to develop a greater understanding of the cellular and molecular mechanisms that cause metastasis and also we need to do more. We must also consider the micro- and macro-environmental factors that influence this disease. Studying this environmental context has led us to update the ‘seed and soil’ hypothesis which dates back to the 19th century. This theory describes cancerous cells as seeds and the substrate as the soil in target organs though this may seem antiquated. Nonetheless, the tissue specificity that researchers have recently observed in metastatic colonisation supports the validity of the seed and soil theory. We now know that the metastatic potential of a tumour cell depends on multiple, reciprocal interactions between the primary tumour and distant sites. These interactions determine tumour progression. Studies of metastasis have allowed us to develop treatments that focus on therapeutic effectiveness. These new treatments account for the frequent metastasis of some tumours to target organs such as bones, lungs, brain, and liver. The purpose of this review is first to describe interactions between the cellular and molecular entities and the target organ tumour environment that enables metastasis. A second aim is to describe the complex mechanisms that mediate these interactions. PMID:28105072

1α,25-Dihydroxyvitamin D Inhibits the Metastatic Capability of MCF10CA1a and MDA-MB-231 Cells in an In Vitro Model of Breast to Bone Metastasis.

PubMed

Wilmanski, Tomasz; Barnard, Alle; Parikh, Mukti R; Kirshner, Julia; Buhman, Kimberly; Burgess, John; Teegarden, Dorothy

2016-10-01

Breast cancer metastasis to the bone continues to be a major health problem, with approximately 80% of advanced breast cancer patients expected to develop bone metastasis. Although the problem of bone metastasis persists, current treatment options for metastatic cancer patients are limited. In this study, we investigated the preventive role of the active vitamin D metabolite, 1α,25-dihydroxyvitamin D (1,25(OH)2D), against the metastatic potential of breast cancer cells using a novel three-dimensional model (rMET) recapitulating multiple steps of the bone metastatic process. Treatment of MCF10CA1a and MDA-MB-231 cells inhibited metastasis in the rMET model by 70% (±5.7%) and 21% (±6%), respectively. In addition, 1,25(OH)2D treatment decreased invasiveness (20 ± 11% of vehicle) and decreased the capability of MCF10CA1a cells to survive in the reconstructed bone environment after successful invasion through the basement membrane (69 ± 5% of vehicle). An essential step in metastasis is epithelial-mesenchymal transition (EMT). Treatment of MCF10CA1a cells with 1,25(OH)2D increased gene (2.04 ± 0.28-fold increase) and protein (1.87 ± 0.20-fold increase) expression of E-cadherin. Additionally, 1,25(OH)2D treatment decreased N-cadherin gene expression (42 ± 8% decrease), a marker for EMT. Collectively, the present study suggests that 1,25(OH)2D inhibits breast cancer cell metastatic capability as well as inhibits EMT, an essential step in the metastatic process.

A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss

PubMed Central

Lozano, Alysia; Wright, Courtney; Vardanyan, Anna; King, Tamara; Largent-Milnes, Tally M.; Nelson, Mark; Jimenez-Andrade, Juan Miguel; Mantyh, Patrick W; Vanderah, Todd W.

2010-01-01

Aims Cannabinoid CB2 agonists have been shown to alleviate behavioral signs of inflammatory and neuropathic pain in animal models. AM1241, a CB2 agonist, does not demonstrate central nervous system side-effects seen with CB1 agonists such as hypothermia and catalepsy. Metastatic bone cancer causes severe pain in patients and is treated with analgesics such as opiates. Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance bone destruction in a murine model of bone cancer. In contrast, CB2 selective agonists have been shown to reduce bone loss associated with a model of osteoporosis. Here we tested whether a CB2 agonist administered over a 7 day period inhibits bone cancer-induced pain as well as attenuates cancer-induced bone degradation. Main Methods A murine bone cancer model was used in which osteolytic sarcoma cells were injected into the intramedullary space of the distal end of the femur. Behavioral and radiographic image analysis was performed at days 7, 10 and 14 after injection of tumor cells into the femur. Key Findings Osteolytic sarcoma within the femur produced spontaneous and touch evoked behavioral signs of pain within the tumor-bearing limb. The systemic administration of AM1241 acutely or for 7 days significantly attenuated spontaneous and evoked pain in the inoculated limb. Sustained AM1241 significantly reduced bone loss and decreased the incidence of cancer-induced bone fractures. Significance These findings suggest a novel therapy for cancer-induced bone pain, bone loss and bone fracture while lacking many unwanted side effects seen with current treatments for bone cancer pain. PMID:20176037

[Encounter of cancer cells with bone. Histological examination of bone metastasis].

PubMed

Kanda, Hiroaki

2011-03-01

Management of the cancer bone metastasis is important clinical problem. The mechanism (s) of bone metastasis has been studied mainly by animal models and in vitro system. There might be discrepancy between model systems and in vivo human clinical materials. But there is surprisingly rare study of histological examination of human skeletal metastasis, since it is hard to obtain human materials without modification by chemotherapy or irradiation. There are many surgical materials suitable for this examination in our hospital and we have been examined histological features of them. Stromal cells between metastatic cancer cells and OCs (osteoclasts) and÷or OBs (osteoblasts) might play a role in bone metastasis, since these cells are frequently accompanied with OCs÷OBs. We called these stromal cells as "fibroblast-like cells" and examined their nature and roles in bone metastasis. We hope these fibroblast-like cells might become the target of anti bone metastasis therapy, same as osteoclasts targeted by bisphosphonates.

Role of TGF-β in breast cancer bone metastases

PubMed Central

Chiechi, Antonella; Waning, David L.; Stayrook, Keith R.; Buijs, Jeroen T.; Guise, Theresa A.; Mohammad, Khalid S.

2014-01-01

Breast cancer is the most prevalent cancer among females worldwide leading to approximately 350,000 deaths each year. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ~70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by increased fracture risk, pain, nerve compression and hypercalcemia, causing severe morbidity. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic tumor cells to secrete factors that further drive osteolytic bone destruction adjacent to the tumor. Thus, TGF-β is a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases. PMID:24558636

Spatiotemporal progression of metastatic breast cancer: a Markov chain model highlighting the role of early metastatic sites

PubMed Central

Newton, Paul K; Mason, Jeremy; Venkatappa, Neethi; Jochelson, Maxine S; Hurt, Brian; Nieva, Jorge; Comen, Elizabeth; Norton, Larry; Kuhn, Peter

2015-01-01

Background: Cancer cell migration patterns are critical for understanding metastases and clinical evolution. Breast cancer spreads from one organ system to another via hematogenous and lymphatic routes. Although patterns of spread may superficially seem random and unpredictable, we explored the possibility that this is not the case. Aims: Develop a Markov based model of breast cancer progression that has predictive capability. Methods: On the basis of a longitudinal data set of 446 breast cancer patients, we created a Markov chain model of metastasis that describes the probabilities of metastasis occurring at a given anatomic site together with the probability of spread to additional sites. Progression is modeled as a random walk on a directed graph, where nodes represent anatomical sites where tumors can develop. Results: We quantify how survival depends on the location of the first metastatic site for different patient subcategories. In addition, we classify metastatic sites as “sponges” or “spreaders” with implications regarding anatomical pathway prediction and long-term survival. As metastatic tumors to the bone (main spreader) are most prominent, we focus in more detail on differences between groups of patients who form subsequent metastases to the lung as compared with the liver. Conclusions: We have found that spatiotemporal patterns of metastatic spread in breast cancer are neither random nor unpredictable. Furthermore, the novel concept of classifying organ sites as sponges or spreaders may motivate experiments seeking a biological basis for these phenomena and allow us to quantify the potential consequences of therapeutic targeting of sites in the oligometastatic setting and shed light on organotropic aspects of the disease. PMID:28721371

Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic prostate cancer.

PubMed

Brown, Matthew S; Kim, Grace Hyun J; Chu, Gregory H; Ramakrishna, Bharath; Allen-Auerbach, Martin; Fischer, Cheryce P; Levine, Benjamin; Gupta, Pawan K; Schiepers, Christiaan W; Goldin, Jonathan G

2018-01-01

A clinical validation of the bone scan lesion area (BSLA) as a quantitative imaging biomarker was performed in metastatic castration-resistant prostate cancer (mCRPC). BSLA was computed from whole-body bone scintigraphy at baseline and week 12 posttreatment in a cohort of 198 mCRPC subjects (127 treated and 71 placebo) from a clinical trial involving a different drug from the initial biomarker development. BSLA computation involved automated image normalization, lesion segmentation, and summation of the total area of segmented lesions on bone scan AP and PA views as a measure of tumor burden. As a predictive biomarker, treated subjects with baseline BSLA [Formula: see text] had longer survival than those with higher BSLA ([Formula: see text] and [Formula: see text]). As a surrogate outcome biomarker, subjects were categorized as progressive disease (PD) if the BSLA increased by a prespecified 30% or more from baseline to week 12 and non-PD otherwise. Overall survival rates between PD and non-PD groups were statistically different ([Formula: see text] and [Formula: see text]). Subjects without PD at week 12 had longer survival than subjects with PD: median 398 days versus 280 days. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different prostate cancer drug treatments.

Engineering a biomimetic three-dimensional nanostructured bone model for breast cancer bone metastasis study.

PubMed

Zhu, Wei; Wang, Mian; Fu, Yebo; Castro, Nathan J; Fu, Sidney W; Zhang, Lijie Grace

2015-03-01

Traditional breast cancer (BrCa) bone metastasis models contain many limitations with regards to controllability, reproducibility and flexibility of design. In this study, a novel biomimetic bone microenvironment was created by integrating hydroxyapatite (HA) and native bioactive factors deposited by osteogenic induction of human bone marrow mesenchymal stem cells (MSCs) within a cytocompatible chitosan hydrogel. It was found that a 10% nanocrystalline HA (nHA) chitosan scaffold exhibited the highest BrCa adhesion and proliferation when compared to chitosan scaffolds with 20% nHA, 10% and 20% microcrystalline HA as well as amorphous HA. This 3-D tunable bone scaffold can provide a biologically relevant environment, increase cell-cell and cell-matrix interactions as found in native bone, and retain the behavior of BrCa cells with different metastasis potential (i.e. highly metastatic MDA-MB-231, less metastatic MCF-7 and transfected MDA-MB-231). The co-culture of MSCs and MDA-MB-231 in this bone model illustrated that MSCs have the capacity to upregulate the expression of the well-known metastasis-associated gene metadherin within BrCa cells. In summary, this study illustrates the ability of our 3-D bone model to create a biomimetic environment conducive to recapitulating the behavior of metastatic BrCa cells, making it a promising tool for in vitro BrCa cell bone metastasis study and for the discovery of potential therapeutics. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Is computed tomography a necessary part of a metastatic evaluation for castration-resistant prostate cancer? Results from the Shared Equal Access Regional Cancer Hospital Database.

PubMed

Hanyok, Brian T; Howard, Lauren E; Amling, Christopher L; Aronson, William J; Cooperberg, Matthew R; Kane, Christopher J; Terris, Martha K; Posadas, Edwin M; Freedland, Stephen J

2016-01-15

Metastatic lesions in prostate cancer beyond the bone have prognostic importance and affect clinical therapeutic decisions. Few data exist regarding the prevalence of soft-tissue metastases at the initial diagnosis of metastatic castration-resistant prostate cancer (mCRPC). This study analyzed 232 men with nonmetastatic (M0) castration-resistant prostate cancer (CRPC) who developed metastases detected by a bone scan or computed tomography (CT). All bone scans and CT scans within the 30 days before or after the mCRPC diagnosis were reviewed. The rate of soft-tissue metastases among those undergoing CT was determined. Then, predictors of soft-tissue metastases and visceral and lymph node metastases were identified. Compared with men undergoing CT (n = 118), men undergoing only bone scans (n = 114) were more likely to have received primary treatment (P = .048), were older (P = .013), and less recently developed metastases (P = .018). Among those undergoing CT, 52 (44%) had soft-tissue metastases, including 20 visceral metastases (17%) and 41 lymph node metastases (35%), whereas 30% had no bone involvement. In a univariable analysis, only prostate-specific antigen (PSA) predicted soft-tissue metastases (odds ratio [OR], 1.27; P = .047), and no statistically significant predictors of visceral metastases were found. A higher PSA level was associated with an increased risk of lymph node metastases (OR, 1.38; P = .014), whereas receiving primary treatment was associated with decreased risk (OR, 0.36; P = .015). The data suggest that there is a relatively high rate of soft-tissue metastasis (44%) among CRPC patients undergoing CT at the initial diagnosis of metastases, including some men with no bone involvement. Therefore, forgoing CT during a metastatic evaluation may lead to an underdiagnosis of soft-tissue metastases and an underdiagnosis of metastases in general. Cancer 2015. © 2015 American Cancer Society. Cancer 2016;122:222-229. �

Retrospective Audit: Does Prior Assessment by Oral and Maxillofacial Surgeons Reduce the Risk of Osteonecrosis of The Jaw in Patients Receiving Bone-Targeted Therapies for Metastatic Cancers to the Skeleton?--Part II.

PubMed

Turner, Bruce; Ali, Sacha; Pati, Jhumur; Nargund, Vinod; Ali, Enamul; Cheng, Leo; Wells, Paula

2016-01-01

Men who receive bone-targeted therapy for metastatic prostate cancer are at increased risk of osteonecrosis of the jaw (ONJ). Development of ONJ has been associated with the administration of bone-targeted therapies in association with other risk factors. ONJ can be distressing for a patient because it can cause pain, risk of jaw fracture, body image disturbance, difficultly eating, and difficulty maintaining good oral hygiene. The aim of this article is to report results of an audit of prior assessment by oral and maxillofacial surgeons (OMFS) before initiation of bone-targeted therapies and whether it may reduce the risk of ONJ in patients receiving bone-targeted therapies for advanced cancers.

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.

Estrogen receptor (ESR1) mutation in bone metastases from breast cancer.

PubMed

Bartels, Stephan; Christgen, Matthias; Luft, Angelina; Persing, Sascha; Jödecke, Kai; Lehmann, Ulrich; Kreipe, Hans

2018-01-01

Activating mutations of estrogen receptor α gene (ESR1) in breast cancer can cause endocrine resistance of metastatic tumor cells. The skeleton belongs to the metastatic sides frequently affected by breast cancer. The prevalence of ESR1 mutation in bone metastasis and the corresponding phenotype are not known. In this study bone metastases from breast cancer (n=231) were analyzed for ESR1 mutation. In 27 patients (12%) (median age 73 years, range: 55-82 years) activating mutations of ESR1 were detected. The most frequent mutation was p.D538G (53%), no mutations in exon 4 (K303) or 7 (S463) were found. Lobular breast cancer was present in 52% of mutated cases (n=14) and in 49% of all samples (n=231), respectively. Mutated cancers constantly displayed strong estrogen receptor expression. Progesterone receptor was positive in 78% of the mutated cases (n=21). From 194 estrogen receptor-positive samples, 14% had ESR1 mutated. Except for one mutated case, no concurrent HER2 overexpression was noted. Metastatic breast cancer with activating mutations of ESR1 had a higher Ki67 labeling index than primary luminal cancers (median 30%, ranging from 5 to 60% with 85% of cases revealing ≥20% Ki67-positive cells). From those patients from whom information on endocrine therapy was available (n=7), two had received tamoxifen only, 4 tamoxifen followed by aromatase inhibitors and one patient had been treated with aromatase inhibitors only. We conclude that ESR1 mutation is associated with estrogen receptor expression and high proliferative activity and affects about 14% of estrogen receptor-positive bone metastases from breast cancer.

Integrative Clinical Genomics of Metastatic Cancer

PubMed Central

Robinson, Dan R.; Wu, Yi-Mi; Lonigro, Robert J.; Vats, Pankaj; Cobain, Erin; Everett, Jessica; Cao, Xuhong; Rabban, Erica; Kumar-Sinha, Chandan; Raymond, Victoria; Schuetze, Scott; Alva, Ajjai; Siddiqui, Javed; Chugh, Rashmi; Worden, Francis; Zalupski, Mark M.; Innis, Jeffrey; Mody, Rajen J.; Tomlins, Scott A.; Lucas, David; Baker, Laurence H.; Ramnath, Nithya; Schott, Ann F.; Hayes, Daniel F.; Vijai, Joseph; Offit, Kenneth; Stoffel, Elena M.; Roberts, J. Scott; Smith, David C.; Kunju, Lakshmi P.; Talpaz, Moshe; Cieslik, Marcin; Chinnaiyan, Arul M.

2017-01-01

SUMMARY Metastasis is the primary cause of cancer-related deaths. While The Cancer Genome Atlas (TCGA) has sequenced primary tumor types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here, we perform whole exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing for the identification of gene fusions, pathway activation, and immune profiling. Integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers. PMID:28783718

The Role of Osteoblast-Derived Inflammatory Cytokines in Bone Metastatic Breast Cancer

DTIC Science & Technology

2008-03-01

Cancer Res. Treat. 59 (2000) 271–278. [2] R.D. Rubens , G.R. Mundy, Cancer and the skeleton, Martin Dunitz, London, 2000. [3] R.D. Rubens , Bone...NIHM01RR10732) for technical advice regarding ELISAs. References 1. Rubens , R. D., & Mundy, G. R. (2000). Cancer and the skeleton. London: Martin...58. Mundy, G. R., & Guise, T. A. (2000). Pathophysiology of bone metastasis. In R. D. Rubens , & G. R. Mundy (Eds.) Cancer and the skeleton (pp. 43–64

Emerging Therapies in Metastatic Prostate Cancer.

PubMed

Sonnenburg, Daniel W; Morgans, Alicia K

2018-04-11

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

Generation of Organ-conditioned Media and Applications for Studying Organ-specific Influences on Breast Cancer Metastatic Behavior.

PubMed

Piaseczny, Matthew M; Pio, Graciella M; Chu, Jenny E; Xia, Ying; Nguyen, Kim; Goodale, David; Allan, Alison

2016-06-13

Breast cancer preferentially metastasizes to the lymph node, bone, lung, brain and liver in breast cancer patients. Previous research efforts have focused on identifying factors inherent to breast cancer cells that are responsible for this observed metastatic pattern (termed organ tropism), however much less is known about factors present within specific organs that contribute to this process. This is in part because of a lack of in vitro model systems that accurately recapitulate the organ microenvironment. To address this, an ex vivo model system has been established that allows for the study of soluble factors present within different organ microenvironments. This model consists of generating conditioned media from organs (lymph node, bone, lung, and brain) isolated from normal athymic nude mice. The model system has been validated by demonstrating that different breast cancer cell lines display cell-line specific and organ-specific malignant behavior in response to organ-conditioned media that corresponds to their in vivo metastatic potential. This model system can be used to identify and evaluate specific organ-derived soluble factors that may play a role in the metastatic behavior of breast and other types of cancer cells, including influences on growth, migration, stem-like behavior, and gene expression, as well as the identification of potential new therapeutic targets for cancer. This is the first ex vivo model system that can be used to study organ-specific metastatic behavior in detail and evaluate the role of specific organ-derived soluble factors in driving the process of cancer metastasis.

High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone

PubMed Central

O'Sullivan, J M; McCready, V R; Flux, G; Norman, A R; Buffa, F M; Chittenden, S; Guy, M; Pomeroy, K; Cook, G; Gadd, J; Treleaven, J; Al-Deen, A; Horwich, A; Huddart, R A; Dearnaley, D P

2002-01-01

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates. British Journal of Cancer (2002) 86, 1715–1720. doi:10.1038/sj.bjc.6600348 www.bjcancer.com © 2002 Cancer Research UK PMID:12087455

cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Son, Jieun; Lee, Jong-Ho; Kim, Ha-Neui

2010-07-23

Research highlights: {yields} CREB is highly expressed in advanced breast cancer cells. {yields} Tumor-related factors such as TGF-{beta} further elevate CREB expression. {yields} CREB upregulation stimulates metastatic potential of breast cancer cells. {yields} CREB signaling is required for breast cancer-induced bone destruction. -- Abstract: cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cellsmore » and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-{beta}. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.« less

Definition of molecular determinants of prostate cancer cell bone extravasation.

PubMed

Barthel, Steven R; Hays, Danielle L; Yazawa, Erika M; Opperman, Matthew; Walley, Kempland C; Nimrichter, Leonardo; Burdick, Monica M; Gillard, Bryan M; Moser, Michael T; Pantel, Klaus; Foster, Barbara A; Pienta, Kenneth J; Dimitroff, Charles J

2013-01-15

Advanced prostate cancer commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. Prostate cancer cells roll on E-selectin(+) BMEC through E-selectin ligand-binding interactions under shear flow, and prostate cancer cells exhibit firm adhesion to BMEC via β1, β4, and αVβ3 integrins in static assays. However, whether these discrete prostate cancer cell-BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Here, we describe how metastatic prostate cancer cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. Prostate cancer cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic prostate cancer tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. Prostate cancer cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1, and Rap1 were constitutively active. In homing studies, prostate cancer cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin, and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases in transgenic adenoma of mouse prostate mice dramatically reduced prostate cancer incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins, and Rac/Rap1 GTPases in mediating prostate cancer cell homing and entry into bone and offer new insight into the role of α1,3 fucosylation in prostate cancer development.

Intravital imaging of tumor bioenergetics in metastatic and non-metastatic breast cancer

NASA Astrophysics Data System (ADS)

Rasul, Raisa; Harper, Mason; Rajaram, Narasimhan

2018-02-01

Early detection of metastatic cancer can reduce patient mortality and decrease cost of cancer treatment. However, current methods of prognosis or genetic screening are expensive and might not be applicable to all tumors. Although previous studies indicated that cancer cells are glycolytic, the link between metabolism and metastatic progression is not fully understood. To better understand the tumor bioenergetics, we investigated in vivo the vascular oxygenation, glucose intake, and optical redox ratio between a metastatic breast cancer cell line (4T1), a non-metastatic isogenic cell line (168FARN), and a non-metastatic derivative of 4T1 (TWIST gene knockout). The vascular oxygenation was measured by injecting 10,000 cells into mouse dorsal window chambers and acquiring and processing trans-illumination images of the tumor from 520 nm-620 nm light wavelength in 10 nm intervals. Glucose intake was measured by continuous fluorescent imaging of the glucose analog, 2-NBDG, for 90 minutes. Optical redox ratio was measured by intrinsic fluorescence imaging of electron carrying intermediates, NADH and FAD, where an increase in the ratio (FAD/FAD+NADH) meant increased oxidative phosphorylation. Our data show that the optical redox ratio and vascular oxygenation are higher and glucose intake is lower in metastatic tumors compared to non-metastatic tumors, suggesting that metastatic tumors display decreased glycolysis and increased oxidative phosphorylation. We observed a similar trend in vitro, where the redox ratio increased as the cell metastatic potential increased, indicating that metastatic cells can efficiently produce energy. These findings indicate that optical redox ratio can be a potential prognosis tool for detecting malignant tumors.

Bone Scan Index and Progression-free Survival Data for Progressive Metastatic Castration-resistant Prostate Cancer Patients Who Received ODM-201 in the ARADES Multicentre Study.

PubMed

Reza, Mariana; Jones, Robert; Aspegren, John; Massard, Christophe; Mattila, Leena; Mustonen, Mika; Wollmer, Per; Trägårdh, Elin; Bondesson, Eva; Edenbrandt, Lars; Fizazi, Karim; Bjartell, Anders

2016-12-01

ODM-201, a new-generation androgen receptor inhibitor, has shown clinical efficacy in prostate cancer (PCa). Quantitative methods are needed to accurately assess changes in bone as a measurement of treatment response. The Bone Scan Index (BSI) reflects the percentage of skeletal mass a given tumour affects. To evaluate the predictive value of the BSI in metastatic castration-resistant PCa (mCRPC) patients undergoing treatment with ODM-201. From a total of 134 mCRPC patients who participated in the Activity and Safety of ODM-201 in Patients with Progressive Metastatic Castration-resistant Prostate Cancer clinical trial and received ODM-201, we retrospectively selected all those patients who had bone scan image data of sufficient quality to allow for both baseline and 12-wk follow-up BSI-assessments (n=47). We used the automated EXINI bone BSI software (EXINI Diagnostics AB, Lund, Sweden) to obtain BSI data. We used the Cox proportional hazards model and Kaplan-Meier estimates to investigate the association among BSI, traditional clinical parameters, disease progression, and radiographic progression-free survival (rPFS). In the BSI assessments, at follow-up, patients who had a decrease or at most a 20% increase from BSI baseline had a significantly longer time to progression in bone (median not reached vs 23 wk, hazard ratio [HR]: 0.20; 95% confidence interval [CI], 0.07-0.58; p=0.003) and rPFS (median: 50 wk vs 14 wk; HR: 0.35; 95% CI, 0.17-0.74; p=0.006) than those who had a BSI increase >20% during treatment. The on-treatment change in BSI was significantly associated with rPFS in mCRPC patients, and an increase >20% in BSI predicted reduced rPFS. BSI for quantification of bone metastases may be a valuable complementary method for evaluation of treatment response in mCRPC patients. An increase in Bone Scan Index (BSI) was associated with shorter time to disease progression in patients treated with ODM-201. BSI may be a valuable method of complementing treatment

Hypocalcaemia in patients with metastatic bone disease treated with denosumab.

PubMed

Body, Jean-Jacques; Bone, Henry G; de Boer, Richard H; Stopeck, Alison; Van Poznak, Catherine; Damião, Ronaldo; Fizazi, Karim; Henry, David H; Ibrahim, Toni; Lipton, Allan; Saad, Fred; Shore, Neal; Takano, Toshimi; Shaywitz, Adam J; Wang, Huei; Bracco, Oswaldo L; Braun, Ada; Kostenuik, Paul J

2015-09-01

This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab. Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836). The overall incidence of laboratory events of hypocalcaemia grade ⩾ 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus ⩽ 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 μg/L [median] versus ⩽ 20.77 μg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with ⩽ 2 bone metastases at baseline. Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab's greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Bone metastases from breast cancer at the time or radical mastectomy as detected by bone scan. Eight-year follow-up.

PubMed

Sklaroff, R B; Sklaroff, D M

1976-07-01

Sixty-four women with Stage II breast cancer who had Sr85 bone scans at the time of radical mastectomy were followed for 8 years in a prospective study. Those women with positive scans had a slight, but statistically significant, increased incidence of metastic disease, particularly for metastases to bone.However, 40% of those women with positive bone scans and negative roentgenograms survived 8 years without evidence of any metastatic disease. Therefore, it has not been shown at this time that bone scans should be obtained in order to exclude bone metastasis before regional therapy for breast cancer is instituted. Also, a significant percentage of women with negative bone scans developed both bone and soft tissue metastases. As many as 30% of asymptomatic women with a history of breast cancer and positive bone scans and negative bone roentgenograms may still harbor disease in bone after 8 years.

Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression

PubMed Central

Xu, Wen Wen; Li, Bin; Guan, Xin Yuan; Chung, Sookja K.; Wang, Yang; Yip, Yim Ling; Law, Simon Y. K.; Chan, Kin Tak; Lee, Nikki P. Y.; Chan, Kwok Wah; Xu, Li Yan; Li, En Min; Tsao, Sai Wah; He, Qing-Yu; Cheung, Annie L. M.

2017-01-01

Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression. Here we show that IGF2 secreted by inhibitor of differentiation (Id1)-overexpressing oesophageal cancer cells instigates VEGFR1-positive bone marrow cells in the tumour macroenvironment to form pre-metastatic niches at distant sites by increasing VEGF secretion from cancer-associated fibroblasts. Cancer cells are then attracted to the metastatic site via the CXCL5/CXCR2 axis. Bone marrow cells transplanted from nude mice bearing Id1-overexpressing oesophageal tumours enhance tumour growth and metastasis in recipient mice, whereas systemic administration of VEGFR1 antibody abrogates these effects. Mechanistically, IGF2 regulates VEGF in fibroblasts via miR-29c in a p53-dependent manner. Analysis of patient serum samples showed that concurrent elevation of IGF2 and VEGF levels may serve as a prognostic biomarker for oesophageal cancer. These findings suggest that the Id1/IGF2/VEGF/VEGFR1 cascade plays a critical role in tumour-driven pathophysiological processes underlying cancer progression. PMID:28186102

Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression.

PubMed

Xu, Wen Wen; Li, Bin; Guan, Xin Yuan; Chung, Sookja K; Wang, Yang; Yip, Yim Ling; Law, Simon Y K; Chan, Kin Tak; Lee, Nikki P Y; Chan, Kwok Wah; Xu, Li Yan; Li, En Min; Tsao, Sai Wah; He, Qing-Yu; Cheung, Annie L M

2017-02-10

Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression. Here we show that IGF2 secreted by inhibitor of differentiation (Id1)-overexpressing oesophageal cancer cells instigates VEGFR1-positive bone marrow cells in the tumour macroenvironment to form pre-metastatic niches at distant sites by increasing VEGF secretion from cancer-associated fibroblasts. Cancer cells are then attracted to the metastatic site via the CXCL5/CXCR2 axis. Bone marrow cells transplanted from nude mice bearing Id1-overexpressing oesophageal tumours enhance tumour growth and metastasis in recipient mice, whereas systemic administration of VEGFR1 antibody abrogates these effects. Mechanistically, IGF2 regulates VEGF in fibroblasts via miR-29c in a p53-dependent manner. Analysis of patient serum samples showed that concurrent elevation of IGF2 and VEGF levels may serve as a prognostic biomarker for oesophageal cancer. These findings suggest that the Id1/IGF2/VEGF/VEGFR1 cascade plays a critical role in tumour-driven pathophysiological processes underlying cancer progression.

Trastuzumab and survival of patients with metastatic breast cancer.

PubMed

Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

2017-08-01

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without

Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study

PubMed Central

Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

2015-01-01

BACKGROUND Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors (“vascular zip codes”) within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. METHODS The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα–based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. RESULTS BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m2). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. CONCLUSIONS These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery

Experimental ex-vivo validation of PMMA-based bone cements loaded with magnetic nanoparticles enabling hyperthermia of metastatic bone tumors

NASA Astrophysics Data System (ADS)

Harabech, Mariem; Kiselovs, Normunds Rungevics; Maenhoudt, Wim; Crevecoeur, Guillaume; Van Roost, Dirk; Dupré, Luc

2017-05-01

Percutaneous vertebroplasty comprises the injection of Polymethylmethacrylate (PMMA) bone cement into vertebrae and can be used for the treatment of compression fractures of vertebrae. Metastatic bone tumors can cause such compression fractures but are not treated when injecting PMMA-based bone cement. Hyperthermia of tumors can on the other hand be attained by placing magnetic nanoparticles (MNPs) in an alternating magnetic field (AMF). Loading the PMMA-based bone cement with MNPs could both serve vertebra stabilization and metastatic bone tumor hyperthermia when subjecting this PMMA-MNP to an AMF. A dedicated pancake coil is designed with a self-inductance of 10 μH in series with a capacitance of 0.1 μF that acts as resonant inductor-capacitor circuit to generate the AMF. The thermal rise is appraised in beef vertebra placed at 10 cm from the AMF generating circuit using optical temperatures sensors, i.e. in the center of the PMMA-MNP bone cement, which is located in the vicinity of metastatic bone tumors in clinical applications; and in the spine, which needs to be safeguarded to high temperature exposures. Results show a temperature rise of about 7 °C in PMMA-MNP whereas the temperature rise in the spine remains limited to 1 °C. Moreover, multicycles heating of PMMA-MNP is experimentally verified, validating the technical feasibility of having PMMA-MNP as basic component for percutaneous vertebroplasty combined with hyperthermia treatment of metastatic bone tumors.

Association of CA 15-3 and CEA with clinicopathological parameters in patients with metastatic breast cancer.

PubMed

Geng, Biao; Liang, Man-Man; Ye, Xiao-Bing; Zhao, Wen-Ying

2015-01-01

The objective of this study was to investigate the association of serum cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) levels with clinicopathological parameters in patients diagnosed with metastatic breast cancer (MBC). We retrospectively evaluated the medical records of 284 patients diagnosed with MBC between January, 2007 and December, 2012 who fulfilled the specified criteria and the association between the levels of the two tumor marker and clinicopathological parameters was analyzed. Of the 284 patients, elevated CA 15-3 and CEA levels at initial diagnosis of recurrence were identified in 163 (57.4%) and 97 (34.2%) patients, respectively. Elevated CA 15-3 and CEA levels were significantly associated with breast cancer molecular subtypes (P<0.001 and P=0.032, respectively). Cases with luminal subtypes exhibited a higher percentage of elevated CA 15-3 and CEA levels compared to non-luminal subtypes. Elevated CA 15-3 level was correlated with bone metastasis (P=0.017). However, elevation of CEA was observed regardless of the site of metastasis. Elevation of CA 15-3 was significantly more common in MBC with multiple metastatic sites compared to MBC with a single metastasis (P=0.001). However, the incidence of elevated CEA levels did not differ between patients with a single and those with multiple metastatic sites. In conclusion, elevated CA 15-3 and CEA levels at initial diagnosis of recurrence were found to be associated with breast cancer molecular subtypes, whereas an elevated CA 15-3 level was significantly correlated with bone metastasis and an elevated CEA level was observed regardless of metastatic site. The proportion of MBC cases with elevated CA 15-3 levels differed according to the number of metastatic sites.

Intravenous pamidronate versus oral and intravenous clodronate in bone metastatic breast cancer: a randomized, open-label, non-inferiority Phase III trial.

PubMed

von Au, Alexandra; Milloth, Eva; Diel, Ingo; Stefanovic, Stefan; Hennigs, Andre; Wallwiener, Markus; Heil, Joerg; Golatta, Michael; Rom, Joachim; Sohn, Christof; Schneeweiss, Andreas; Schuetz, Florian; Domschke, Christoph

2016-01-01

Patients with metastasized breast cancer often suffer from discomfort caused by metastatic bone disease. Thus, osteoprotection is an important part of therapy in breast cancer metastasized to bone, and bisphosphonates (BPs) are a major therapeutic option. In this study, our objectives were to compare the side effects of oral versus intravenous BP treatment and to assess their clinical effectiveness. In this prospective randomized, open-label, non-inferiority trial, we enrolled breast cancer patients with at least one bone metastasis and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned to one of the three treatment groups: A, 60 mg pamidronate intravenously q3w; B-iv, 900 mg clodronate intravenously q3w; and B-o, 2,400 mg oral clodronate daily. Assessments were performed at baseline and every 3 months thereafter. Between 1995 and 1999, 321 patients with confirmed bone metastases from breast cancer were included in the study. At first follow-up, gastrointestinal (GI) tract side effects were most common, and adverse effects on the GI tract were more frequent in the oral treatment group (P=0.002 and P<0.001, respectively). There were no statistically significant differences among the treatment cohorts for other documented side effects (skin, serum electrolytes, urinary tract, immune system, and others). No significant differences in clinical effectiveness of BP treatment, as assessed by pain score, were detected among the groups; however, pathologic fractures were more effectively prevented by intravenous than oral BP administration (P=0.03). Noncompliance rates were similar among the study cohorts. We conclude that oral BP treatment is significantly associated with higher rates of adverse GI side effects. Additionally, our data indicate that intravenous BP administration is more effective than oral treatment in prevention of pathologic fractures; hence, oral administration should be considered with caution.

Incidence of bone metastases and survival after a diagnosis of bone metastases in breast cancer patients.

PubMed

Harries, M; Taylor, A; Holmberg, L; Agbaje, O; Garmo, H; Kabilan, S; Purushotham, A

2014-08-01

Bone is the most common metastatic site associated with breast cancer. Using a database of women with breast cancer treated at Guy's Hospital, London 1976-2006 and followed until end 2010, we determined incidence of and survival after bone metastases. We calculated cumulative incidence of bone metastases considering death without prior bone metastases as a competing risk. Risk of bone metastases was modelled through Cox-regression. Survival after bone metastases diagnosis was calculated using Kaplan-Meier methodology. Of the 7064 women, 589 (22%) developed bone metastases during 8.4 years (mean). Incidence of bone metastases was significantly higher in younger women, tumour size >5 cm, higher tumour grade, lobular carcinoma and ≥ four positive nodes, but was not affected by hormone receptor status. Median survival after bone metastases diagnosis was 2.3 years in women with bone-only metastases compared with <1 year in women with visceral and bone metastases. There was a trend for decreased survival for patients who developed visceral metastases early, and proportionately fewer patients in this group. Incidence of bone metastases has decreased but bone metastases remain a highly relevant clinical problem due to the large number of patients being diagnosed with breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Denosumab Reduces Risk of Bone Side Effects in Advanced Prostate Cancer

Cancer.gov

The biological agent denosumab (Xgeva) is more effective than zoledronic acid at decreasing the risk of bone fractures and other skeletal-related events (SRE) in men with castration-resistant metastatic prostate cancer, according to results from a randomi

Awareness, concern, and communication between physicians and patients on bone health in cancer.

PubMed

Tripathy, Debu; Durie, Brian G M; Mautner, Beatrice; Ferenz, Krag S; Moul, Judd W

2014-06-01

This study aims to explore physician-patient communications about bone metastases and cancer treatment-induced bone loss (CTIBL). The study utilizes online survey of patients with breast cancer, prostate cancer, and multiple myeloma, and the physicians who treat them. Even though 69 and 48 % of patients with nonmetastatic breast and prostate cancer aware of treatment-induced bone loss, only 39 and 23 %, respectively, were concerned about bone loss. Yet, 62 and 71 % of oncologists treating breast and prostate cancer felt that their patients were concerned. Among patients with metastatic breast and prostate cancer, two thirds had not discussed treatment for bone metastases with their doctor; when discussed, 88 and 91 % of discussions were initiated by the doctor, usually prior to initiating treatment. Most myeloma patients (77 %) had discussed treatment options with their physicians; 99 % of hematologists reported discussing treatment of bone disease with patients. Physicians are primary sources of information to patients regarding bone health. There is a gap between what physicians assume their patients know about bone health and the patients' perceptions, presenting a need for systematic awareness and education.

Label-free Raman spectroscopy provides early determination and precise localization of breast cancer-colonized bone alterations.

PubMed

Zhang, Chi; Winnard, Paul T; Dasari, Sidarth; Kominsky, Scott L; Doucet, Michele; Jayaraman, Swaathi; Raman, Venu; Barman, Ishan

2018-01-21

Breast neoplasms frequently colonize bone and induce development of osteolytic bone lesions by disrupting the homeostasis of the bone microenvironment. This degenerative process can lead to bone pain and pathological bone fracture, a major cause of cancer morbidity and diminished quality of life, which is exacerbated by our limited ability to monitor early metastatic disease in bone and assess fracture risk. Spurred by its label-free, real-time nature and its exquisite molecular specificity, we employed spontaneous Raman spectroscopy to assess and quantify early metastasis driven biochemical alterations to bone composition. As early as two weeks after intracardiac inoculations of MDA-MB-435 breast cancer cells in NOD-SCID mice, Raman spectroscopic measurements in the femur and spine revealed consistent changes in carbonate substitution, overall mineralization as well as crystallinity increase in tumor-bearing bones when compared with their normal counterparts. Our observations reveal the possibility of early stage detection of biochemical changes in the tumor-bearing bones - significantly before morphological variations are captured through radiographic diagnosis. This study paves the way for a better molecular understanding of altered bone remodeling in such metastatic niches, and for further clinical studies with the goal of establishing a non-invasive tool for early metastasis detection and prediction of pathological fracture risk in breast cancer.

Olaparib In Metastatic Breast Cancer

ClinicalTrials.gov

2018-03-27

Metastatic Breast Cancer; Invasive Breast Cancer; Somatic Mutation Breast Cancer (BRCA1); Somatic Mutation Breast Cancer (BRCA2); CHEK2 Gene Mutation; ATM Gene Mutation; PALB2 Gene Mutation; RAD51 Gene Mutation; BRIP1 Gene Mutation; NBN Gene Mutation

Paired high-content analysis of prostate cancer cells in bone marrow and blood characterizes increased androgen receptor expression in tumor cell clusters

PubMed Central

Carlsson, Anders; Kuhn, Peter; Luttgen, Madelyn S.; Dizon, Kevin K.; Troncoso, Patricia; Corn, Paul G.; Kolatkar, Anand; Hicks, James B.; Logothetis, Christopher J.; Zurita., Amado J.

2017-01-01

Purpose Recent studies demonstrate that prostate cancer clones from different metastatic sites are dynamically represented in the blood of patients over time, suggesting that the paired evaluation of tumor cells in circulation and bone marrow, the primary target for prostate cancer metastasis, may provide complementary information. Experimental Design We adapted our single-cell high-content liquid biopsy platform to bone marrow aspirates (BMA), to concurrently identify and characterize prostate cancer cells in patients’ blood and bone and thus discern features associated to tumorigenicity and dynamics of metastatic progression. Results The incidence of tumor cells in BMAs increased as the disease advanced: 0% in biochemically-recurrent (n=52), 26% in newly diagnosed metastatic hormone-naïve (n=26), and 39% in metastatic castration-resistant (mCRPC; n=63) patients, and their number was often higher than in paired blood. Tumor cell detection in metastatic patients’ BMAs was concordant but 45% more sensitive than using traditional histopathologic interpretation of core bone marrow biopsies. Tumor cell clusters were more prevalent and bigger in BMAs than in blood, expressed higher levels of the androgen receptor protein per tumor cell and were prognostic in mCRPC. Moreover, the patterns of genomic copy number variation in single tumor cells in paired blood and BMAs showed significant inter and intrapatient heterogeneity. Conclusions Paired analysis of single prostate cancer cells in blood and bone shows promise for clinical application and provides complementary information. The high prevalence and prognostic significance of tumor cell clusters particularly in BMAs, suggest that these structures are key mediators of prostate cancer’s metastatic progression. PMID:27702818

C-C motif ligand 5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment.

PubMed

Urata, Satoko; Izumi, Kouji; Hiratsuka, Kaoru; Maolake, Aerken; Natsagdorj, Ariunbold; Shigehara, Kazuyoshi; Iwamoto, Hiroaki; Kadomoto, Suguru; Makino, Tomoyuki; Naito, Renato; Kadono, Yoshifumi; Lin, Wen-Jye; Wufuer, Guzailinuer; Narimoto, Kazutaka; Mizokami, Atsushi

2018-03-01

Chemokines and their receptors have key roles in cancer progression. The present study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when C-C motif ligand 5 (CCL5) neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Costal chondrosarcoma requiring differential diagnosis from metastatic tumor.

PubMed

Matsuoka, Katsunari; Ueda, Mitsuhiro; Miyamoto, Yoshihiro

2017-02-01

Although chondrosarcoma is a common malignant bone tumor, cases arising in the rib are relatively rare. We experienced a case of chondrosarcoma arising in the right 10th rib during follow-up after lung cancer surgery. Although the finding of an osteolytic mass suggested a metastatic bone tumor, 18F-fluorodeoxyglucose positron-emission tomography demonstrated low fluorodeoxyglucose uptake, and a primary bone tumor was suspected. The bone tumor was resected and diagnosed as chondrosarcoma. Four years after resection, there has been no recurrence or metastasis. Positron-emission tomography was useful for differential diagnosis between a chondrosarcoma and a metastatic bone tumor.

Modeling invasion of metastasizing cancer cells to bone marrow utilizing ecological principles.

PubMed

Chen, Kun-Wan; Pienta, Kenneth J

2011-10-03

The invasion of a new species into an established ecosystem can be directly compared to the steps involved in cancer metastasis. Cancer must grow in a primary site, extravasate and survive in the circulation to then intravasate into target organ (invasive species survival in transport). Cancer cells often lay dormant at their metastatic site for a long period of time (lag period for invasive species) before proliferating (invasive spread). Proliferation in the new site has an impact on the target organ microenvironment (ecological impact) and eventually the human host (biosphere impact). Tilman has described mathematical equations for the competition between invasive species in a structured habitat. These equations were adapted to study the invasion of cancer cells into the bone marrow microenvironment as a structured habitat. A large proportion of solid tumor metastases are bone metastases, known to usurp hematopoietic stem cells (HSC) homing pathways to establish footholds in the bone marrow. This required accounting for the fact that this is the natural home of hematopoietic stem cells and that they already occupy this structured space. The adapted Tilman model of invasion dynamics is especially valuable for modeling the lag period or dormancy of cancer cells. The Tilman equations for modeling the invasion of two species into a defined space have been modified to study the invasion of cancer cells into the bone marrow microenvironment. These modified equations allow a more flexible way to model the space competition between the two cell species. The ability to model initial density, metastatic seeding into the bone marrow and growth once the cells are present, and movement of cells out of the bone marrow niche and apoptosis of cells are all aspects of the adapted equations. These equations are currently being applied to clinical data sets for verification and further refinement of the models.

Lobular Metastatic Breast Cancer Patients With Gastrointestinal Involvement: Features and Outcomes.

PubMed

Montagna, Emilia; Pirola, Sara; Maisonneuve, Patrick; De Roberto, Giuseppe; Cancello, Giuseppe; Palazzo, Antonella; Viale, Giuseppe; Colleoni, Marco

2017-07-10

Metastatic breast cancer typically involves the lungs, bones, brain, and liver and only occasionally affects the gastrointestinal (GI) tract. The relevant published data have been limited to case reports and small series of patients. The present study focused on the treatment and outcomes of breast cancer patients with GI involvement diagnosed at the European Institute of Oncology. We analyzed the clinicopathologic features of the GI metastases and compared them with those of the primary tumors according to their histologic type (ductal or lobular carcinoma). From the database of the Department of Pathology, 40 patients who had undergone endoscopy or GI surgery with a final diagnosis of metastatic breast cancer from 2000 to 2014 were identified. The greatest proportion of patients (75%) had had primary invasive lobular carcinoma. Of the 40 patients, 82% had hormone receptor-positive disease in the metastatic lesion; 34 patients were candidates for systemic therapy. The median length of observation after GI metastasis was 18 months (range, 0.6-79 months). The overall survival from the diagnosis of GI involvement was 33 months (95% confidence interval, 16.8-38.3 months). Lobular breast carcinoma has a greater propensity to metastasize to the GI tract compared with other breast cancer subtypes. In the presence of GI symptoms, even if nonspecific, the GI tract should be thoroughly studied. Systemic treatment, including hormonal therapy, should be considered. Copyright © 2017 Elsevier Inc. All rights reserved.

ErbB2 and bone sialoprotein as markers for metastatic osteosarcoma cells

PubMed Central

Valabrega, G; Fagioli, F; Corso, S; Madon, E; Brach del Prever, A; Biasin, E; Linari, A; Aglietta, M; Giordano, S

2003-01-01

Osteosarcoma is the most common malignant bone neoplasia occurring in young patients in the first two decades of life, and represents 20% of all primitive malignant bone tumours. At present, treatment of metastatic osteosarcoma is unsatisfactory. High-dose chemotherapy followed by CD34+ leukapheresis rescue may improve these poor results. Neoplastic cells contaminating the apheresis may, however, contribute to relapse. To identify markers suitable for detecting osteosarcoma cells in aphereses we analysed the expression of bone-specific genes (Bone Sialoprotein (BSP) and Osteocalcin) and oncogenes (Met and ErbB2) in 22 patients with metastatic osteosarcoma and six healthy stem cell donors. The expression of these genes in aphereses of patients affected by metastatic osteosarcoma was assessed by RT–PCR and Southern blot analysis. Met and Osteocalcin proved to be not useful markers since they are positive in aphereses of both patients with metastatic osteosarcoma and healthy stem cell donors. On the contrary, BSP was expressed at significant levels in 85% of patients. Moreover, 18% of patients showed a strong and significantly positive (seven to 16 times higher than healthy stem cell donors) ErbB2 expression. In all positive cases, neoplastic tissue also expressed ErbB2. Our data show that ErbB2 can be a useful marker for tumour contamination in aphereses of patients affected by ErbB2-expressing osteosarcomas and that analysis of Bone Sialoprotein expression can be an alternative useful marker. PMID:12569382

Novel (188)Re multi-functional bone-seeking compounds: Synthesis, biological and radiotoxic effects in metastatic breast cancer cells.

PubMed

Fernandes, Célia; Monteiro, Sofia; Belchior, Ana; Marques, Fernanda; Gano, Lurdes; Correia, João D G; Santos, Isabel

2016-02-01

Radiolabeled bisphosphonates (BPs) have been used for bone imaging and delivery of β(-) emitting radionuclides for bone pain palliation. As a β(-) emitter, (188)Re has been considered particularly promising for bone metastases therapy. Aimed at finding innovative bone-seeking agents for systemic radiotherapy of bone metastases, we describe herein novel organometallic compounds of the type fac-[(188)Re(CO)3(k(3)-L)], (L=BP-containing chelator), their in vitro and in vivo stability, and their cellular damage in MDAMB231 cells, a metastatic breast cancer cell line. After synthesis and characterization of the novel organometallic compounds of the type fac-[(188)Re(CO)3(k(3)-L)] their radiochemical purity and in vitro stability was assessed by HPLC. In vivo stability and pharmacokinetic profile were evaluated in mice and the radiocytotoxic activity and DNA damage were assessed by MTT assay and by the cytokinesis-block micronucleus (CBMN) assay, respectively. Among all complexes, (188)Re3 was obtained with high radiochemical purity (>95%) and high specific activity and presented high in vitro and in vivo stability. Biodistribution studies of (188)Re3 in Balb/c mice showed fast blood clearance, high bone uptake (16.1 ± 3.3% IA/g organ, 1h p.i.) and high bone-to-blood and bone-to-muscle radioactivity ratios, indicating that it is able to deliver radiation to bone in a very selective way. The radiocytotoxic effect elicited by (188)Re3 in the MDAMB231 cells was dependent on its concentration, and was higher than that induced by identical concentrations of [(188)ReO4](-). Additionally, (188)Re3 elicited morphological changes in the cells and induced DNA damage by the increased number of MN observed. Altogether, our results demonstrate that (188)Re3 could be considered an attractive candidate for further preclinical evaluation for systemic radionuclide therapy of bone metastases considering its ability to deliver radiation to bone in a very selective way and to induce

Activation of NF-kappa B Signaling Promotes Growth of Prostate Cancer Cells in Bone

PubMed Central

Jin, Renjie; Sterling, Julie A.; Edwards, James R.; DeGraff, David J.; Lee, Changki; Park, Serk In; Matusik, Robert J.

2013-01-01

Patients with advanced prostate cancer almost invariably develop osseous metastasis. Although many studies indicate that the activation of NF-κB signaling appears to be correlated with advanced cancer and promotes tumor metastasis by influencing tumor cell migration and angiogenesis, the influence of altered NF-κB signaling in prostate cancer cells within boney metastatic lesions is not clearly understood. While C4-2B and PC3 prostate cancer cells grow well in the bone, LNCaP cells are difficult to grow in murine bone following intraskeletal injection. Our studies show that when compared to LNCaP, NF-κB activity is significantly higher in C4-2B and PC3, and that the activation of NF-κB signaling in prostate cancer cells resulted in the increased expression of the osteoclast inducing genes PTHrP and RANKL. Further, conditioned medium derived from NF-κB activated LNCaP cells induce osteoclast differentiation. In addition, inactivation of NF-κB signaling in prostate cancer cells inhibited tumor formation in the bone, both in the osteolytic PC3 and osteoblastic/osteoclastic mixed C4-2B cells; while the activation of NF-κB signaling in LNCaP cells promoted tumor establishment and proliferation in the bone. The activation of NF-κB in LNCaP cells resulted in the formation of an osteoblastic/osteoclastic mixed tumor with increased osteoclasts surrounding the new formed bone, similar to metastases commonly seen in patients with prostate cancer. These results indicate that osteoclastic reaction is required even in the osteoblastic cancer cells and the activation of NF-κB signaling in prostate cancer cells increases osteoclastogenesis by up-regulating osteoclastogenic genes, thereby contributing to bone metastatic formation. PMID:23577181

Cancer stemness and metastatic potential of the novel tumor cell line K3: an inner mutated cell of bone marrow-derived mesenchymal stem cells.

PubMed

Qian, Hui; Ding, Xiaoqing; Zhang, Jiao; Mao, Fei; Sun, Zixuan; Jia, Haoyuan; Yin, Lei; Wang, Mei; Zhang, Xu; Zhang, Bin; Yan, Yongmin; Zhu, Wei; Xu, Wenrong

2017-06-13

Mesenchymal stem cells (MSCs) transplantation has been used for therapeutic applications in various diseases. Here we report MSCs can malignantly transform in vivo. The novel neoplasm was found on the tail of female rat after injection with male rat bone marrow-derived MSCs (rBM-MSCs) and the new tumor cell line, K3, was isolated from the neoplasm. The K3 cells expressed surface antigens and pluripotent genes similar to those of rBM-MSCs and presented tumor cell features. Moreover, the K3 cells contained side population cells (SP) like cancer stem cells (CSCs), which might contribute to K3 heterogeneity and tumorigenic capacity. To investigate the metastatic potential of K3 cells, we established the nude mouse models of liver and lung metastases and isolated the corresponding metastatic cell lines K3-F4 and K3-B6. Both K3-F4 and K3-B6 cell lines with higher metastatic potential acquired more mesenchymal and stemness-related features. Epithelial-mesenchymal transition is a potential mechanism of K3-F4 and K3-B6 formation.

Omentum and bone marrow: how adipocyte-rich organs create tumour microenvironments conducive for metastatic progression

PubMed Central

Gusky, H. Chkourko; Diedrich, J.; MacDougald, O. A.; Podgorski, I.

2016-01-01

Summary A number of clinical studies have linked adiposity with increased cancer incidence, progression and metastasis, and adipose tissue is now being credited with both systemic and local effects on tumour development and survival. Adipocytes, a major component of benign adipose tissue, represent a significant source of lipids, cytokines and adipokines, and their presence in the tumour microenvironment substantially affects cellular trafficking, signalling and metabolism. Cancers that have a high predisposition to metastasize to the adipocyte-rich host organs are likely to be particularly affected by the presence of adipocytes. Although our understanding of how adipocytes influence tumour progression has grown significantly over the last several years, the mechanisms by which adipocytes regulate the meta-static niche are not well-understood. In this review, we focus on the omentum, a visceral white adipose tissue depot, and the bone, a depot for marrow adipose tissue, as two distinct adipocyte-rich organs that share common characteristic: they are both sites of significant metastatic growth. We highlight major differences in origin and function of each of these adipose depots and reveal potential common characteristics that make them environments that are attractive and conducive to secondary tumour growth. Special attention is given to how omental and marrow adipocytes modulate the tumour microenvironment by promoting angiogenesis, affecting immune cells and altering metabolism to support growth and survival of metastatic cancer cells. PMID:27432523

[Evaluation and classification of drug therapy for breast cancer with bone-only metastasis].

PubMed

Meng, X Y; Song, S T

2017-03-23

Skeleton is one of the most common metastatic organs for breast cancer, which has a better prognosis than visceral metastases. Bone-only metastasis was defined"non-measurable" in the RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and was excluded by clinical trials. However, patients with bone-only metastasis are also in need of effective treatment to prolong survival. Endocrine therapy is the most important treatment for bone metastatic patients. Tumor response of bone metastases can be determined objectively by bone-window CT. Effective treatment should be continued if the symptoms are relieved or osteogenesis is observed. Osteoblastic change in bone-window CT is a sign of improvement after treatment. Endocrine therapy is proper for ER-positive patients. The patients with initial osteoblastic metastasis should not be treated with salvage chemotherapy or anti-HER2 treatment, only if osteolytic metastasis or visceral metastasis is observed. Bishosphonates are just auxiliary drugs in bone metastasis, which should not be abused.

Prognostic impact of metastatic pattern in stage IV breast cancer at initial diagnosis.

PubMed

Leone, Bernardo Amadeo; Vallejo, Carlos Teodoro; Romero, Alberto Omar; Machiavelli, Mario Raúl; Pérez, Juan Eduardo; Leone, Julieta; Leone, José Pablo

2017-02-01

To analyze the prognostic influence of metastatic pattern (MP) compared with other biologic and clinical factors in stage IV breast cancer at initial diagnosis (BCID) and evaluate factors associated with specific sites of metastases (SSM). We evaluated women with stage IV BCID with known metastatic sites, reported to the Surveillance, Epidemiology and End Results program from 2010 to 2013. MP was categorized as bone-only, visceral, bone and visceral (BV), and other. Univariate and multivariate analyses determined the effects of each variable on overall survival (OS). Logistic regression examined factors associated with SSM. We included 9143 patients. Bone represented 37.5% of patients, visceral 21.9%, BV 28.8%, and other 11.9%. Median OS by MP was as follows: bone 38 months, visceral 21 months, BV 19 months, and other 33 months (P < 0.0001). Univariate analysis showed that higher number of metastatic sites had worse prognosis. In multivariate analysis, older age (hazard ratio 1.9), black race (hazard ratio 1.17), grade 3/4 tumors (hazard ratio 1.6), triple-negative (hazard ratio 2.24), BV MP (hazard ratio 2.07), and unmarried patients (hazard ratio 1.25) had significantly shorter OS. As compared with HR+/HER2- tumors, triple-negative and HR-/HER2+ had higher odds of brain, liver, lung, and other metastases. HR+/HER2+ had higher odds of liver metastases. All three subtypes had lower odds of bone metastases. There were substantial differences in OS according to MP. Tumor subtypes have a clear influence among other factors on SSM. We identified several prognostic factors that could guide therapy selection in treatment naïve patients.

Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study.

PubMed

Pasqualini, Renata; Millikan, Randall E; Christianson, Dawn R; Cardó-Vila, Marina; Driessen, Wouter H P; Giordano, Ricardo J; Hajitou, Amin; Hoang, Anh G; Wen, Sijin; Barnhart, Kirstin F; Baze, Wallace B; Marcott, Valerie D; Hawke, David H; Do, Kim-Anh; Navone, Nora M; Efstathiou, Eleni; Troncoso, Patricia; Lobb, Roy R; Logothetis, Christopher J; Arap, Wadih

2015-07-15

Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature. The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer. BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that

Gastric cancer bone metastases together with osteopoikilosis diagnosed using bone scintigraphy and 18F-FDG PET/CT.

PubMed

Prado Wohlwend, S; Sánchez Vaño, R; Sopena Novales, P; Uruburu García, E; Aparisi Rodríguez, F; Martínez Carsí, C

The coexistence of different bone diseases in the same patient involves a complex differential diagnosis. A patient is presented who was studied due to a renal mass that showed many sclerotic lesions in spine and limbs in conventional radiology and CT. These lesions were evaluated with 99m TC-HDP bone scintigraphy and 18 F-FDG PET/CT, which helped to obtain the definitive pathological diagnosis of osteopoikilosis (OP) co-existing with gastric cancer bone metastases. Of the different imaging scans performed, bone scintigraphy was particularly relevant due to its ability to discriminate between benign and metastatic bone disease. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

Hyperparathyroidism Mimicking Metastatic Bone Disease: A Case Report and Review of Literature.

PubMed

Gupta, Monica; Singhal, Lalita; Kumar, Akshay

2018-06-01

Multiple osteolytic lesions are usually associated with metastatic involvement of the bone; however, metabolic bone diseases should also be included in the differential diagnosis. In this study, we describe a case of primary hyperparathyroidism (PHPT) with multiple osteolytic lesions that was diagnosed initially as having metastatic bone involvement. The laboratory results showed hypercalcemia and raised alkaline phosphatase along with fibrosis in the bone marrow biopsy with no increase in tumor markers and normal serum protein electrophoresis. The parathyroid hormone levels were high, which pointed toward a diagnosis of PHPT. Sestamibi scan revealed uptake at the level of the left inferior pole of the thyroid gland, which was suggestive of parathyroid adenoma. The possibility of hyperparathyroidism should be kept in mind when a patient presents with multiple osteolytic lesions and hypercalcemia.

The efficacy of choline magnesium trisalicylate (CMT) in the management of metastatic bone pain: a pilot study.

PubMed

Johnson, J R; Miller, A J

1994-01-01

Twenty-six patients with painful, bony metastases were recruited into a randomized, double-blind, single dose, two-treatment, three-part crossover study of choline magnesium trisalicylate (CMT) and placebo. Assessments were made prior to and at one, two, three and four hours after dosing. Bone pain caused by metastatic cancer was significantly relieved one hour after the administration of 1500 mg CMT (p = 0.04). At all four time points the pain was less than baseline with CMT and at three time points greater than baseline with placebo but these results did not reach statistical significance. The summed pain intensity difference for patients was greater with CMT than with placebo, but this also did not reach significance. The incidence of volunteered side-effects was similar for both treatments. The results suggest that a nonacetylating, nonsteroidal anti-inflammatory drug may have a role complementary to that of an opioid in the management of metastatic bone pain.

Bone-Induced Expression of Tumoral Integrin beta3 Enables Targeted Nanotherapy of Breast Cancer Metastases

NASA Astrophysics Data System (ADS)

Ross, Michael H.

Breast cancer is the most common cancer for women worldwide, representing approximately 25% of all new cancer cases in this population. While early detection and removal of breast cancer still confined to the primary site results in a good prognosis, approximately one- third of patients will develop distant metastases. In these patients, overall survival is markedly reduced. Of the common sites for breast cancer metastasis, the skeletal system is the most frequent. Treating breast cancer bone metastases has proven particularly difficult for several reasons, such as dissemination of metastases throughout the skeleton, poor drug localization to sites of interest, a lack of tumor-specific targets expressed across breast cancer subtypes, and the chemo-protective nature of the bone microenvironment. This dissertation is focused on investigating a potential tumor-target expressed on breast cancer bone metastases, and to improve drug treatment efficacy against tumor cells in the bone microenvironment. Integrins are heterodimeric cell surface receptors, composed of an alpha and beta subunit from a large family of selectively-compatible integrin subunits. As a heterodimeric complex, integrins can bind to components of the extracellular matrix or to other cells. One particular integrin complex, integrin alphavbeta3, is composed of the tightly regulated integrin subunit beta3 and the more widely expressed alphav subunit. I examined the expression of integrin beta3 on primary breast cancer as compared to metastases in murine cancer models, and observed that integrin expression is significantly elevated on bone metastases as compared to the primary tumors or visceral metastases. In addition, I evaluated tumor-associated integrin beta3 expression on a tissue microarray (TMA) composed of primary breast cancer and patient-matched bone metastatic tissue from 42 patients. Across nearly all patients, tumor-associated integrin beta3 expression was significantly elevated on bone

Optical imaging of metabolic adaptability in metastatic and non-metastatic breast cancer

NASA Astrophysics Data System (ADS)

Rebello, Lisa; Rajaram, Narasimhan

2018-02-01

Accurate methods for determining metastatic risk from the primary tumor are crucial for patient survival. Cell metabolism could potentially be used as a marker of metastatic risk. Optical imaging of the endogenous fluorescent molecules nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) provides a non-destructive and label-free method for determining cell metabolism. The optical redox ratio (FAD/FAD+NADH) is sensitive to the balance between glycolysis and oxidative phosphorylation (OXPHOS). We have previously established that hypoxia-reoxygenation stress leads to metastatic potential-dependent changes in optical redox ratio. The objective of this study was to monitor the changes in optical redox ratio in breast cancer cells in response to different periods of hypoxic stress as well various levels of hypoxia to establish an optimal protocol. We measured the optical redox ratio of highly metastatic 4T1 murine breast cancer cells under normoxic conditions and after exposure to 30, 60, and 120 minutes of 0.5% O2. This was followed by an hour of reoxygenation. We found an increase in the optical redox ratio following reoxygenation from hypoxia for all durations. Statistically significant differences were observed at 60 and 120 minutes (p˂0.01) compared with normoxia, implying an ability to adapt to OXPHOS after reoxygenation. The switch to OXPHOS has been shown to be a key promoter of cell invasion. We will present our results from these investigations in human breast cancer cells as well as non-metastatic breast cancer cells exposed to various levels of hypoxia.

Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Se Young; Kim, Hyun-Jeong; Kim, Ki Rim

Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulatedmore » with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatment-induced estrogen deficiency. - Highlights: • Betulinic acid reduced PTHrP production in human metastatic breast cancer cells. • Betulinic acid blocked RANKL/OPG ratio in PTHrP-stimulated human osteoblastic cells. �

Use of Bone Scan During Initial Prostate Cancer Workup, Downstream Procedures, and Associated Medicare Costs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Falchook, Aaron D.; Salloum, Ramzi G.; Hendrix, Laura H.

Purpose: For patients with a high likelihood of having metastatic disease (high-risk prostate cancer), bone scan is the standard, guideline-recommended test to look for bony metastasis. We quantified the use of bone scans and downstream procedures, along with associated costs, in patients with high-risk prostate cancer, and their use in low- and intermediate-risk patients for whom these tests are not recommended. Methods and Materials: Patients in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database diagnosed with prostate cancer from 2004 to 2007 were included. Prostate specific antigen (PSA), Gleason score, and clinical T stage were used to define D'Amico riskmore » categories. We report use of bone scans from the date of diagnosis to the earlier of treatment or 6 months. In patients who underwent bone scans, we report use of bone-specific x-ray, computed tomography (CT), and magnetic resonance imaging (MRI) scans, and bone biopsy within 3 months after bone scan. Costs were estimated using 2012 Medicare reimbursement rates. Results: In all, 31% and 48% of patients with apparent low- and intermediate-risk prostate cancer underwent a bone scan; of these patients, 21% underwent subsequent x-rays, 7% CT, and 3% MRI scans. Bone biopsies were uncommon. Overall, <1% of low- and intermediate-risk patients were found to have metastatic disease. The annual estimated Medicare cost for bone scans and downstream procedures was $11,300,000 for low- and intermediate-risk patients. For patients with apparent high-risk disease, only 62% received a bone scan, of whom 14% were found to have metastasis. Conclusions: There is overuse of bone scans in patients with low- and intermediate-risk prostate cancers, which is unlikely to yield clinically actionable information and results in a potential Medicare waste. However, there is underuse of bone scans in high-risk patients for whom metastasis is likely.« less

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms.

PubMed

Herroon, Mackenzie K; Rajagurubandara, Erandi; Hardaway, Aimalie L; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-11-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

PubMed Central

Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-01-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease. PMID:24240026

WE-FG-202-05: Quantification of Bone Flare On [F-18] NaF PET/CT in Metastatic Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weisman, A; Harmon, S; Perk, T

Purpose: Bone flare has been observed on Tc-99m bone scans during early assessment in metastatic Castration-Resistant Prostate Cancer (mCRPC) patients receiving select androgen-signaling pathway (AR) targeted treatments, including CYP17-inhibitor Abiraterone. This study investigates the appearance and potential clinical impact of bone flare in mCRPC patients receiving CYP17-inhibitors using {sup 18}F-NaF PET/CT. Methods: Twenty-three mCRPC patients being treated with CYP17-inhibitors received NaF PET/CT scans at baseline, week 6, and week 12 of treatment. Individual lesions were identified using a SUV>15 threshold within skeletal regions and articulated bone registration was used to track lesions between scans. Standard SUV metrics were extracted globallymore » for each patient (pSUV) and for each individual lesion (iSUV). Differences in metrics across time-points were compared using Wilcoxon signed-rank tests. Cox proportional hazard regression analyses were conducted between global metrics and progression-free survival (PFS). Results: Nineteen patients (83%) showed increasing NaF PET global metrics at week 6, with pSUV{sub total} reflecting consensus change across other global metrics with median increase +33% (range +2 to 205%). Of these patients, 14 showed subsequent decrease in pSUV{sub total}, with a median of −17% (range −76 to −1%), indicating flare phenomenon. Increasing pSUV{sub mean} at week 6 correlated with extended clinical PFS (HR = 0.58, p=0.02). New lesions did not account for the initial increase in global NaF metrics. Lesion-level analysis reveals 316 lesions in the 14 patients exhibiting global flare. On average, 75% (sd: 22%) of lesions follow global trends with iSUV{sub total} increasing at week 6 and 65% (sd: 17%) showing iSUV{sub total} decrease at week 12. Conclusion: Bone flare was detected on NaF PET/CT in the first 6 weeks of treatment for mCRPC patients receiving CYP17-inhibitors, subsiding by week 12. Characterization provided

Musculoskeletal Complications and Bone Metastases in Breast Cancer Patients Undergoing Estrogen Deprivation Therapy

DTIC Science & Technology

2016-10-01

are that any treatment or environmental factor that leads to bone loss (e.g., glucocorticoids, GnRH inhibitors, radiation, fracture , osteoporosis...recurrence and mortality. Previous cell culture and clinical studies have demonstrated that peripheral adipose ( fat ) tissue promotes cancer growth, yet the...contribution of increased MAT on metastatic tumor growth in bone is currently unknown. MAT, which is a historically understudied fat depot, accounts

Bone marrow invasion in multiple myeloma and metastatic disease.

PubMed

Vilanova, J C; Luna, A

2016-04-01

Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

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

[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo.

PubMed

Martin, Ana Carolina B M; Fuzer, Angelina M; Becceneri, Amanda B; da Silva, James Almada; Tomasin, Rebeka; Denoyer, Delphine; Kim, Soo-Hyun; McIntyre, Katherine A; Pearson, Helen B; Yeo, Belinda; Nagpal, Aadya; Ling, Xiawei; Selistre-de-Araújo, Heloisa S; Vieira, Paulo Cézar; Cominetti, Marcia R; Pouliot, Normand

2017-09-22

There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin ( Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo . We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro . In addition, [10]-gingerol is well tolerated in vivo , induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients.

[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo

PubMed Central

Becceneri, Amanda B.; da Silva, James Almada; Tomasin, Rebeka; Denoyer, Delphine; Kim, Soo-Hyun; McIntyre, Katherine A.; Pearson, Helen B.; Yeo, Belinda; Nagpal, Aadya; Ling, Xiawei; Selistre-de-Araújo, Heloisa S.; Vieira, Paulo Cézar

2017-01-01

There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin (Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo. We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro. In addition, [10]-gingerol is well tolerated in vivo, induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients. PMID:29069785

Surgery of primary tumour has survival benefit in metastatic breast cancer with single-organ metastasis, especially bone.

PubMed

Rhu, Jinsoo; Lee, Se Kyung; Kil, Won Ho; Lee, Jeong Eon; Nam, Seok Jin

2015-04-01

Surgery for the primary breast tumour is usually not recommended in metastatic breast cancer (MBC); however, some reports have suggested a benefit of locoregional treatment. We designed this study to evaluate the efficacy of locoregional surgery in MBC. Data for patients diagnosed with MBC at Samsung Medical Center between 1995 and 2011 were retrospectively collected. We compared the survival benefit of all treatment modalities using Cox regression analysis. Subgroup analyses based on number of metastases were performed to delineate the indication for each treatment. Among 262 patients, 40 (15.3%) underwent surgery. Other treatments included chemotherapy (n = 213, 81.3%), radiotherapy (n = 138, 52.7%), hormone therapy (n = 118, 45.0%) and HER2/neu receptor (HER2)-targeted therapy (n = 37, 14.1%). Cox regression analysis showed that surgery (hazard ratios (HR) = 0.51, P < 0.01), hormone therapy (HR = 0.31, P < 0.01) and HER2-targeted therapy (HR = 0.33, P < 0.01) were associated with improved survival, whereas presence of three or more metastatic organs (HR = 1.62, P = 0.03) was associated with poor survival. In patients with metastasis to a single organ, surgery (HR = 0.43, P < 0.01), chemotherapy (HR = 0.62, P = 0.05), hormone therapy (HR = 0.39, P < 0.01) and HER2-targeted therapy (HR = 0.39, P = 0.02) had a survival benefit. Furthermore, for patients with bone-only metastasis, surgery (HR = 0.37, P = 0.02), chemotherapy (HR = 0.42, P < 0.01), hormone therapy (HR = 0.22, P < 0.01) and HER2-targeted therapy (HR = 0.09, P = 0.02) showed a survival benefit. However, only hormone therapy and HER2-targeted therapy had a survival benefit in MBC with metastasis to multiple organs. Surgical control of the primary breast tumour should be considered as a locoregional therapy in combination with systemic therapy in MBC with metastasis to a single organ, especially bone-only metastasis.

Prevention and treatment of bone fragility in cancer patient

PubMed Central

Ottanelli, Silva

2015-01-01

vitamin D. Bisphosphonates and denosumab are used for the management of bone remodeling and bone loss induced by cancer treatments. Bisphosphonates also have anti-tumor effects per se, which are expressed in potentially prevent the development of bone metastases. In men with metastatic prostate cancer and which is induced androgen deprivation, it is usefully used denosumab 120 mg monthly or zoledronic acid 4 mg monthly. PMID:26604936

Management of Bone Metastases From Breast Cancer in Upper and Lower Body at the Same Time: A Case Report.

PubMed

Ciaglia, Gian Franco; Martino, Antonia; Sayad, Khadija; Scoglio, Claudio; Pezzulla, Donato; Cappabianca, Salvatore

2016-06-01

Breast cancer is by far the most common cancer in women, and it has the highest incidence rates in western Europe. At breast cancer diagnosis, approximately 5-6% of women present with distant spread with bone, representing the most common site of metastatic lesions. More than half of the women, who present with metastatic breast cancer at the primary diagnosis, will develop bone metastases. We report a clinical case of a 75-year-old woman, with a history of breast cancer who undergone surgery 7 years ago, presenting bone metastases in different areas. We tried to determinate the major areas of pain and then to quantify it with a one-dimensional scale. After that, we analyzed the images of the previous instrumental exams and the centering CT in order to compare them with what the patient reported and then to decide what we should have targeted first. The aim of our work was to try finding a methodology in order to determinate the priority in the selecting of the area to treat to apply in this kind of patients.

Management of Bone Metastases From Breast Cancer in Upper and Lower Body at the Same Time: A Case Report

PubMed Central

Ciaglia, Gian Franco; Martino, Antonia; Sayad, Khadija; Scoglio, Claudio; Pezzulla, Donato; Cappabianca, Salvatore

2016-01-01

Breast cancer is by far the most common cancer in women, and it has the highest incidence rates in western Europe. At breast cancer diagnosis, approximately 5-6% of women present with distant spread with bone, representing the most common site of metastatic lesions. More than half of the women, who present with metastatic breast cancer at the primary diagnosis, will develop bone metastases. We report a clinical case of a 75-year-old woman, with a history of breast cancer who undergone surgery 7 years ago, presenting bone metastases in different areas. We tried to determinate the major areas of pain and then to quantify it with a one-dimensional scale. After that, we analyzed the images of the previous instrumental exams and the centering CT in order to compare them with what the patient reported and then to decide what we should have targeted first. The aim of our work was to try finding a methodology in order to determinate the priority in the selecting of the area to treat to apply in this kind of patients. PMID:28983365

Increased risk of SSEs in bone-only metastatic breast cancer patients treated with zoledronic acid.

PubMed

Yanae, Masashi; Fujimoto, Shinichiro; Tane, Kaori; Tanioka, Maki; Fujiwara, Kimiko; Tsubaki, Masanobu; Yamazoe, Yuzuru; Morishima, Yoshiyuki; Chiba, Yasutaka; Takao, Shintaro; Komoike, Yoshifumi; Tsurutani, Junji; Nakagawa, Kazuhiko; Nishida, Shozo

2017-09-01

Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.

[Efficacy of Radiation Therapy for Esophageal Cancer with Bone Metastases].

PubMed

Katayanagi, So; Watanabe, Takafumi; Makuuchi, Yosuke; Shigoka, Masatoshi; Sumi, Tetsuo; Takagaki, Shinichi; Okubo, Mitsuru; Tachibana, Shingo; Oosaka, Yoshiaki; Tsuchida, Akihiko; Kawachi, Shigeyuki

2015-11-01

We retrospectively considered the validity of radiotherapy for patients with bone metastases from esophageal cancer. Eight patients have received radiotherapy in our hospital since 2007. The median age of the patients was 63 years, with 5 men and 3 women. Bone metastatic sites were 4 to the vertebrae, 3 to the ribs, 3 to the femur and 1 each to the humerus, ulna, and radius, respectively. All of the patients had other unresectable sites of metastasis. Radiotherapy reduced pain of 3 patients of PS 1 clearly. Median survival time from the start of radiation therapy was 50 days. When PS was relatively good, the possibility of easing pain and improving QOL was suggested by our data. There is a possibility that radiation therapy for patients with bone metastases from esophageal cancer can improve the QOL and alleviate pain.

Metastatic breast cancer: The Odyssey of personalization.

PubMed

Sonnenblick, A; Pondé, N; Piccart, M

2016-10-01

Metastatic breast cancer is the most frequent cause of cancer death for women worldwide. In the last 15 years, a large number of new agents have entered clinical use, a result of the dramatic increase in our understanding of the molecular underpinnings of metastatic breast cancer. However, while these agents have led to better outcomes, they are also at the root cause of increasing financial pressure on healthcare systems. Moreover, decision making in an era where every year new agents are added to the therapeutic armamentarium has also become a significant challenge for medical oncologists. In the present article, we will provide an ample review on the most recent developments in the field of treatment of the different subtypes of metastatic breast cancer with a critical discussion on the slow progress made in identifying response biomarkers. New hopes in the form of ctDNA monitoring and functional imaging will be presented. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Treatments for Metastatic Prostate Cancer (mPC): A Review of Costing Evidence.

PubMed

Norum, Jan; Nieder, Carsten

2017-12-01

Prostate cancer (PC) is the most common cancer in Western countries. More than one third of PC patients develop metastatic disease, and the 5-year expected survival in distant disease is about 35%. During the last few years, new treatments have been launched for metastatic castrate-resistant prostate cancer (mCRPC). We aimed to review the current literature on health economic analysis on the treatment of metastatic prostate cancer (mPC), compare the studies, summarize the findings and make the results available to administrators and decision makers. A systematic literature search was done for economic evaluations (cost-minimization, cost-effectiveness, cost-utility, cost-of-illness, cost-of-drug, and cost-benefit analyses). We employed the PubMed ® search engine and searched for publications published between 2012 and 2016. The terms used were "prostate cancer", "metastatic" and "cost". An initial screening of all headlines was performed, selected abstracts were analysed, and finally the full papers investigated. Study characteristics, treatment and comparator, country, type of evaluation, perspective, year of value, time horizon, efficacy data, discount rate, total costs and sensitivity analysis were analysed. The quality was assessed using the Quality of Health Economic Studies (QHES) instrument. A total of 227 publications were detected and screened, 58 selected for full-text assessment and 31 included in the final analyses. Despite the significant international literature on the treatment of mCRPC, there were only 15 studies focusing on cost-effectiveness analysis (CEA). Medical treatment constituted two thirds of the selected studies. Significant costs in the treatment of mCRPC were disclosed. In the pre-docetaxel setting, both abiraterone acetate (AA) and enzalutamide were concluded beyond accepted cost/quality-adjusted life year limits. In the docetaxel refractory setting, most studies concluded that enzalutamide was cost-effective and superior to AA. In

Polyurethane foam scaffold as in vitro model for breast cancer bone metastasis.

PubMed

Angeloni, Valentina; Contessi, Nicola; De Marco, Cinzia; Bertoldi, Serena; Tanzi, Maria Cristina; Daidone, Maria Grazia; Farè, Silvia

2017-11-01

Breast cancer (BC) represents the most incident cancer case in women (29%), with high mortality rate. Bone metastasis occurs in 20-50% cases and, despite advances in BC research, the interactions between tumor cells and the metastatic microenvironment are still poorly understood. In vitro 3D models gained great interest in cancer research, thanks to the reproducibility, the 3D spatial cues and associated low costs, compared to in vivo and 2D in vitro models. In this study, we investigated the suitability of a poly-ether-urethane (PU) foam as 3D in vitro model to study the interactions between BC tumor-initiating cells and the bone microenvironment. PU foam open porosity (>70%) appeared suitable to mimic trabecular bone structure. The PU foam showed good mechanical properties under cyclic compression (E=69-109kPa), even if lower than human trabecular bone. The scaffold supported osteoblast SAOS-2 cell line proliferation, with no cytotoxic effects. Human adipose derived stem cells (ADSC) were cultured and differentiated into osteoblast lineage on the PU foam, as shown by alizarin red staining and RT-PCR, thus offering a bone biomimetic microenvironment to the further co-culture with BC derived tumor-initiating cells (MCFS). Tumor aggregates were observed after three weeks of co-culture by e-cadherin staining and SEM; modification in CaP distribution was identified by SEM-EDX and associated to the presence of tumor cells. In conclusion, we demonstrated the suitability of the PU foam to reproduce a bone biomimetic microenvironment, useful for the co-culture of human osteoblasts/BC tumor-initiating cells and to investigate their interaction. 3D in vitro models represent an outstanding alternative in the study of tumor metastases development, compared to traditional 2D in vitro cultures, which oversimplify the 3D tissue microenvironment, and in vivo studies, affected by low reproducibility and ethical issues. Several scaffold-based 3D in vitro models have been proposed

Bone Cancer

MedlinePlus

Cancer that starts in a bone is uncommon. Cancer that has spread to the bone from another ... more common. There are three types of bone cancer: Osteosarcoma - occurs most often between ages 10 and ...

Metastatic breast cancer presenting as linitis plastica of the stomach.

PubMed

Whitty, Lisa A; Crawford, David L; Woodland, Jay H; Patel, Jitendra C; Nattier, Bryce; Thomas, Charles R

2005-01-01

Early detection and treatment of breast cancer, leading to longer survival, has revealed the natural history of this disease process. Linitis plastica of the stomach is a potential long-term sequela of metastatic breast cancer. Here we present a case of metastatic breast cancer presenting as linitis plastica, as well as the treatment algorithm for this rare clinical entity. The world literature describes a clear pattern of linitis plastica for metastatic infiltrating lobular breast cancer and a discrete nodular pattern for infiltrating ductal cancer, in regard to metastasis to the stomach. To our knowledge, this is the first case of infiltrating ductal cancer presenting as linitis plastica of the stomach.

A Comprehensive Review of Contemporary Role of Local Treatment of the Primary Tumor and/or the Metastases in Metastatic Prostate Cancer

PubMed Central

Aoun, Fouad; Peltier, Alexandre; van Velthoven, Roland

2014-01-01

To provide an overview of the currently available literature regarding local control of primary tumor and oligometastases in metastatic prostate cancer and salvage lymph node dissection of clinical lymph node relapse after curative treatment of prostate cancer. Evidence Acquisition. A systematic literature search was conducted in 2014 to identify abstracts, original articles, review articles, research articles, and editorials relevant to the local control in metastatic prostate cancer. Evidence Synthesis. Local control of primary tumor in metastatic prostate cancer remains experimental with low level of evidence. The concept is supported by a growing body of genetic and molecular research as well as analogy with other cancers. There is only one retrospective observational population based study showing prolonged survival. To eradicate oligometastases, several options exist with excellent local control rates. Stereotactic body radiotherapy is safe, well tolerated, and efficacious treatment for lymph node and bone lesions. Both biochemical and clinical progression are slowed down with a median time to initiate ADT of 2 years. Salvage lymph node dissection is feasible in patients with clinical lymph node relapse after local curable treatment. Conclusion. Despite encouraging oncologic midterm results, a complete cure remains elusive in metastatic prostate cancer patients. Further advances in imaging are crucial in order to rapidly evolve beyond the proof of concept. PMID:25485280

CXXL 14 Blockade of CXCL12/CXCR4 Signaling in Prostate Cancer Bone Metastasis

DTIC Science & Technology

2016-10-01

is a common and unfortunate complication of advanced prostate cancer resulting in significant pain and fractures . The most devastating consequence...metastasis often experience bone pain and pathological fractures . Metastatic spread accounts for the majority of cancer mortalities, highlighting the...These data suggest a mechanism of increased migration and invasion is due to EMT. Regulation of Kinase Signaling by CXCL14 CXCL12 activates

Measuring the metastatic potential of cancer cells

NASA Technical Reports Server (NTRS)

Morrison, Dennis R.; Gratzner, Howard; Atassi, M. Z.

1993-01-01

Cancer cells must secrete proteolytic enzymes to invade adjacent tissues and migrate to a new metastatic site. Urokinase (uPA) is a key enzyme related to metastasis in cancers of the lung, colon, gastric, uterine, breast, brain, and malignant melanoma. A NASA technology utilization project has combined fluorescence microscopy, image analysis, and flow cytometry, using fluorescent dyes, and urokinase-specific antibodies to measure uPA and abnormal DNA levels (related to cancer cell proliferation) inside the cancer cells. The project is focused on developing quantitative measurements to determine if a patient's tumor cells are actively metastasizing. If a significant number of tumor cells contain large amounts of uPA (esp. membrane-bound) then the post-surgical chemotherapy or radiotherapy can be targeted for metastatic cells that have already left the primary tumor. These analytical methods have been applied to a retrospective study of biopsy tissues from 150 node negative, stage 1 breast cancer patients. Cytopathology and image analysis has shown that uPA is present in high levels in many breast cancer cells, but not found in normal breast. Significant amounts of uPA also have been measured in glioma cell lines cultured from brain tumors. Commercial applications include new diagnostic tests for metastatic cells, in different cancers, which are being developed with a company that provides a medical testing service using flow cytometry for DNA analysis and hormone receptors on tumor cells from patient biopsies. This research also may provide the basis for developing a new 'magic bullet' treatment against metastasis using chemotherapeutic drugs or radioisotopes attached to urokinase-specific monoclonal antibodies that will only bind to metastatic cells.

Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology.

PubMed

Walker, Steven M; Knight, Laura A; McCavigan, Andrena M; Logan, Gemma E; Berge, Viktor; Sherif, Amir; Pandha, Hardev; Warren, Anne Y; Davidson, Catherine; Uprichard, Adam; Blayney, Jaine K; Price, Bethanie; Jellema, Gera L; Steele, Christopher J; Svindland, Aud; McDade, Simon S; Eden, Christopher G; Foster, Chris; Mills, Ian G; Neal, David E; Mason, Malcolm D; Kay, Elaine W; Waugh, David J; Harkin, D Paul; Watson, R William; Clarke, Noel W; Kennedy, Richard D

2017-10-01

Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation. The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential. The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in

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

2018-03-07

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

A Prospective Study of Bone Tumor Response Assessment in Metastatic Breast Cancer

PubMed Central

Hayashi, Naoki; Costelloe, Colleen M.; Hamaoka, Tsuyoshi; Wei, Caimiao; Niikura, Naoki; Theriault, Richard L.; Hortobagyi, Gabriel N.; Madewell, John E.; Ueno, Naoto T.

2013-01-01

In this pilot study, we prospectively compared the response of bone metastasis assessed by our MD Anderson (MDA) bone tumor response criteria (computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) with the response assessed by the World Health Organization (WHO) criteria (XR and SS). Both MDA and WHO criteria predicted progression-free survival (PFS) of patients at 6 months but not at an earlier time point. Background In our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases. Methods We prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions. Results The median follow-up period was 26.7 months (range, 6.1–53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases. Conclusion MDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA

RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer.

PubMed

Yaeger, Rona; Cowell, Elizabeth; Chou, Joanne F; Gewirtz, Alexandra N; Borsu, Laetitia; Vakiani, Efsevia; Solit, David B; Rosen, Neal; Capanu, Marinela; Ladanyi, Marc; Kemeny, Nancy

2015-04-15

RAS and PIK3CA mutations in metastatic colorectal cancer (mCRC) have been associated with worse survival. We sought to evaluate the impact of RAS and PIK3CA mutations on cumulative incidence of metastasis to potentially curable sites of liver and lung and other sites such as bone and brain. We performed a computerized search of the electronic medical record of our institution for mCRC cases genotyped for RAS or PIK3CA mutations from 2008 to 2012. Cases were reviewed for patient characteristics, survival, and site-specific metastasis. Among the 918 patients identified, 477 cases were RAS wild type, and 441 cases had a RAS mutation (394 at KRAS exon 2, 29 at KRAS exon 3 or 4, and 18 in NRAS). RAS mutation was significantly associated with shorter median overall survival (OS) and on multivariate analysis independently predicted worse OS (HR, 1.6; P < .01). RAS mutant mCRC exhibited a significantly higher cumulative incidence of lung, bone, and brain metastasis and on multivariate analysis was an independent predictor of involvement of these sites (HR, 1.5, 1.6, and 3.7, respectively). PIK3CA mutations occurred in 10% of the 786 cases genotyped, did not predict for worse survival, and did not exhibit a site-specific pattern of metastatic spread. The metastatic potential of CRC varies with the presence of RAS mutation. RAS mutation is associated with worse OS and increased incidence of lung, bone, and brain metastasis. An understanding of this site-specific pattern of spread may help to inform physicians' assessment of symptoms in patients with mCRC. © 2014 American Cancer Society.

The role of Runx2 in facilitating autophagy in metastatic breast cancer cells.

PubMed

Tandon, Manish; Othman, Ahmad H; Ashok, Vivek; Stein, Gary S; Pratap, Jitesh

2018-01-01

Breast cancer metastases cause significant patient mortality. During metastases, cancer cells use autophagy, a catabolic process to recycle nutrients via lysosomal degradation, to overcome nutritional stress for their survival. The Runt-related transcription factor, Runx2, promotes cell survival under metabolic stress, and regulates breast cancer progression and bone metastases. Here, we identify that Runx2 enhances autophagy in metastatic breast cancer cells. We defined Runx2 function in cellular autophagy by monitoring microtubule-associated protein light chain (LC3B-II) levels, an autophagy-specific marker. The electron and confocal microscopic analyses were utilized to identify alterations in autophagic vesicles. The Runx2 knockdown cells accumulate LC3B-II protein and autophagic vesicles due to reduced turnover. Interestingly, Runx2 promotes autophagy by enhancing trafficking of LC3B vesicles. Our mechanistic studies revealed that Runx2 promotes autophagy by increasing acetylation of α-tubulin sub-units of microtubules. Inhibiting autophagy decreased cell adhesion and survival of Runx2 knockdown cells. Furthermore, analysis of LC3B protein in clinical breast cancer specimens and tumor xenografts revealed significant association between high Runx2 and low LC3B protein levels. Our studies reveal a novel regulatory mechanism of autophagy via Runx2 and provide molecular insights into the role of autophagy in metastatic cancer cells. © 2017 Wiley Periodicals, Inc.

Paranuclear blue inclusions in metastatic undifferentiated small cell carcinoma in the bone marrow.

PubMed

Wittchow, R; Laszewski, M; Walker, W; Dick, F

1992-09-01

Paranuclear blue inclusions (PBIs) are frequently identified within metastatic undifferentiated small cell carcinoma (SCC) cells on air-dried bone marrow aspirates stained with Wright's stain. To determine the sensitivity and specificity of this finding, 116 bone marrow aspirates containing metastatic neoplasms were evaluated for the presence and frequency of PBIs. Bone marrow specimens included 47 cases of metastatic SCC of the lung, 13 cases of large cell lymphoma, 19 cases of neuroblastoma, five cases of small, noncleaved cell lymphoma, seven cases of rhabdomyosarcoma, three cases of Ewing's sarcoma, three cases of other sarcomas, and 19 cases of non-small cell carcinoma (adenocarcinoma). PBIs were identified in 40 of 47 (85%) cases of SCC and their frequency varied from 0 to 24% of tumor cells among different cases. In approximately half the cases of SCC, PBIs were identified in 1 to 4% tumor cells; and in eight cases, PBIs were present in 5% or more of tumor cells. PBIs were also identified in two of seven (29%) cases of rhabdomyosarcoma and one case of malignant peripheral nerve sheath tumor, but they were not seen in Ewing's sarcoma, small non-cleaved cell lymphoma, large cell lymphoma, neuroblastoma, or non-small cell carcinoma. In addition, PBIs were not seen in alcohol-fixed, Papanicolaou-stained cytology specimens containing SCC. Ultrastructurally, PBIs may represent phagocytized nuclear/cellular material. PBIs are a feature of small cell carcinoma on air-dried, cytologic material stained with Romanowsky type stains. Their presence may provide diagnostic information with regard to the differential diagnosis of metastatic SCC in the bone marrow. Future studies evaluating non-bone marrow Wright's stained fine-needle aspiration specimens are needed to determine if PBIs are useful in distinguishing SCC from other poorly differentiated tumors in the cytology laboratory.

Importance of Metastatic Lymph Node Ratio in Non-Metastatic, Lymph Node-Invaded Colon Cancer: A Clinical Trial

PubMed Central

Isik, Arda; Peker, Kemal; Firat, Deniz; Yilmaz, Bahri; Sayar, Ilyas; Idiz, Oguz; Cakir, Coskun; Demiryilmaz, Ismail; Yilmaz, Ismayil

2014-01-01

Background The aim of this study was to evaluate the prognostic importance of the metastatic lymph node ratio for stage III colon cancer patients and to find a cut-off value at which the overall survival and disease-free survival change. Material/Methods Patients with pathological stage III colon cancer were retrospectively evaluated for: age; preoperative values of Crp, Cea, Ca 19-9, and Afp; pathologic situation of vascular, perineural, lymphatic, and serosal involvement; and metastatic lymph node ratio values were calculated. Results The study included 58 stage III colon cancer patients: 20 (34.5%) females and 38 (65.5%) males were involved in the study. Multivariate analysis was applied to the following variables to evaluate significance for overall survival and disease-free survival: age, Crp, Cea, perineural invasion, and metastatic lymph node ratio. The metastatic lymph node ratio (<0.25 or ≥0.25) is the only independent variable significant for overall and disease-free survival. Conclusions Metastatic lymph node ratio is an ideal prognostic marker for stage III colon cancer patients, and 0.25 is the cut-off value for prognosis. PMID:25087904

Regulation of Metastatic Breast Cancer Dormancy

DTIC Science & Technology

2015-09-01

individual cell motility to disseminate and eventually extravasate into common metastatic niches such as the brain, bone and liver. Once attaining the...Engineer tagged MCF7 cells with shRNA against E-cadherin and engineer tagged MDA-MB-361 and MDA- MB-231 cells to express or prevent expression of E

Cost-effectiveness of oral ibandronate compared with intravenous (i.v.) zoledronic acid or i.v. generic pamidronate in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy.

PubMed

De Cock, E; Hutton, J; Canney, P; Body, J J; Barrett-Lee, P; Neary, M P; Lewis, G

2005-12-01

Ibandronate is the first third-generation bisphosphonate to have both oral and intravenous (i.v.) efficacy. An incremental cost-effectiveness model compared oral ibandronate with i.v. zoledronic acid and i.v. generic pamidronate in female breast cancer patients with metastatic bone disease, undergoing i.v. chemotherapy. A global economic model was adapted to the UK National Health Service (NHS), with primary outcomes of direct healthcare costs and quality-adjusted life years (QALYs). Efficacy, measured as relative risk reduction of skeletal-related events (SREs), was obtained from clinical trials. Resource use data for i.v. bisphosphonates and the cost of managing SREs were obtained from published studies. Hospital management and SRE treatment costs were taken from unit cost databases. Monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with/without an SRE to adjust survival for quality of life. Model design and inputs were validated through expert UK clinician review. Total cost, including drug acquisition, was pound 386 less per patient with oral ibandronate vs. i.v. zoledronic acid and pound 224 less vs. i.v. generic pamidronate. Oral ibandronate gained 0.019 and 0.02 QALYs vs. i.v. zoledronic acid and i.v. pamidronate, respectively, making it the economically dominant option. At a threshold of pound 30,000 per QALY, oral ibandronate was cost-effective vs. zoledronic acid in 85% of simulations and vs. pamidronate in 79%. Oral ibandronate is a cost-effective treatment for metastatic bone disease from breast cancer due to reduced SREs, bone pain, and cost savings from avoidance of resource use commonly associated with bisphosphonate infusions.

Organtropic Metastatic Secretomes and Exosomes in Breast Cancer

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0427 TITLE: Organtropic Metastatic Secretomes and Exosomes in Breast Cancer PRINCIPAL INVESTIGATOR: Dr. David Lyden...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Organtropic Metastatic Secretomes and Exosomes in Breast Cancer 5b. GRANT NUMBER W81XWH-13-1-0427 5c...understanding of secreted metastasis regulators (extracellular proteins, cell-free nucleic acids and small vesicles – exosomes -) has tremendous

Metastatic colonic and gastric polyps from breast cancer resembling hyperplastic polyps.

PubMed

Horimoto, Yoshiya; Hirashima, Tetsuro; Arakawa, Atsushi; Miura, Hiroyoshi; Saito, Mitsue

2018-03-23

Breast cancer metastasis to the gastrointestinal tract is relatively rare and is generally found when patients complain of symptoms such as gastrointestinal obstruction. Herein, we report a case with metastatic colonic and gastric lesions from breast cancer, with the formation of mucosal polyps which resembled typical hyperplastic polyps.A 47-year-old woman underwent curable surgery for breast cancer and received standard systemic treatments. Her primary tumor was composed of a mix of invasive lobular and ductal carcinomas. During adjuvant endocrine therapy, she developed multiple colonic metastases, identified by colonoscopy performed as part of a general health check-up. She had no symptoms. Small elevated sessile polyps in the transverse colon and rectum showed histological features of signet-ring cell type adenocarcinoma, similar to the invasive lobular component of the primary breast cancer. During treatments for recurrent disease, she also developed multiple gastric metastases, with the same endoscopic and pathological features as the colonic lesions. Her treatment regimen was switched to oral chemotherapy, and she has since maintained stable disease for nearly 3 years. Multiple bone metastases eventually developed, and she was again switched to another systemic treatment but, to date, has remained free of symptoms.We emphasize that the endoscopic findings of the metastatic lesions in the colon and stomach in this case highly resembled hyperplastic polyps. Since biopsy is not always performed for hyperplastic polyps in the gastrointestinal tract, we believe that this case report may encourage endoscopists to offer biopsies to the patient who has a history of breast cancer.

ERBB2 Increases Metastatic Potentials Specifically in Androgen-Insensitive Prostate Cancer Cells

PubMed Central

Tome-Garcia, Jessica; Li, Dan; Ghazaryan, Seda; Shu, Limin; Wu, Lizhao

2014-01-01

Despite all the blood-based biomarkers used to monitor prostate cancer patients, prostate cancer remains as the second common cause of cancer mortality in men in the United States. This is largely due to a lack of understanding of the molecular pathways that are responsible for the aggressive forms of prostate cancers, the castrate-resistant prostate cancer and the metastatic prostate cancer. Cell signaling pathways activated by the ERBB2 oncogene or the RAS oncogene are frequently found to be altered in metastatic prostate cancers. To evaluate and define the role of the ERBB2/RAS pathway in prostate cancer metastasis, we have evaluated the impact of ERBB2- or RAS-overexpression on the metastatic potentials for four prostate cancer cell lines derived from tumors with different androgen sensitivities. To do so, we transfected the human DU145, LnCaP, and PC3 prostate cancer cells and the murine Myc-CaP prostate cancer cells with the activated form of ERBB2 or H-RAS and assessed their metastatic potentials by three complementary assays, a wound healing assay, a transwell motility assay, and a transwell invasion assay. We showed that while overexpression of ERBB2 increased the metastatic potential of the androgen-insensitive prostate cancer cells (i.e. PC3 and DU145), it did not affect metastatic potentials of the androgen-sensitive prostate cancer cells (i.e. LnCaP and Myc-CaP). In contrast, overexpression of H-RAS only increased the cell motility of Myc-CaP cells, which overexpress the human c-MYC oncogene. Our data suggest that ERBB2 collaborates with androgen signaling to promote prostate cancer metastasis, and that although RAS is one of the critical downstream effectors of ERBB2, it does not phenocopy ERBB2 for its impact on the metastatic potentials of prostate cancer cell lines. PMID:24937171

Osteoprotegerin in bone metastases: mathematical solution to the puzzle.

PubMed

Ryser, Marc D; Qu, Yiding; Komarova, Svetlana V

2012-01-01

Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.

Trespassing cancer cells: 'fingerprinting' invasive protrusions reveals metastatic culprits.

PubMed

Klemke, Richard L

2012-10-01

Metastatic cancer cells produce invasive membrane protrusions called invadopodia and pseudopodia, which play a central role in driving cancer cell dissemination in the body. Malignant cells use these structures to attach to and degrade extracellular matrix proteins, generate force for cell locomotion, and to penetrate the vasculature. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks that control the protrusion of invasive membranes. Here I highlight how these powerful spatial 'omics' approaches reveal important signatures of metastatic cancer cells and possible new therapeutic targets aimed at treating metastatic disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Circulating Bone-related Markers and YKL-40 Versus HER2 and TOPO2a in Bone Metastatic and Nonmetastatic Breast Cancer: Diagnostic Implications.

PubMed

Shaker, Olfat Gamil; Helmy, Hebatullah Samy

2018-06-01

The bone represents one of the most common sites of metastases in breast cancer. The aim of the current study was to evaluate the diagnostic potential of several circulating markers to detect metastasis to bones in patients with breast cancer. Receptor activator of Nuclear Factor-kappa β (NF-Kβ) ligand (RANKL), osteoprotegrin (OPG), vitamin D (VIT D), Chitinase-3-like protein 1; also known as YKL-40, topoisomerase IIα (TOPO2a), and human epidermal growth factor receptor 2 (HER2) were measured in blood samples obtained from 122 patients with breast cancer and 25 healthy controls. All biomarkers were significantly elevated in patients with breast cancer with bone metastasis compared with nonmetastatic patients except YKL-40. RANKL had the highest diagnostic performance for bone metastasis detection with an area under the curve of 97.3, a sensitivity of 85%, and a specificity of 98.6%. Furthermore, logistic regression analysis resulted in a model of RANKL combined with HER2 that had even higher discriminatory power of metastasis to bones than that of RANKL alone. Overall correct classification of the model was 98.9%. We recommend that measuring RANKL together with HER2 can be routinely applied to allow early detection of bone metastases in patients with breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Modifying the osteoblastic niche with zoledronic acid in vivo—Potential implications for breast cancer bone metastasis

PubMed Central

Haider, Marie-Therese; Holen, Ingunn; Dear, T. Neil; Hunter, Keith; Brown, Hannah K.

2014-01-01

Introduction Bone metastasis is the most common complication of advanced breast cancer. The associated cancer-induced bone disease is treated with bone-sparing agents like zoledronic acid. Clinical trials have shown that zoledronic acid also reduces breast cancer recurrence in bone; potentially by modifying the bone microenvironment surrounding disseminated tumour cells. We have characterised the early effects of zoledronic acid on key cell types of the metastatic niche in vivo, and investigated how these modify the location of breast tumour cells homing to bone. Methods Female mice were treated with a single, clinically achievable dose of zoledronic acid (100 μg/kg) or PBS. Bone integrity, osteoclast and osteoblast activity and number/mm trabecular bone on 1, 3, 5 and 10 days after treatment were assessed using μCT, ELISA (TRAP, PINP) and bone histomorphometry, respectively. The effect of zoledronic acid on osteoblasts was validated in genetically engineered mice with GFP-positive osteoblastic cells. The effects on growth plate cartilage were visualised by toluidine blue staining. For tumour studies, mice were injected i.c. with DID-labelled MDA-MB-231-NW1-luc2 breast cancer cells 5 days after zoledronic acid treatment, followed by assessment of tumour cell homing to bone and soft tissues by multiphoton microscopy, flow cytometry and ex vivo cultures. Results As early as 3 days after treatment, animals receiving zoledronic acid had significantly increased trabecular bone volume vs. control. This rapid bone effect was reflected in a significant reduction in osteoclast and osteoblast number/mm trabecular bone and reduced bone marker serum levels (day 3–5). These results were confirmed in mice expressing GFP in osteoblastic linage cells. Pre-treatment with zoledronic acid caused accumulation of an extra-cellular matrix in the growth plate associated with a trend towards preferential [1] homing of tumour cells to osteoblast-rich areas of bone, but without

Working after a metastatic cancer diagnosis: Factors affecting employment in the metastatic setting from ECOG-ACRIN's Symptom Outcomes and Practice Patterns study.

PubMed

Tevaarwerk, Amye J; Lee, Ju-Whei; Terhaar, Abigail; Sesto, Mary E; Smith, Mary Lou; Cleeland, Charles S; Fisch, Michael J

2016-02-01

Improved survival for individuals with metastatic cancer accentuates the importance of employment for cancer survivors. A better understanding of how metastatic cancer affects employment is a necessary step toward the development of tools for assisting survivors in this important realm. The ECOG-ACRIN Symptom Outcomes and Practice Patterns study was analyzed to investigate what factors were associated with the employment of 680 metastatic cancer patients. Univariate and multivariate logistic regression analyses were conducted to compare patients stably working with patients no longer working. There were 668 metastatic working-age participants in the analysis: 236 (35%) worked full- or part-time, whereas 302 (45%) had stopped working because of illness. Overall, 58% reported some change in employment due to illness. A better performance status and non-Hispanic white ethnicity/race were significantly associated with continuing to work despite a metastatic cancer diagnosis in the multivariate analysis. The disease type, time since metastatic diagnosis, number of metastatic sites, location of metastatic disease, and treatment status had no significant impact. Among the potentially modifiable factors, receiving hormonal treatment (if a viable option) and decreasing symptom interference were associated with continuing to work. A significant percentage of the metastatic patients remained employed; increased symptom burden was associated with a change to no longer working. Modifiable factors resulting in work interference should be minimized so that patients with metastatic disease may continue working if this is desired. Improvements in symptom control and strategies developed to help address workplace difficulties have promise for improving this aspect of survivorship. © 2015 American Cancer Society.

Nanoparticles for imaging and treatment of metastatic breast cancer

PubMed Central

Mu, Qingxin; Wang, Hui; Zhang, Miqin

2017-01-01

Introduction Metastatic breast cancer is one of the most devastating cancers that have no cure. Many therapeutic and diagnostic strategies have been extensively studied in the past decade. Among these strategies, cancer nanotechnology has emerged as a promising strategy in preclinical studies by enabling early identification of primary tumors and metastases, and by effective killing of cancer cells. Areas covered This review covers the recent progress made in targeting and imaging of metastatic breast cancer with nanoparticles, and treatment using nanoparticle-enabled chemo-, gene, photothermal- and radio-therapies. This review also discusses recent developments of nanoparticle-enabled stem cell therapy and immunotherapy. Expert opinion Nanotechnology is expected to play important roles in modern therapy for cancers, including metastatic breast cancer. Nanoparticles are able to target and visualize metastasis in various organs, and deliver therapeutic agents. Through targeting cancer stem cells, nanoparticles are able to treat resistant tumors with minimal toxicity to healthy tissues/organs. Nanoparticles are also able to activate immune cells to eliminate tumors. Owing to their multifunctional, controllable and trackable features, nanotechnology-based imaging and therapy could be a highly potent approach for future cancer research and treatment. PMID:27401941

Sorafenib for Metastatic Thyroid Cancer

Cancer.gov

A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy.

PubMed

Kast, Richard E; Skuli, Nicolas; Cos, Samuel; Karpel-Massler, Georg; Shiozawa, Yusuke; Goshen, Ran; Halatsch, Marc-Eric

2017-01-01

Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways - RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E - that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial.

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

PubMed Central

Kast, Richard E; Skuli, Nicolas; Cos, Samuel; Karpel-Massler, Georg; Shiozawa, Yusuke; Goshen, Ran; Halatsch, Marc-Eric

2017-01-01

Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways – RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E – that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial. PMID:28744157

Therapeutic Strategies for Bone Metastases and Their Clinical Sequelae in Prostate Cancer

PubMed Central

Autio, Karen A.; Scher, Howard I.

2013-01-01

Opinion statement Skeletal metastases threaten quality of life, functionality, and longevity in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapeutic strategies for bone metastases in prostate cancer can palliate pain, delay/prevent skeletal complications, and prolong survival. Pharmacologic agents representing several drug classes have demonstrated the ability to achieve these treatment goals in men with mCRPC. Skeletal-related events such as fracture and the need for radiation can be delayed using drugs that target the osteoclast/osteoblast pathway. Cancer-related bone pain can be palliated using beta-emitting bone-seeking radiopharmaceuticals such as samarium-153 EDTMP and strontium-89. Also, prospective randomized studies have demonstrated that cytotoxic chemotherapy can palliate bone pain. For the first time, bone-directed therapy has been shown to prolong survival using the novel alpha-emitting radiopharmaceutical radium-223. Given these multifold clinical benefits, treatments targeting bone metabolism, tumor-bone stromal interactions, and bone metastases themselves are now central elements of routine clinical care. Decisions about which agents, alone or in combination, will best serve the patient’s and clinician’s clinical goals is contingent on the treatment history to date, present disease manifestations, and symptomatology. Clinical trials exploring novel agents such as those targeting c-Met and Src are under way, using endpoints that directly address how patients feel, function, and survive. PMID:22528368

Radium-223 in metastatic castration resistant prostate cancer

PubMed Central

Vuong, Winston; Sartor, Oliver; Pal, Sumanta K

2014-01-01

In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently) radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89), radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation. PMID:24713838

Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells

NASA Astrophysics Data System (ADS)

Mansur, Nuzhat; Raziul Hasan, Mohammad; Kim, Young-tae; Iqbal, Samir M.

2017-09-01

Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

Targeting Alpha5 Beta1 Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site Definition and Plasma Stability

DTIC Science & Technology

2015-11-01

systemic therapy to prevent breast cancer bone colony progression. Figure 6. Colocalization of Ac-PhscNGGK-Bio with DiI in lung– extravasated SUM149PT cells...breast cancer progression that are ultimately fatal. Hence, prevention of extravasation which leads to colony formation would increase life...1 Award Number: W81XWH-12-1-0097 TITLE: “Targeting Alpha5 Beta1 Integrin to Prevent Metastatic Breast Cancer Cell Invasion: PhScN Target Site

Neutropenia as a Predictive Factor in Metastatic Colorectal Cancer Treated With TAS-102.

PubMed

Hamauchi, Satoshi; Yamazaki, Kentaro; Masuishi, Toshiki; Kito, Yosuke; Komori, Azusa; Tsushima, Takahiro; Narita, Yukiya; Todaka, Akiko; Ishihara, Makoto; Yokota, Tomoya; Tanaka, Tsutomu; Machida, Nozomu; Kadowaki, Shigenori; Fukutomi, Akira; Ura, Takashi; Onozawa, Yusuke; Ando, Masashi; Tajika, Masahiro; Muro, Kei; Yasui, Hirofumi; Mori, Keita; Taniguchi, Hiroya

2017-03-01

TAS-102 significantly improves overall survival in patients with metastatic colorectal cancer. The most common treatment-related adverse event of TAS-102 is bone marrow suppression, which leads to neutropenia. The potential predictive value of neutropenia caused by cytotoxic drugs has been reported in various types of cancer. We retrospectively analyzed 95 consecutive patients with metastatic colorectal cancer who received TAS-102 at 2 Japanese institutions between May 2014 and May 2015. To evaluate the association between efficacy and neutropenia, patients were divided into 4 categories according to the grade of neutropenia during the first cycle of TAS-102: Category A (grade 0-1), B (grade 2-4), C (grade 0-2), and D (grade 3-4). Patient characteristics were as follows: median age, 64 years; male, 58%; Eastern Cooperative Oncology Group performance status 0 to 1, 91%; primary site colon, 49%; KRAS exon 2 wild, 57%; and number of metastatic site ≥ 3, 55%. The disease control rate was significantly different between Category A and B (29.2% vs. 52.6%; P = .045) and between Category C and D (30.9% vs. 72.2%; P = .002). In multivariate analysis, Category D remained a significant predictive factor for progression-free survival compared with Category C (4.3 vs. 2.0 months; hazard ratio, 0.45; P = .01). Neutropenia caused by TAS-102 during the first cycle was associated with better efficacy. Neutropenia may be a surrogate marker for adequate antitumor doses of TAS-102. Copyright © 2016 Elsevier Inc. All rights reserved.

Innovations in imaging modalities for recurrent and metastatic prostate cancer: a systematic review.

PubMed

Albisinni, Simone; Aoun, Fouad; Marcelis, Quentin; Jungels, Claude; Al Hajj Obeid, Walid; Zanaty, Marc; Tubaro, Andrea; Roumeguere, Thierry; DE Nunzio, Cosimo

2018-01-31

The last decade has witnessed tremendous changes in the management of advanced and metastatic castration resistant prostate cancer (mCRPC). In the current systematic review, we analyze novel imaging techniques in the setting of recurrent and metastatic PCa, exploring available data and highlighting future exams which could enter clinical practice in the upcoming years. The National Library of Medicine Database was searched for relevant articles published between January 2012 and August 2017. A wide search was performed including the combination of following words: "Prostate" AND "Cancer" AND ("Metastatic" OR "Recurrent") AND "imaging" AND ("MRI" OR "PET"). The selection procedure followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) principles and is presented using a PRISMA flow chart. Novel imaging techniques, as multiparametric MRI, whole-body MRI and Choline and PSMA PET imaging techniques are currently revolutioning the treatment planning in patients with advanced and metastatic PCa, allowing a better characterization of the disease. Multiparametric MRI performs well in the detection of local recurrences, with sensitivity rates of 67-98% and overall diagnostic accuracy of 83-93%, depending on the type of magnetic field strength (1.5 vs 3T). Whole body MRI instead shows a high specificity (>95%) for bone metastases. PET imaging, and in particular PSMA PET/CT, showed promising results in the detection of both local and distant recurrences, even for low PSA values (<0.5ng/ml). Sensitivity varies from 77-98% depending on PSA value and PSA velocity. Whole body-MRI, NaF PET, Choline-PET/CT and PSMA PET/CT are flourishing techniques which find great application in the field of recurrent and metastatic PCa, in the effort to reduce treatment of "PSA only" and rather focus our therapies on clinical tumor entities. Standardization is urgently needed to allow adequate comparison of results and diffusion on a large scale.

Trespassing cancer cells: ‘fingerprinting’ invasive protrusions reveals metastatic culprits

PubMed Central

Klemke, Richard L.

2012-01-01

Metastatic cancer cells produce invasive membrane protrusions called invadopodia and pseudopodia, which play a central role in driving cancer cell dissemination in the body. Malignant cells use these structures to attach to and degrade extracellular matrix proteins, generate force for cell locomotion, and to penetrate the vasculature. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks that control the protrusion of invasive membranes. Here I highlight how these powerful spatial “omics” approaches reveal important signatures of metastatic cancer cells and possible new therapeutic targets aimed at treating metastatic disease. PMID:22980730

The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer.

PubMed

Evans, Christopher P; Higano, Celestia S; Keane, Thomas; Andriole, Gerald; Saad, Fred; Iversen, Peter; Miller, Kurt; Kim, Choung-Soo; Kimura, Go; Armstrong, Andrew J; Sternberg, Cora N; Loriot, Yohann; de Bono, Johann; Noonberg, Sarah B; Mansbach, Hank; Bhattacharya, Suman; Perabo, Frank; Beer, Tomasz M; Tombal, Bertrand

2016-10-01

Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup analyses included nonvisceral (only bone and/or nodal; n=1513), visceral (lung and/or liver; n=204), low-volume bone disease (<4 bone metastases; n=867), high-volume bone disease (≥4 bone metastases; n=850), lymph node only disease (n=195). Oral enzalutamide (160mg) or placebo once daily while continuing androgen deprivation therapy. Coprimary endpoints (rPFS, OS) were prospectively evaluated in nonvisceral and visceral subgroups. All other efficacy analyses were post hoc. Enzalutamide improved rPFS versus placebo in patients with nonvisceral disease (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.14-0.22), visceral disease (HR, 0.28; 95% CI, 0.16-0.49), low- or high-volume bone disease (HR, 0.16; 95% CI, 0.11-0.22; HR, 0.22; 95% CI, 0.16-0.29, respectively), and lymph node only disease (HR, 0.09; 95% CI, 0.04-0.19). For OS, HRs favored enzalutamide (<1) across all disease subgroups, although 95% CI was >1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55-1.23). Enzalutamide was well tolerated in patients with or without visceral disease. Enzalutamide provided clinically significant benefits in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease

Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis

PubMed Central

Liang, Yajun; Wu, Heng; Lei, Rong; Chong, Robert A.; Wei, Yong; Lu, Xin; Tagkopoulos, Ilias; Kung, Sun-Yuan; Yang, Qifeng; Hu, Guohong; Kang, Yibin

2012-01-01

The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes. PMID:22875853

(-)-Gossypol reduces invasiveness in metastatic prostate cancer cells

USDA-ARS?s Scientific Manuscript database

Acquisition of metastatic ability by prostatic cancer cells is the most lethal aspect of prostatic cancer progression. (-)-Gossypol, a polyphenolic compound present in cottonseeds, possesses anti-proliferation and pro-apoptotic effects in various cancer cells. In this study, the differences betwee...

Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter-Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth.

PubMed

Sung, Shian-Ying; Chang, Junn-Liang; Chen, Kuan-Chou; Yeh, Shauh-Der; Liu, Yun-Ru; Su, Yen-Hao; Hsueh, Chia-Yen; Chung, Leland W K; Hsieh, Chia-Ling

2016-01-01

Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.

Laser immunotherapy for metastatic pancreatic cancer (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhou, Feifan

2017-02-01

Pancreatic cancer is an extremely malignant disease with high mortality rate. Currently there is no effective therapeutic strategy for highly metastatic pancreatic cancers. Laser immunotherapy (LIT) is a combination therapeutic approach of targeted phototherapy and immunotherapy, which could destroy treated primary tumors with elimination of untreated metastases. LIT affords a remarkable efficacy in suppressing tumor growth in pancreatic tumors in mice, and results in complete tumor regression in many cases. LIT could synergize targeted phototherapy and immunological effects of immunoadjuvant, which represent a promising treatment modality to induce systemic antitumor response through a local intervention, paving the way for the treatment of highly metastatic pancreatic cancers.

Paradoxical expression of E-cadherin in prostatic bone metastases.

PubMed

Bryden, A A; Freemont, A J; Clarke, N W; George, N J

1999-12-01

To determine whether the calcium-dependent cell adhesion molecule E-cadherin is expressed in metastatic deposits of prostate cancer in bone. Ten bone biopsies containing metastatic deposits of untreated prostatic cancer were obtained and immunohistochemically stained for E-cadherin with the monoclonal antibody HECD-1, using the streptavidin-biotin complex technique. Benign prostatic tissue was used as the control. Of the 10 specimens, nine showed positive expression of E-cadherin, graded as strong in four. E-cadherin expression was strongest in well-differentiated metastases and decreased with increasing tumour grade. In some specimens there were mixed patterns of expression. E-cadherin is strongly expressed in prostatic bone metastases and the degree of expression appears to reflect local tumour grade. This suggests that loss of E-cadherin expression may not be critically linked to metastatic potential.

Unusual asymptomatic presentation of bladder cancer metastatic to the penis.

PubMed

Giunchi, Francesca; Vasuri, Francesco; Valerio, Vagnoni; Montagnani, Ilaria; Nelli, Federico; Fiorentino, Michelangelo; Raspollini, Maria Rosaria

2017-06-01

Penile metastasis is an extremely rare event and mainly originate from primary pelvic tumor sites such us urinary bladder, gastro-intestinal tract and prostate and more rarely from respiratory system, bone tumors and melanoma. Here we describe the unusual presentation of two bladder urothelial cancer metastatic to the penis with no relevant clinical symptoms. Namely, a 69 years-old man with a warthy lesions of the foreskin and the glans misunderstood for a condylomata that at histological and immunohistochemical analysis showed a bladder urothelial carcinoma; and a 71 years-old man with reddish skin lesion of the glans, a previous history of bladder and urethral carcinoma and histological pagetoid spread of urothelial cancer to the glans. Recurrent bladder urothelial carcinoma is usually a visceral disease that rarely presents as a superficial asymptomatic skin lesion. The two reported cases were asymptomatic superficial penis metastases with a relatively slow growth and a fairy good prognosis after conservative surgical approach. Accurate clinical examination of the penis is mandatory for males with history of bladder cancer. Copyright © 2016 Elsevier GmbH. All rights reserved.

Role of the neural niche in brain metastatic cancer

PubMed Central

Termini, John; Neman, Josh; Jandial, Rahul

2014-01-01

Metastasis is the relenteless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically brain metastases were rarely investigated since patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts – the brain. The central nervous system is the most complex biological system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us towards new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of the bidirectional interactions between the brain milieu and metastatic cancer. PMID:25035392

Role of the neural niche in brain metastatic cancer.

PubMed

Termini, John; Neman, Josh; Jandial, Rahul

2014-08-01

Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically, brain metastases were rarely investigated because patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts, the brain. The central nervous system is the most complex biologic system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us toward new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of bidirectional interactions between the brain milieu and metastatic cancer. ©2014 American Association for Cancer Research.

Palliative systemic therapy for young women with metastatic breast cancer.

PubMed

Eng, Lee Guek; Dawood, Shaheenah; Dent, Rebecca

2015-09-01

Breast cancer in young women age less than 40 years remains a relatively rare disease. Emerging data suggest that the biology of breast cancer in younger women may differ from that of older women. Although metastatic breast cancer remains incurable, it is definitely treatable; especially in this era of emerging novel therapeutics. Most women have hormone receptor-positive disease and strategies that interfere with proliferation and the PI3 kinase pathway are reporting exciting results. The prognosis of the metastatic HER2 subtype has been extended to a median survival of 56 months with dual HER2 targeting agents in the first-line setting. Finally, triple negative breast cancer has an enlarging range of therapeutic options including immunotherapy, antiangiogenesis therapy, and targeted therapies including agents that interfere with androgen receptor signaling. Combined palliative and holistic approaches are essential to help young women navigate the marathon of treatment for metastatic breast cancer.

Cost-Effectiveness Analysis of Regorafenib for Metastatic Colorectal Cancer

PubMed Central

Goldstein, Daniel A.; Ahmad, Bilal B.; Chen, Qiushi; Ayer, Turgay; Howard, David H.; Lipscomb, Joseph; El-Rayes, Bassel F.; Flowers, Christopher R.

2015-01-01

Purpose Regorafenib is a standard-care option for treatment-refractory metastatic colorectal cancer that increases median overall survival by 6 weeks compared with placebo. Given this small incremental clinical benefit, we evaluated the cost-effectiveness of regorafenib in the third-line setting for patients with metastatic colorectal cancer from the US payer perspective. Methods We developed a Markov model to compare the cost and effectiveness of regorafenib with those of placebo in the third-line treatment of metastatic colorectal cancer. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2014. Model robustness was addressed in univariable and probabilistic sensitivity analyses. Results Regorafenib provided an additional 0.04 QALYs (0.13 life-years) at a cost of $40,000, resulting in an incremental cost-effectiveness ratio of $900,000 per QALY. The incremental cost-effectiveness ratio for regorafenib was > $550,000 per QALY in all of our univariable and probabilistic sensitivity analyses. Conclusion Regorafenib provides minimal incremental benefit at high incremental cost per QALY in the third-line management of metastatic colorectal cancer. The cost-effectiveness of regorafenib could be improved by the use of value-based pricing. PMID:26304904

Working after a metastatic cancer diagnosis: factors affecting employment in the metastatic setting from ECOG’s Symptom Outcomes and Practice Patterns (SOAPP) study

PubMed Central

Tevaarwerk, Amye; Lee, Ju-Whei; Terhaar, Abigail; Sesto, Mary; Smith, Mary Lou; Cleeland, Charles; Fisch, Michael

2015-01-01

Background Improved survival for individuals with metastatic cancer accentuates the importance of employment for cancer survivors. Better understanding of how metastatic cancer affects employment is a necessary step towards the development of tools to assist survivors in this important realm. Methods We analyzed the Eastern Cooperative Oncology Group’s “Symptom Outcomes and Practice Patterns (SOAPP)” study to investigate what factors were associated with employment of 680 metastatic cancer patients. Univariable and multivariable logistic regression analyses were conducted to compare patients stably working (Group A) to patients no longer working (Group B). Results There were 668 metastatic working-age participants in our analysis; 236 (35%) worked full or part-time while 302 (45%) stopped working due to illness. Overall, 58% reported some change in employment due to illness. Better performance status and non-Hispanic White ethnicity/race were significantly associated with continuing to work despite a metastatic cancer diagnosis on multivariable analysis. Disease type, time since metastatic diagnosis, number of metastatic sites, location of metastatic disease, and treatment status had no significant impact. Among the potentially modifiable factors, receiving hormonal treatment (if a viable option) and decreasing symptom interference were associated with continuing to work. Conclusions A significant percentage of metastatic patients remain employed; symptom burden was associated with change to no longer working. Modifiable factors resulting in work interference should be minimized so that patients with metastatic disease may continue working, if desired. Improvements in symptom control and strategies developed to help address work place difficulties have promise to improve this aspect of survivorship. PMID:26687819

A primer of bone metastases management in breast cancer patients.

PubMed

Petrut, B; Trinkaus, M; Simmons, C; Clemons, M

2008-01-01

Bone is the most common site for distant spread of breast cancer. Following a diagnosis of metastatic bone disease, patients can suffer from significant morbidity because of pain and skeletal related events (SRES). Bisphosphonates are potent inhibitors of osteoclastic function and the mainstay of bone-directed therapy for bone metastases. The aims of bisphosphonates are to prevent and delay SRES, to reduce bone pain, and to improve quality of life. Bisphosphonate therapy appears to have revolutionized treatment of bone metastases, but bisphosphonate use has several limitations. Those limitations include the high cost of the agents and the need for return trips to the clinic for intravenous treatment. Moreover, many uncertainties surround bisphosphonate use-for example, the timing of bisphosphonate initiation, the choice of bisphosphonate to use, the optimal duration of treatment, and the appropriate means to identify patients who will and will not benefit. In addition, potentially serious adverse effects have been associated with bisphosphonate use-for example, renal toxicity, gastrointestinal side effects, and osteonecrosis of the jaw. The present review is intended as a primer for oncology specialists who treat patients with bone metastases secondary to breast cancer. It focuses on bisphosphonate treatment guidelines, the evidence for those guidelines, and a discussion of new therapeutic agents. It also discusses the use of biochemical markers of bone metabolism, which show promise for predicting the risk of a patient's developing a SRE and of benefiting from bisphosphonate treatment.

A primer of bone metastases management in breast cancer patients

PubMed Central

Petrut, B.; Trinkaus, M.; Simmons, C.; Clemons, M.

2008-01-01

Bone is the most common site for distant spread of breast cancer. Following a diagnosis of metastatic bone disease, patients can suffer from significant morbidity because of pain and skeletal related events (sres). Bisphosphonates are potent inhibitors of osteoclastic function and the mainstay of bone-directed therapy for bone metastases. The aims of bisphosphonates are to prevent and delay sres, to reduce bone pain, and to improve quality of life. Bisphosphonate therapy appears to have revolutionized treatment of bone metastases, but bisphosphonate use has several limitations. Those limitations include the high cost of the agents and the need for return trips to the clinic for intravenous treatment. Moreover, many uncertainties surround bisphosphonate use—for example, the timing of bisphosphonate initiation, the choice of bisphosphonate to use, the optimal duration of treatment, and the appropriate means to identify patients who will and will not benefit. In addition, potentially serious adverse effects have been associated with bisphosphonate use—for example, renal toxicity, gastrointestinal side effects, and osteonecrosis of the jaw. The present review is intended as a primer for oncology specialists who treat patients with bone metastases secondary to breast cancer. It focuses on bisphosphonate treatment guidelines, the evidence for those guidelines, and a discussion of new therapeutic agents. It also discusses the use of biochemical markers of bone metabolism, which show promise for predicting the risk of a patient’s developing a sre and of benefiting from bisphosphonate treatment. PMID:18231649

Cervical Spine pain as a presenting complaint in metastatic pancreatic cancer: a case report.

PubMed

Rosenberg, Emily; Buchtel, Lindsey

2016-01-01

A 48 year-old female presented to her primary care physician with a two-month history of neck pain with negative cervical spine x-rays. During that office visit, the patient was noted to be tachycardic with EKG revealing ST depressions, which led to hospital admission. Acute coronary syndrome was ruled out, however, persistent neck pain warranted inpatient MRI of the cervical spine, which revealed a cervical spine lesion. Extensive investigation and biopsy ultimately confirmed stage IV pancreatic adenocarcinoma with metastases to the bone, liver, and likely lung. In the literature, the findings of a primary metastatic site being bone is rare with only a few case reports showing vertebral or sternal metastasis as the first clinical manifestation of pancreatic cancer. The uniqueness of this case lies in the only presenting complaint being cervical spine pain in the setting of extensive metastases to the liver, bone, and likely lung.

Mutational analysis of multiple lung cancers: Discrimination between primary and metastatic lung cancers by genomic profile.

PubMed

Goto, Taichiro; Hirotsu, Yosuke; Mochizuki, Hitoshi; Nakagomi, Takahiro; Shikata, Daichi; Yokoyama, Yujiro; Oyama, Toshio; Amemiya, Kenji; Okimoto, Kenichiro; Omata, Masao

2017-05-09

In cases of multiple lung cancers, individual tumors may represent either a primary lung cancer or both primary and metastatic lung cancers. Treatment selection varies depending on such features, and this discrimination is critically important in predicting prognosis. The present study was undertaken to determine the efficacy and validity of mutation analysis as a means of determining whether multiple lung cancers are primary or metastatic in nature. The study involved 12 patients who underwent surgery in our department for multiple lung cancers between July 2014 and March 2016. Tumor cells were collected from formalin-fixed paraffin-embedded tissues of the primary lesions by using laser capture microdissection, and targeted sequencing of 53 lung cancer-related genes was performed. In surgically treated patients with multiple lung cancers, the driver mutation profile differed among the individual tumors. Meanwhile, in a case of a solitary lung tumor that appeared after surgery for double primary lung cancers, gene mutation analysis using a bronchoscopic biopsy sample revealed a gene mutation profile consistent with the surgically resected specimen, thus demonstrating that the tumor in this case was metastatic. In cases of multiple lung cancers, the comparison of driver mutation profiles clarifies the clonal origin of the tumors and enables discrimination between primary and metastatic tumors.

Living Well? Strategies Used by Women Living With Metastatic Breast Cancer.

PubMed

Lewis, Sophie; Willis, Karen; Yee, Jasmine; Kilbreath, Sharon

2016-07-01

Metastatic breast cancer is a disease of changing status-once an imminent death sentence, now a chronic (albeit incurable) disease. Medical intervention advances mean women with metastatic breast cancer now have symptoms alleviated and, potentially, life extended. Living with this disease, however, requires more than a medical approach to symptoms. We were interested to know whether women manage, and if so, how, to "live well" with metastatic cancer. We conducted interviews with 18 women. Women differed in the approaches they used. Most common was the attempt to reestablish a sense of normality in their lives. However, a second group reevaluated and reprioritized their lives; and a third group was restricted in their capacity to live well because of symptoms. The findings provide the foundation for future research exploring normalization of experiences of metastatic cancer, and other chronic illnesses, where people are living with knowledge that they have contracted time. © The Author(s) 2015.

Benzimidazole as Novel Therapy for Hormone-Refractory Metastatic Prostate Cancer

DTIC Science & Technology

2011-05-01

8 4 INTRODUCTION The focus of this project is to evaluate the anti-tumor effects of benzimidazoles as a...potential anti-metastatic prostate cancer therapy. We identified benzimidazoles , a class of anti-parasitic drug, in a drug screening process for...preferential anti-tumor activity on metastatic prostate cancer cells. We have data indicate that benzimidazoles have potent anti-tumor activities

Optical detection of metastatic cancer cells using a scanned laser pico-projection system

NASA Astrophysics Data System (ADS)

Huang, Chih-Ling; Chiu, Wen-Tai; Lo, Yu-Lung; Chuang, Chin-Ho; Chen, Yu-Bin; Chang, Shu-Jing; Ke, Tung-Ting; Cheng, Hung-Chi; Wu, Hua-Lin

2015-03-01

Metastasis is responsible for 90% of all cancer-related deaths in humans. As a result, reliable techniques for detecting metastatic cells are urgently required. Although various techniques have been proposed for metastasis detection, they are generally capable of detecting metastatic cells only once migration has already occurred. Accordingly, the present study proposes an optical method for physical characterization of metastatic cancer cells using a scanned laser pico-projection system (SLPP). The validity of the proposed method is demonstrated using five pairs of cancer cell lines and two pairs of non-cancer cell lines treated by IPTG induction in order to mimic normal cells with an overexpression of oncogene. The results show that for all of the considered cell lines, the SLPP speckle contrast of the high-metastatic cells is significantly higher than that of the low-metastatic cells. As a result, the speckle contrast measurement provides a reliable means of distinguishing quantitatively between low- and high-metastatic cells of the same origin. Compared to existing metastasis detection methods, the proposed SLPP approach has many advantages, including a higher throughput, a lower cost, a larger sample size and a more reliable diagnostic performance. As a result, it provides a highly promising solution for physical characterization of metastatic cancer cells in vitro.

Bone metastases and non-small cell lung cancer: from bisphosphonates to targeted therapy.

PubMed

Rossi, A; Gridelli, C; Ricciardi, S; de Marinis, F

2012-01-01

About 30-40% of patients affected by non-small cell lung cancer (NSCLC) develop, during the course of their disease, bone metastases. The prognosis of these patients is poor with a median survival of less than 1 year. The therapeutic approach includes: palliative radiotherapy, and systemic therapy. In clinical practice, zoledronate is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events in patients with metastatic NSCLC. However, an Italian Association of Thoracic Oncology (AIOT) survey, conducted to evaluate how bisphosphonates were used in clinical practice for the treatment of lung cancer bone metastases in Italy, showed that the bisphosphonates treatment is still not routine and varies in duration. Denosumab is a fully human monoclonal antibody directed against the receptor activator of nuclear factor kappa-B (RANK)-Ligand inhibiting the maturation of pre-osteoclasts into osteoclasts and is the first example of targeted therapy for bone metastases. An exploratory analysis showed that denosumab was associated with improved overall survival compared with zoledronate in patients with bone metastases from lung cancer. Biochemical markers of bone turnover to predict what patients are at greatest risk of developing skeletal-related events, and to direct treatment of bone metastases with either bisphosphonates or denosumab, are under investigation. This review is focused on the systemic management of bone metastases from NSCLC.

Secretomes reveal several novel proteins as well as TGF-β1 as the top upstream regulator of metastatic process in breast cancer.

PubMed

Erin, Nuray; Ogan, Nur; Yerlikaya, Azmi

2018-03-20

Metastatic breast cancer is resistant to many conventional treatments and novel therapeutic targets are needed. We previously isolated subsets of 4T1 murine breast cancer cells which metastasized to liver (4TLM), brain (4TBM), and heart (4THM). Among these cells, 4TLM is the most aggressive one, demonstrating mesenchymal phenotype. Here we compared secreted proteins from 4TLM, 4TBM, and 4THM cells and compared with that of hardly metastatic 67NR cells to detect differentially secreted factors involved in organ-specific metastasis. Label-free LC-MS/MS proteomic technique was used to detect the differentially secreted proteins. Eighty-five of over 500 secreted proteins were significantly altered in metastatic breast cancer cells. Differential expression of several proteins such as fibulin-4, Bone Morphogenetic Protein 1, TGF-β1 MMP-3, MMP-9, and Thymic Stromal Lymphopoietin were further verified using ELISA or Western blotting. Many of these identified proteins were also present in human metastatic breast carcinomas. Annexin A1 and A5, laminin beta 1, Neutral alpha-glucosidase AB were commonly found at least in three out of six studies examined here. Ingenuity Pathway Analysis showed that proteins differentially secreted from metastatic cells are involved primarily in carcinogenesis and TGF-β1 is the top upstream regulator in all metastatic cells. Cells metastasized to different organs displayed significant differences in several of secreted proteins. Proteins differentially altered were fibronectin, insulin-like growth factor-binding protein 7, and Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1. On the other hand, many exosomal proteins were also common to all metastatic cells, demonstrating involvement of key universal factors in distant metastatic process.

Osteolytic and mixed cancer metastasis modulates collagen and mineral parameters within rat vertebral bone matrix.

PubMed

Burke, Mikhail V; Atkins, Ayelet; Akens, Margarete; Willett, Thomas L; Whyne, Cari M

2016-12-01

Metastatic involvement in vertebral bone diminishes the mechanical integrity of the spine; however minimal data exist on the potential impact of metastases on the intrinsic material characteristics of the bone matrix. Thirty-four (34) female athymic rats were inoculated with HeLa (N = 17) or Ace-1 (N = 17) cancer cells lines producing osteolytic or mixed (osteolytic and osteoblastic) metastases, respectively. A maximum of 21 days was allowed between inoculation and rat sacrifice for vertebrae extraction. High performance liquid chromatography (HPLC) was utilized to determine modifications in collagen-I parameters such as proline hydroxylation and the formation of specific enzymatic and non-enzymatic (pentosidine) cross-links. Raman spectroscopy was used to determine relative changes in mineral crystallinity, mineral carbonation, mineral/collagen matrix ratio, collagen quality ratio, and proline hydroxylation. HPLC results showed significant increase in the formation of pentosidine and decrease in the formation of the enzymatic cross-link deoxy-pryridinoline within osteolytic bone compared to mixed bone. Raman results showed decreased crystallinity, increased carbonation, and collagen quality (aka 1660/1690 sub-band) ratio with osteolytic bone compared to mixed bone and healthy controls along with an observed increase in proline hydroxylation with metastatic involvement. The mineral/matrix ratio decreased in both osteolytic and mixed bone compared to healthy controls. Quantifying modifications within the intrinsic characteristics of bone tissue will provide a foundation to assess the impact of current therapies on the material behavior of bone tissue in the metastatic spine and highlight targets for the development of new therapeutics and approaches for treatment. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2126-2136, 2016. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.

PubMed

Pritchard, Colin C; Mateo, Joaquin; Walsh, Michael F; De Sarkar, Navonil; Abida, Wassim; Beltran, Himisha; Garofalo, Andrea; Gulati, Roman; Carreira, Suzanne; Eeles, Rosalind; Elemento, Olivier; Rubin, Mark A; Robinson, Dan; Lonigro, Robert; Hussain, Maha; Chinnaiyan, Arul; Vinson, Jake; Filipenko, Julie; Garraway, Levi; Taplin, Mary-Ellen; AlDubayan, Saud; Han, G Celine; Beightol, Mallory; Morrissey, Colm; Nghiem, Belinda; Cheng, Heather H; Montgomery, Bruce; Walsh, Tom; Casadei, Silvia; Berger, Michael; Zhang, Liying; Zehir, Ahmet; Vijai, Joseph; Scher, Howard I; Sawyers, Charles; Schultz, Nikolaus; Kantoff, Philip W; Solit, David; Robson, Mark; Van Allen, Eliezer M; Offit, Kenneth; de Bono, Johann; Nelson, Peter S

2016-08-04

Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001). In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by

m-RNA mammaglobin expression in metastatic breast cancer patient at Medan city, Indonesia

NASA Astrophysics Data System (ADS)

Rimbun, S.; Siregar, Y.

2018-03-01

Breast cancer is the most common causes of women’s death in the world. Metastatic spread presents a major clinical problem in about 30% of the patients. The study aims to investigate the clinical reliability of mammaglobin mRNA as a marker of circulating cancer cells in breast cancer patients. The positivity of blood was analyzed in relation to clinical and pathological characteristics. This study was on 29 breast cancer patients (13 metastatic, 16 non- metastatic patients), where28 were invasive intraductal carcinoma type and 1 was invasive lobular carcinoma type. Breast cancer patients were according to the histologic grade into grade I (7 patients),grade II (6 patients) and grade III (15 patients). All individuals included in this study were subjected to detection of mammaglobin m-RNA of circulating tumor cells in peripheral blood using RT-PCR technique. Positivity for mammaglobin in blood samples was in 38% of patients with metastatic but not in the non-metastatic patients. The presence of mammaglobin correlated with metastatic tumor (P = 0.011). Mammaglobin overexpression in breast tissue was significantly positive in low-grade tumors (I and II).

Metastatic squamous cell carcinoma thyroid from functionally cured cancer cervix

PubMed Central

Vamsy, Mohana; Dattatreya, Palanki Satya; Sarma, Lella Yugandhar; Dayal, Monal; Janardhan, Nandigam; Rao, Vatturi Venkata Satya Prabhakar

2013-01-01

The authors report a very unusual occurrence of a metastatic squamous carcinoma to thyroid gland from a treated squamous cell carcinoma cervix 12 years before with no recurrence at the primary site. The case also has an additional complexity of rapid progression of the metastatic thyroid carcinoma to wide spread dissemination to lungs and bones while on concurrent chemo radio therapy confirming the aggressiveness of the entity. PMID:24163519

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin

PubMed Central

Roy, Jahnabi; Wycislo, Kathryn L.; Pondenis, Holly; Fan, Timothy M.

2017-01-01

Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics. PMID:28910304

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin.

PubMed

Roy, Jahnabi; Wycislo, Kathryn L; Pondenis, Holly; Fan, Timothy M; Das, Aditi

2017-01-01

Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics.

Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.

PubMed

Zhao, Shanshan; Geybels, Milan S; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Yan, Qingxiang; Klotzle, Brandy; Bibikova, Marina; Hurtado-Coll, Antonio; Troyer, Dean; Lance, Raymond; Lin, Daniel W; Wright, Jonathan L; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

2017-01-01

Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P <0.05). Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer; Report From the 2016 Coffey-Holden Prostate Cancer Academy Meeting.

PubMed

Miyahira, Andrea K; Roychowdhury, Sameek; Goswami, Sangeeta; Ippolito, Joseph E; Priceman, Saul J; Pritchard, Colin C; Sfanos, Karen S; Subudhi, Sumit K; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2017-02-01

The 2016 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer," was held from June 23 to June 26, 2016, in Coronado, California. For the 4th year in a row, the Prostate Cancer Foundation (PCF) hosted the CHPCA Meeting, a think tank-structured scientific conference, which focuses on a specific topic of critical unmet need on the biology and treatment of advanced prostate cancer. The 2016 CHPCA Meeting was attended by 71 investigators from prostate cancer and other fields, who discussed the biology, study methodologies, treatment strategies, and critical unmet needs concerning metastatic prostate cancer, with the ultimate goal of advancing strategies to treat and eliminate this disease. The major topics of discussion included: the molecular landscape and molecular heterogeneity of metastatic prostate cancer, the role of the metastatic microenvironment, optimizing immunotherapy in metastatic prostate cancer, learning from exceptional responders and non-responders, targeting DNA repair deficiency in advanced prostate cancer, developing and applying novel biomarkers and imaging techniques, and potential roles for the microbiome in prostate cancer. This article reviews the topics presented and discussions held at the CHPCA Meeting, with a focus on the unknowns and next steps needed to advance our understanding of the biology and most effective treatment strategies for metastatic prostate cancer. Prostate 77:123-144, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation

PubMed Central

Cianferotti, Luisella; Bertoldo, Francesco; Carini, Marco; Kanis, John A.; Lapini, Alberto; Longo, Nicola; Martorana, Giuseppe; Mirone, Vincenzo; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-01-01

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects. PMID:29088899

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation.

PubMed

Cianferotti, Luisella; Bertoldo, Francesco; Carini, Marco; Kanis, John A; Lapini, Alberto; Longo, Nicola; Martorana, Giuseppe; Mirone, Vincenzo; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-09-26

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects.

Periostin is identified as a putative metastatic marker in breast cancer-derived exosomes

PubMed Central

Vardaki, Ioulia; Ceder, Sophia; Rutishauser, Dorothea; Baltatzis, George; Foukakis, Theodoros; Panaretakis, Theocharis

2016-01-01

Breast cancer (BrCa) is the most frequent cancer type in women and a leading cause of cancer related deaths in the world. Despite the decrease in mortality due to better diagnostics and palliative care, there is a lack of prognostic markers of metastasis. Recently, the exploitation of liquid biopsies and in particular of the extracellular vesicles has shown promise in the identification of such prognostic markers. In this study we compared the proteomic content of exosomes derived from metastatic and non-metastatic human (MCF7 and MDA-MB-231) and mouse (67NR and 4T1) cell lines. We found significant differences not only in the amount of secreted exosomes but most importantly in the protein content of exosomes secreted from metastatic versus non-metastatic ones. We identified periostin as a protein that is enriched in exosomes secreted by metastatic cells and validated its presence in a pilot cohort of breast cancer patient samples with localized disease or lymph node (LN) metastasis. PMID:27589561

Periostin is identified as a putative metastatic marker in breast cancer-derived exosomes.

PubMed

Vardaki, Ioulia; Ceder, Sophia; Rutishauser, Dorothea; Baltatzis, George; Foukakis, Theodoros; Panaretakis, Theocharis

2016-11-15

Breast cancer (BrCa) is the most frequent cancer type in women and a leading cause of cancer related deaths in the world. Despite the decrease in mortality due to better diagnostics and palliative care, there is a lack of prognostic markers of metastasis. Recently, the exploitation of liquid biopsies and in particular of the extracellular vesicles has shown promise in the identification of such prognostic markers. In this study we compared the proteomic content of exosomes derived from metastatic and non-metastatic human (MCF7 and MDA-MB-231) and mouse (67NR and 4T1) cell lines. We found significant differences not only in the amount of secreted exosomes but most importantly in the protein content of exosomes secreted from metastatic versus non-metastatic ones. We identified periostin as a protein that is enriched in exosomes secreted by metastatic cells and validated its presence in a pilot cohort of breast cancer patient samples with localized disease or lymph node (LN) metastasis.

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers

PubMed Central

Weinberg, Benjamin A.; Gowen, Kyle; Lee, Thomas K.; Ou, Sai‐Hong Ignatius; Bristow, Robert; Krill, Lauren; Almira‐Suarez, M. Isabel; Ali, Siraj M.; Miller, Vincent A.; Liu, Stephen V.

2017-01-01

Abstract Background. Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer‐specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios. Materials and Methods. We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next‐generation sequencing‐based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities. Results. A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination. Conclusions. Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. Implications for Practice. Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic

Olaparib With or Without Cediranib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

ClinicalTrials.gov

2018-06-04

Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Prostate Adenocarcinoma With Focal Neuroendocrine Differentiation; Prostate Carcinoma Metastatic in the Bone; Prostate Small Cell Carcinoma; PSA Progression; Stage IV Prostate Adenocarcinoma AJCC v7

Well-Designed Bone-Seeking Radiolabeled Compounds for Diagnosis and Therapy of Bone Metastases

PubMed Central

2015-01-01

Bone-seeking radiopharmaceuticals are frequently used as diagnostic agents in nuclear medicine, because they can detect bone disorders before anatomical changes occur. Furthermore, their effectiveness in the palliation of metastatic bone cancer pain has been demonstrated in the clinical setting. With the aim of developing superior bone-seeking radiopharmaceuticals, many compounds have been designed, prepared, and evaluated. Here, several well-designed bone-seeking compounds used for diagnostic and therapeutic use, having the concept of radiometal complexes conjugated to carrier molecules to bone, are reviewed. PMID:26075256

PATHOLOGICAL SPROUTING OF ADULT NOCICEPTORS IN CHRONIC PROSTATE CANCER-INDUCED BONE PAIN

PubMed Central

Jimenez-Andrade, Juan M.; Bloom, Aaron P.; Stake, James I.; Mantyh, William G.; Taylor, Reid N.; Freeman, Katie T.; Ghilardi, Joseph R.; Kuskowski, Michael A.; Mantyh, Patrick W.

2012-01-01

Pain frequently accompanies cancer. What remains unclear is why this pain frequently becomes more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression, sensory nerve fibers that innervate the tumor-bearing tissue undergo a pathological sprouting and reorganization, which in other non-malignant pathologies has been shown to generate and maintain chronic pain. Injection of canine prostate cancer cells into mouse bone induces a remarkable sprouting of calcitonin gene related peptide (CGRP+) and neurofilament 200 kDa (NF200+) sensory nerve fibers. Nearly all sensory nerve fibers that undergo sprouting also co-express tropomyosin receptor kinase A (TrkA+). This ectopic sprouting occurs in sensory nerve fibers that are in close proximity to colonies of prostate cancer cells, tumor-associated stromal cells and newly formed woven bone, which together form sclerotic lesions that closely mirror the osteoblastic bone lesions induced by metastatic prostate tumors in humans. Preventive treatment with an antibody that sequesters nerve growth factor (NGF), administered when the pain and bone remodeling were first observed, blocks this ectopic sprouting and attenuates cancer pain. Interestingly, RT-PCR analysis indicated that the prostate cancer cells themselves do not express detectable levels of mRNA coding for NGF. This suggests that the tumor-associated stromal cells express and release NGF, which drives the pathological reorganization of nearby TrkA+ sensory nerve fibers. Therapies that prevent this reorganization of sensory nerve fibers may provide insight into the evolving mechanisms that drive cancer pain and lead to more effective control of this chronic pain state. PMID:21048122

Metastatic Squamous Neck Cancer with Occult Primary Treatment (PDQ®)—Health Professional Version

Cancer.gov

Metastatic squamous neck cancer with occult primary treatment options include surgery, radiation therapy or a combination of both. Get detailed information about newly diagnosed or recurrent metastatic squamous neck cancer in this summary for clinicians.

Sequence therapy in metastatic pancreatic cancer.

PubMed

Waidmann, Oliver; Pelzer, Uwe; Boeck, Stefan; Waldschmidt, Dirk-Thomas

2018-06-01

Pancreatic cancer is one of the most lethal cancer diseases. For years, gemcitabine has been the standard of care and the only therapeutic option in patients with metastatic pancreatic cancer. Within the last years, new combination therapies have been established for first-line treatment, which significantly improve overall survival in comparison to gemcitabine monotherapy. Furthermore, new second-line therapies have been identified, which significantly improve overall survival. The current manuscript summarizes briefly standard of care first- and second-line chemotherapies and discusses possible treatment sequences. © Georg Thieme Verlag KG Stuttgart · New York.

Abiraterone Improves Survival in Metastatic Prostate Cancer

Cancer.gov

A multinational phase III trial found that the drug abiraterone acetate prolonged the median survival of patients with metastatic castration-resistant prostate cancer by 4 months compared with patients who received a placebo.

Altered Redox Status Accompanies Progression to Metastatic Human Bladder Cancer

PubMed Central

Hempel, Nadine; Ye, Hanqing; Abessia, Bryan; Mian, Badar; Melendez, J. Andres

2009-01-01

The role of reactive oxygen species (ROS) in bladder cancer progression remains an unexplored field. Expression levels of enzymes regulating ROS levels are often altered in cancer. Search of publicly available micro-array data reveals that expression of mitochondrial manganese superoxide dismutase (Sod2), responsible for the conversion of superoxide (O2-.) to hydrogen peroxide (H2O2), is consistently increased in high grade and advanced stage bladder tumors. Here we aim to identify the role of Sod2 expression and ROS in bladder cancer. Using an in vitro human bladder tumor model we monitored the redox state of both non-metastatic (253J) and highly metastatic (253J B-V) bladder tumor cell lines. 253J B-V cells displayed significantly higher Sod2 protein and activity levels compared to their parental 253J cell line. The increase in Sod2 expression was accompanied by a significant decrease in catalase activity, resulting in a net increase in H2O2 production in the 253J B-V line. Expression of pro-metastatic and –angiogenic factors, matrix metalloproteinase 9 (MMP-9) and vascular endothelial derived growth factor (VEGF), respectively, were similarly upregulated in the metastatic line. Expression of both MMP-9 and VEGF were shown to be H2O2-dependent, as removal of H2O2 by overexpression of catalase attenuated their expression. Similarly, expression of catalase effectively reduced the clonogenic activity of 253J B-V cells. These findings indicate that metastatic bladder cancer cells display an altered antioxidant expression profile, resulting in a net increase in ROS production, which leads to the induction of redox-sensitive pro-tumorigenic and pro-metastatic genes such as VEGF and MMP-9. PMID:18930813

Metastatic Lymph Node Burden and Survival in Oral Cavity Cancer

PubMed Central

Kim, Sungjin; Tighiouart, Mourad; Gudino, Cynthia; Mita, Alain; Scher, Kevin S.; Laury, Anna; Prasad, Ravi; Shiao, Stephen L.; Van Eyk, Jennifer E.; Zumsteg, Zachary S.

2017-01-01

Purpose Current staging systems for oral cavity cancers incorporate lymph node (LN) size and laterality, but place less weight on the total number of positive metastatic nodes. We investigated the independent impact of numerical metastatic LN burden on survival. Methods Adult patients with oral cavity squamous cell carcinoma undergoing upfront surgical resection for curative intent were identified in the National Cancer Data Base between 2004 and 2013. A neck dissection of a minimum of 10 LNs was required. Multivariable models were constructed to assess the association between the number of metastatic LNs and survival, adjusting for factors such as nodal size, laterality, extranodal extension, margin status, and adjuvant treatment. Results Overall, 14,554 patients met inclusion criteria (7,906 N0 patients; 6,648 node-positive patients). Mortality risk escalated continuously with increasing number of metastatic nodes without plateau, with the effect most pronounced with up to four LNs (HR, 1.34; 95% CI, 1.29 to 1.39; P < .001). Extranodal extension (HR, 1.41; 95% CI, 1.20 to 1.65; P < .001) and lower neck involvement (HR, 1.16; 95% CI, 1.06 to 1.27; P < .001) also predicted increased mortality. Increasing number of nodes examined was associated with improved survival, plateauing at 35 LNs (HR, 0.98; 95% CI, 0.98 to 0.99; P < .001). In multivariable models accounting for the number of metastatic nodes, contralateral LN involvement (N2c status) and LN size were not associated with mortality. A novel nodal staging system derived by recursive partitioning analysis exhibited greater concordance than the American Joint Committee on Cancer (8th edition) system. Conclusion The number of metastatic nodes is a critical predictor of oral cavity cancer mortality, eclipsing other features such as LN size and contralaterality in prognostic value. More robust incorporation of numerical metastatic LN burden may augment staging and better inform adjuvant treatment decisions. PMID

Biocompatible, Biodegradable, and Enzymatic-Cleavable MRI Contrast Agents for Early Detection of Bone Metastatic Breast cancer

DTIC Science & Technology

2013-04-01

metastasis from breast cancer. The proposed imaging agent is consist of bone targeting moiety of Asp8 and MRI imaging moiety of DOTA (Gd) with a cathepsin K...the Gd chelator of DOTA . Asp8 has a high affinity for bone mineral and has been used as bone-targeting moiety in molecular therapeutics.(1-6) The use...findings in literature.(4, 7, 17) To obtain imaging agents for MRI studies, the above mentioned peptides were allowed to react with DOTA -NHS

Mechanisms of, and Adjuvants for, Bone Pain.

PubMed

Figura, Nicholas; Smith, Joshua; Yu, Hsiang-Hsuan Michael

2018-06-01

Metastatic bone pain is a complex, poorly understood process. Understanding the unique mechanisms causing cancer-induced bone pain may lead to potential therapeutic targets. This article discusses the effects of osteoclast overstimulation within the tumor microenvironment; the role of inflammatory factors at the tumor-nociceptor interface; the development of structural instability, causing mechanical nerve damage; and, ultimately, the neuroplastic changes in the setting of sustained pain. Several adjuvant therapies are available to attenuate metastatic bone pain. This article discusses the role of pharmacologic therapies, surgery, kyphoplasty, vertebroplasty, and radiofrequency ablation. Copyright © 2018 Elsevier Inc. All rights reserved.

Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles.

PubMed

Sansone, Pasquale; Berishaj, Marjan; Rajasekhar, Vinagolu K; Ceccarelli, Claudio; Chang, Qing; Strillacci, Antonio; Savini, Claudia; Shapiro, Lauren; Bowman, Robert L; Mastroleo, Chiara; De Carolis, Sabrina; Daly, Laura; Benito-Martin, Alberto; Perna, Fabiana; Fabbri, Nicola; Healey, John H; Spisni, Enzo; Cricca, Monica; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

2017-04-15

The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ER lo /Notch hi feed-forward loop responsible for the generation of CD133 hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221 hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133 hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133 hi CSCs. Conversely, in models of CD133 neg , HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133 hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927-41. ©2017 AACR . ©2017 American Association for Cancer Research.

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. ©2016 American Association for Cancer Research.

Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells

NASA Astrophysics Data System (ADS)

Xu, Wenwei; Mezencev, Roman; Kim, Byungkyu; Wang, Lijuan; McDonald, John; Sulchek, Todd; Sulchek Team; McDonald Team

2013-03-01

The metastatic potential of cells is an important parameter in the design of optimal strategies for the personalized treatment of cancer. Using atomic force microscopy (AFM), we show that ovarian cancer cells are generally softer and display lower intrinsic variability in cell stiffness than non-malignant ovarian epithelial cells. A detailed study of highly invasive ovarian cancer cells (HEY A8) and their less invasive parental cells (HEY), demonstrates that deformability can serve as an accurate biomarker of metastatic potential. Comparative gene expression profiling indicate that the reduced stiffness of highly metastatic HEY A8 cells is associated with actin cytoskeleton remodeling, microscopic examination of actin fiber structure in these cell lines is consistent with this prediction. Our results indicate that cell stiffness not only distinguishes ovarian cancer cells from non-malignant cells, but may also be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.

Patient-reported Quality of Life and Treatment Satisfaction in Patients With HR+/HER2- Advanced/Metastatic Breast Cancer.

PubMed

Wood, Robert; Mitra, Debanjali; de Courcy, Jonathan; Iyer, Shrividya

2017-08-01

Globally, around 1.67 million new cases of breast cancer are diagnosed each year, with advanced breast cancer (ABC-Stage III) and metastatic breast cancer (MBC-Stage IV) together accounting for up to 22% of incident cases. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 - ) breast cancer comprises 66% of ABC/MBC. Understanding disease-specific health-related quality of life and patient satisfaction with treatments currently available for HR + /HER2 - ABC/MBC in clinical practice is essential for assessing potential unmet need in this patient population. Data on treatment patterns in patients with HR + /HER2 - ABC/MBC were collected from oncology practices across the United States and Europe in a cross-sectional study in a clinical practice setting, the Adelphi Real World Advanced Breast Cancer Disease Specific Programme. A subset of patients included in the study completed several self-reported tools, including the Functional Assessment of Cancer Therapy-Breast and the Cancer Therapy Satisfaction Questionnaire. Analyses were conducted using data from the overall cohort and stratified by current treatment, metastatic sites, and number of prior therapy lines. Overall, 739 patients were recruited by 173 oncologists; 83% of patients had MBC, with the balance having ABC. The majority of patients with MBC had visceral metastases without bone metastases, and similar percentages of the total study population (≈40%) were receiving chemotherapy and endocrine therapy. Patients receiving only endocrine therapy had significantly better cancer-specific quality of life than did those receiving chemotherapy. Endocrine therapy also associated with fewer concerns about side effects and higher treatment satisfaction than chemotherapy. Statistically lower scores, indicating poorer well-being, were observed in patients with both bone and visceral metastases compared with those with either bone-only or visceral-only metastases for all but the

The clinical significance of occult gynecologic primary tumours in metastatic cancer.

PubMed

Hannouf, M B; Winquist, E; Mahmud, S M; Brackstone, M; Sarma, S; Rodrigues, G; Rogan, P K; Hoch, J S; Zaric, G S

2017-10-01

We estimated the frequency of occult gynecologic primary tumours (gpts) in patients with metastatic cancer from an uncertain primary and evaluated the effect on disease management and overall survival (os). We used Manitoba administrative health databases to identify all patients initially diagnosed with metastatic cancer during 2002-2011. We defined patients as having an "occult" primary tumour if the primary was classified at least 6 months after the initial diagnosis. Otherwise, we considered patients to have "obvious" primaries. We then compared clinicopathologic and treatment characteristics and 2-year os for women with occult and with obvious gpts. We used Cox regression adjustment and propensity score methods to assess the effect on os of having an occult gpt. Among the 5953 patients diagnosed with metastatic cancer, occult primary tumours were more common in women ( n = 285 of 2552, 11.2%) than in men ( n = 244 of 3401, 7.2%). In women, gpts were the most frequent occult primary tumours ( n = 55 of 285, 19.3%). Compared with their counterparts having obvious gpts, women with occult gpts ( n = 55) presented with similar histologic and metastatic patterns but received fewer gynecologic diagnostic examinations during diagnostic work-up. Women with occult gpts were less likely to undergo surgery, waited longer for radiotherapy, and received a lesser variety of chemotherapeutic agents. Having an occult compared with an obvious gpt was associated with decreased os (hazard ratio: 1.62; 95% confidence interval: 1.2 to 2.35). Similar results were observed in adjusted analyses. In women with metastatic cancer from an uncertain primary, gpts constitute the largest clinical entity. Accurate diagnosis of occult gpts early in the course of metastatic cancer might lead to more effective treatment decisions and improved survival outcomes.

The clinical significance of occult gynecologic primary tumours in metastatic cancer

PubMed Central

Hannouf, M.B.; Winquist, E.; Mahmud, S.M.; Brackstone, M.; Sarma, S.; Rodrigues, G.; Rogan, P.K.; Hoch, J.S.; Zaric, G.S.

2017-01-01

Objective We estimated the frequency of occult gynecologic primary tumours (gpts) in patients with metastatic cancer from an uncertain primary and evaluated the effect on disease management and overall survival (os). Methods We used Manitoba administrative health databases to identify all patients initially diagnosed with metastatic cancer during 2002–2011. We defined patients as having an “occult” primary tumour if the primary was classified at least 6 months after the initial diagnosis. Otherwise, we considered patients to have “obvious” primaries. We then compared clinicopathologic and treatment characteristics and 2-year os for women with occult and with obvious gpts. We used Cox regression adjustment and propensity score methods to assess the effect on os of having an occult gpt. Results Among the 5953 patients diagnosed with metastatic cancer, occult primary tumours were more common in women (n = 285 of 2552, 11.2%) than in men (n = 244 of 3401, 7.2%). In women, gpts were the most frequent occult primary tumours (n = 55 of 285, 19.3%). Compared with their counterparts having obvious gpts, women with occult gpts (n = 55) presented with similar histologic and metastatic patterns but received fewer gynecologic diagnostic examinations during diagnostic work-up. Women with occult gpts were less likely to undergo surgery, waited longer for radiotherapy, and received a lesser variety of chemotherapeutic agents. Having an occult compared with an obvious gpt was associated with decreased os (hazard ratio: 1.62; 95% confidence interval: 1.2 to 2.35). Similar results were observed in adjusted analyses. Conclusions In women with metastatic cancer from an uncertain primary, gpts constitute the largest clinical entity. Accurate diagnosis of occult gpts early in the course of metastatic cancer might lead to more effective treatment decisions and improved survival outcomes. PMID:29089807

Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases

PubMed Central

Hardaway, Aimalie L.; Herroon, Mackenzie K.; Rajagurubandara, Erandi

2014-01-01

Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease. PMID:24398857

Label-free Raman spectroscopy provides early determination and precise localization of breast cancer-colonized bone alterations† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc02905e

PubMed Central

Zhang, Chi; Winnard Jr, Paul T.; Dasari, Sidarth; Kominsky, Scott L.; Doucet, Michele; Jayaraman, Swaathi

2017-01-01

Breast neoplasms frequently colonize bone and induce development of osteolytic bone lesions by disrupting the homeostasis of the bone microenvironment. This degenerative process can lead to bone pain and pathological bone fracture, a major cause of cancer morbidity and diminished quality of life, which is exacerbated by our limited ability to monitor early metastatic disease in bone and assess fracture risk. Spurred by its label-free, real-time nature and its exquisite molecular specificity, we employed spontaneous Raman spectroscopy to assess and quantify early metastasis driven biochemical alterations to bone composition. As early as two weeks after intracardiac inoculations of MDA-MB-435 breast cancer cells in NOD-SCID mice, Raman spectroscopic measurements in the femur and spine revealed consistent changes in carbonate substitution, overall mineralization as well as crystallinity increase in tumor-bearing bones when compared with their normal counterparts. Our observations reveal the possibility of early stage detection of biochemical changes in the tumor-bearing bones – significantly before morphological variations are captured through radiographic diagnosis. This study paves the way for a better molecular understanding of altered bone remodeling in such metastatic niches, and for further clinical studies with the goal of establishing a non-invasive tool for early metastasis detection and prediction of pathological fracture risk in breast cancer. PMID:29629144

Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

PubMed Central

Tan, Antoinette R.; Alexe, Gabriela; Reiss, Michael

2009-01-01

In most human breast cancers, lowering of TGFβ receptor- or Smad gene expression combined with increased levels of TGFβs in the tumor microenvironment is sufficient to abrogate TGFβs tumor suppressive effects and to induce a mesenchymal, motile and invasive phenotype. In genetic mouse models, TGFβ signaling suppresses de novo mammary cancer formation but promotes metastasis of tumors that have broken through TGFβ tumor suppression. In mouse models of “triple-negative” or basal-like breast cancer, treatment with TGFβ neutralizing anti-bodies or receptor kinase inhibitors strongly inhibits development of lung- and bone metastases. These TGFβ antagonists do not significantly affect tumor cell proliferation or apoptosis. Rather, they de-repress anti-tumor immunity, inhibit angiogenesis and reverse the mesenchymal, motile, invasive phenotype characteristic of basal-like and HER2-positive breast cancer cells. Patterns of TGFβ target genes upregulation in human breast cancers suggest that TGFβ may drive tumor progression in estrogen-independent cancer, while it mediates a suppressive host cell response in estrogen-dependent luminal cancers. In addition, TGFβ appears to play a key role in maintaining the mammary epithelial (cancer) stem cell pool, in part by inducing a mesenchymal phenotype, while differentiated, estrogen receptor-positive, luminal cells are unresponsive to TGFβ because the TGFBR2 receptor gene is transcriptionally silent. These same cells respond to estrogen by downregulating TGFβ, while antiestrogens act by upregulating TGFβ. This model predicts that inhibiting TGFβ signaling should drive the differentiation of mammary stem cells into ductal cells. Consequently, TGFβ antagonists may convert basal-like or HER2-positive cancers to a more epithelioid, non-proliferating (and, perhaps, non-metastatic) phenotype. Conversely, these agents might antagonize the therapeutic effects of anti-estrogens in estrogen-dependent luminal cancers. These

Integrated approach to pain management for a patient with multiple bone metastases of uterine cervical cancer.

PubMed

Qin, De-An; Song, Jie-Fu; Song, Li-Ping; Feng, Gui-Sheng

2018-05-01

Background Pain management for multiple bone metastases is complex and often requires multidisciplinary treatment. We herein describe patient-centered multidisciplinary pain management for metastatic cancer. A 61-year-old woman with multiple bone metastases of uterine cervical cancer developed intractable low back pain. After external beam radiotherapy failed, we performed lumbar spinal intralesional curettage, pedicle screw fixation, and nerve decompression. However, the neuralgia persisted. We then percutaneously injected epirubicin into the intervertebral foramina under computed tomography guidance for L5 dorsal root ganglion destruction. Osteoplasty was performed under C-arm X-ray guidance; however, the sacrum was mistaken for the ilium, and treatment was ineffective. We administered zoledronic acid and strontium-89. The last resort was outpatient implantation of an epidural bupivacaine-morphine infusion system. A visual analog scale (VAS) was used for pain evaluation. Lumbar spinal intralesional curettage and fixation, epirubicin-induced ganglion destruction, and administration of zoledronic acid and strontium-89 decreased her VAS pain score from 7-8 to 3-4. Radiotherapy and nerve decompression and release were ineffective, as was osteoplasty because of the location error. The epidural infusion system decreased the VAS score from 7-8 to 2-3 and was highly efficient. Conclusions Multidisciplinary integrated treatment for metastatic cancer can be effective.

PSMA-Based [(18)F]DCFPyL PET/CT Is Superior to Conventional Imaging for Lesion Detection in Patients with Metastatic Prostate Cancer.

PubMed

Rowe, Steven P; Macura, Katarzyna J; Mena, Esther; Blackford, Amanda L; Nadal, Rosa; Antonarakis, Emmanuel S; Eisenberger, Mario; Carducci, Michael; Fan, Hong; Dannals, Robert F; Chen, Ying; Mease, Ronnie C; Szabo, Zsolt; Pomper, Martin G; Cho, Steve Y

2016-06-01

Current standard of care conventional imaging modalities (CIM) such as X-ray computed tomography (CT) and bone scan can be limited for detection of metastatic prostate cancer and therefore improved imaging methods are an unmet clinical need. We evaluated the utility of a novel second-generation low molecular weight radiofluorinated prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer, [(18)F]DCFPyL, in patients with metastatic prostate cancer. Nine patients with suspected prostate cancer recurrence, eight with CIM evidence of metastatic prostate cancer and one with biochemical recurrence, were imaged with [(18)F]DCFPyL PET/CT. Eight of the patients had contemporaneous CIM for comparison. A lesion-by-lesion comparison of the detection of suspected sites of metastatic prostate cancer was carried out between PET and CIM. Statistical analysis for estimated proportions of inter-modality agreement for detection of metastatic disease was calculated accounting for intra-patient correlation using general estimating equation (GEE) intercept-only regression models. One hundred thirty-nine sites of PET positive [(18)F]DCFPyL uptake (138 definite, 1 equivocal) for metastatic disease were detected in the eight patients with available comparison CIM. By contrast, only 45 lesions were identified on CIM (30 definite, 15 equivocal). When lesions were negative or equivocal on CIM, it was estimated that a large portion of these lesions or 0.72 (95 % confidence interval (CI) 0.55-0.84) would be positive on [(18)F]DCFPyL PET. Conversely, of those lesions negative or equivocal on [(18)F]DCFPyL PET, it was estimated that only a very small proportion or 0.03 (95 % CI 0.01-0.07) would be positive on CIM. Delayed 2-h-post-injection time point PET yielded higher tumor radiotracer uptake and higher tumor-to-background ratios than an earlier 1-h-post-injection time point. A novel PSMA-targeted PET radiotracer, [(18)F]DCFPyL, was able to a large

Efficacy of Exemestane in Korean Patients with Metastatic Breast Cancer after Failure of Nonsteroidal Aromatase Inhibitors

PubMed Central

Lee, June Koo; Lee, Daewon; Kim, Ji-Yeon; Lim, Yoojoo; Lee, Eunyoung; Moon, Hyeong-Gon; Kim, Tae-Yong; Han, Sae-Won; Oh, Do-Youn; Lee, Se-Hoon; Han, Wonshik; Kim, Dong-Wan; Kim, Tae-You; Noh, Dong-Young

2013-01-01

Purpose Exemestane has shown good efficacy and tolerability in postmenopausal women with hormone receptor-positive metastatic breast cancer. However, clinical outcomes in Korean patients have not yet been reported. Methods Data on 112 postmenopausal women with metastatic breast cancer were obtained retrospectively. Clinicopathological characteristics and treatment history were extracted from medical records. All patients received 25 mg exemestane daily until objective disease progression. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR=complete response+partial response+stable disease for 6 months). Results The median age of the subjects was 55 years (range, 28-76 years). Exemestane treatment resulted in a median PFS of 5.7 months (95% confidence interval [CI], 4.4-7.0 months) and median OS of 21.9 months (95% CI, 13.6-30.3 months). ORR was 6.4% and CBR was 46.4% for the 110 patients with evaluable lesions. Symptomatic visceral disease was independently associated with shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001), compared with bone-dominant disease in a multivariate analysis of PFS after adjusting for age, hormone receptor, human epidermal growth factor receptor 2, Ki-67 status, dominant metastasis site, and sensitivity to nonsteroidal aromatase inhibitor (AI) treatment. Sensitivity to previous nonsteroidal AI treatment was not associated with PFS, suggesting no cross-resistance between exemestane and nonsteroidal AIs. Conclusion Exemestane was effective in postmenopausal Korean women with hormone receptor-positive metastatic breast cancer who failed previous nonsteroidal AI treatment. PMID:23593084

Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

DOE PAGES

Hong, Matthew K. H.; Macintyre, Geoff; Wedge, David C.; ...

2015-04-01

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones,more » even years after removal of the prostate. As a result, analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.« less

Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer.

PubMed

Hong, Matthew K H; Macintyre, Geoff; Wedge, David C; Van Loo, Peter; Patel, Keval; Lunke, Sebastian; Alexandrov, Ludmil B; Sloggett, Clare; Cmero, Marek; Marass, Francesco; Tsui, Dana; Mangiola, Stefano; Lonie, Andrew; Naeem, Haroon; Sapre, Nikhil; Phal, Pramit M; Kurganovs, Natalie; Chin, Xiaowen; Kerger, Michael; Warren, Anne Y; Neal, David; Gnanapragasam, Vincent; Rosenfeld, Nitzan; Pedersen, John S; Ryan, Andrew; Haviv, Izhak; Costello, Anthony J; Corcoran, Niall M; Hovens, Christopher M

2015-04-01

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

Vectors for Treatment of Metastatic Breast Cancer

DTIC Science & Technology

2006-08-01

Breast Cancer 5b. GRANT NUMBER DAMD17-03-1-0554 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Albert B. Deisseroth, M.D., Ph.D. 5d. PROJECT NUMBER...14. ABSTRACT: The objective is to design, build and study vectors which would be able to break tolerance to breast cancer associated TAA and to be...used to suppress the recurrence of metastatic breast cancer following surgical resection. The hypothesis is that by fusing the CD40 ligand stripped of

Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone

PubMed Central

Delliaux, Carine; Gervais, Manon; Kan, Casina; Benetollo, Claire; Pantano, Francesco; Vargas, Geoffrey; Bouazza, Lamia; Croset, Martine; Bala, Yohann; Leroy, Xavier; Rosol, Thomas J; Rieusset, Jennifer; Bellahcène, Akeila; Castronovo, Vincent; Aubin, Jane E; Clézardin, Philippe; Duterque-Coquillaud, Martine; Bonnelye, Edith

2016-01-01

Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events. PMID:27776343

Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

DTIC Science & Technology

2015-10-01

metastasis and responses to curcumin 19 Goals: This proposal tests the hypothesis that chemokine biomarkers that predict biochemical recurrence of...prostate cancer regulate metastatic progression of the cancer and curcumin can inhibit metastasis of prostate cancer by antagonizing inflammatory signaling

68Ga-PSMA PET-CT Imaging of Metastatic Adenoid Cystic Carcinoma.

PubMed

de Keizer, Bart; Krijger, Gerard C; Ververs, F Tessa; van Es, Robert J J; de Bree, Remco; Willems, Stefan

2017-12-01

A patient with a history of adenoid cystic carcinoma of the nasal cavity presented himself with bone pain and an elevated PSA level. On suspicion of metastatic prostate cancer a 68 Ga-PSMA PET-CT was performed. The PET-CT showed numerous lung and non-sclerotic bone metastasis. Biopsy of a bone metastasis was performed and pathology showed adenoid cystic carcinoma instead of prostate cancer. Immunohistochemical PSMA staining of the primary tumour showed intense PSMA expression in adenoid cystic carcinoma tumour cells. Because of the high PSMA expression of adenoid cystic carcinoma, 68 Ga-PSMA PET-CT might be a promising imaging modality for this malignancy.

Role of connexins in metastatic breast cancer and melanoma brain colonization

PubMed Central

Stoletov, Konstantin; Strnadel, Jan; Zardouzian, Erin; Momiyama, Masashi; Park, Frederick D.; Kelber, Jonathan A.; Pizzo, Donald P.; Hoffman, Robert; VandenBerg, Scott R.; Klemke, Richard L.

2013-01-01

Summary Breast cancer and melanoma cells commonly metastasize to the brain using homing mechanisms that are poorly understood. Cancer patients with brain metastases display poor prognosis and survival due to the lack of effective therapeutics and treatment strategies. Recent work using intravital microscopy and preclinical animal models indicates that metastatic cells colonize the brain, specifically in close contact with the existing brain vasculature. However, it is not known how contact with the vascular niche promotes microtumor formation. Here, we investigate the role of connexins in mediating early events in brain colonization using transparent zebrafish and chicken embryo models of brain metastasis. We provide evidence that breast cancer and melanoma cells utilize connexin gap junction proteins (Cx43, Cx26) to initiate brain metastatic lesion formation in association with the vasculature. RNAi depletion of connexins or pharmacological blocking of connexin-mediated cell–cell communication with carbenoxolone inhibited brain colonization by blocking tumor cell extravasation and blood vessel co-option. Activation of the metastatic gene twist in breast cancer cells increased Cx43 protein expression and gap junction communication, leading to increased extravasation, blood vessel co-option and brain colonization. Conversely, inhibiting twist activity reduced Cx43-mediated gap junction coupling and brain colonization. Database analyses of patient histories revealed increased expression of Cx26 and Cx43 in primary melanoma and breast cancer tumors, respectively, which correlated with increased cancer recurrence and metastasis. Together, our data indicate that Cx43 and Cx26 mediate cancer cell metastasis to the brain and suggest that connexins might be exploited therapeutically to benefit cancer patients with metastatic disease. PMID:23321642

CXCR4 regulates growth of both primary and metastatic breast cancer.

PubMed

Smith, Matthew C P; Luker, Kathryn E; Garbow, Joel R; Prior, Julie L; Jackson, Erin; Piwnica-Worms, David; Luker, Gary D

2004-12-01

The chemokine receptor CXCR4 and its cognate ligand CXCL12 recently have been proposed to regulate the directional trafficking and invasion of breast cancer cells to sites of metastases. However, effects of CXCR4 on the growth of primary breast cancer tumors and established metastases and survival have not been determined. We used stable RNAi to reduce expression of CXCR4 in murine 4T1 cells, a highly metastatic mammary cancer cell line that is a model for stage IV human breast cancer. Using noninvasive bioluminescence and magnetic resonance imaging, we showed that knockdown of CXCR4 significantly limited the growth of orthotopically transplanted breast cancer cells. Mice in which parental 4T1 cells were implanted had progressively enlarging tumors that spontaneously metastasized, and these animals all died from metastatic disease. Remarkably, RNAi of CXCR4 prevented primary tumor formation in some mice, and all mice transplanted with CXCR RNAi cells survived without developing macroscopic metastases. To analyze effects of CXCR4 on metastases to the lung, an organ commonly affected by metastatic breast cancer, we injected tumor cells intravenously and monitored cell growth with bioluminescence imaging. Inhibiting CXCR4 with RNAi, or the specific antagonist AMD3100, substantially delayed the growth of 4T1 cells in the lung, although neither RNAi nor AMD3100 prolonged overall survival in mice with experimental lung metastases. These data indicate that CXCR4 is required to initiate proliferation and/or promote survival of breast cancer cells in vivo and suggest that CXCR4 inhibitors will improve treatment of patients with primary and metastatic breast cancer.

Osteoblast-secreted WISP-1 promotes adherence of prostate cancer cells to bone via the VCAM-1/integrin α4β1 system.

PubMed

Chang, An-Chen; Chen, Po-Chun; Lin, Yu-Feng; Su, Chen-Ming; Liu, Ju-Fang; Lin, Tien-Huang; Chuang, Show-Mei; Tang, Chih-Hsin

2018-07-10

Bone metastasis is a frequent occurrence in prostate cancer (PCa) that is associated with severe complications such as fracture, bone pain and hypercalcemia. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. In our previous data, we have described how the involvement of the Wnt-induced secreted protein-1/vascular cell adhesion molecule-1 (WISP-1/VCAM-1) system in this tumor-bone interaction contributes to human PCa cell motility. In this study, we found that WISP-1 regulates bone mineralization by inducing bone morphogenetic protein-2 (BMP2), BMP4 and osteopontin (OPN) expression in osteoblasts. We also found that WISP-1 inhibited RANKL-dependent osteoclastogenesis. Moreover, osteoblast-derived WISP-1 enhanced VCAM-1 expression in PCa cells and subsequently promoted the adherence of cancer cells to osteoblasts. Furthermore, endothelin-1 (ET-1) expression in PCa cells was regulated by osteoblast-derived WISP-1, which promoted integrin α4β1 expression in osteoblasts via the MAPK pathway. Pretreatment of PCa cells with VCAM-1 antibody or osteoblasts with integrin α4β1 antibody attenuated the adherence of PCa cells to osteoblasts, suggesting that integrin α4β1 serves as a ligand that captures VCAM-1 + metastatic tumor cells adhering to osteoblasts. Our findings reveal that osteoblast-derived WISP-1 plays a key role in regulating the adhesion of PCa cells to osteoblasts via the VCAM-1/integrin α4β1 system. Osteoblast-derived WISP-1 is a promising target for the prevention and inhibition of PCa-bone interaction. Copyright © 2018 Elsevier B.V. All rights reserved.

Diagnostic imaging to detect and evaluate response to therapy in bone metastases from prostate cancer: current modalities and new horizons.

PubMed

Evangelista, Laura; Bertoldo, Francesco; Boccardo, Francesco; Conti, Giario; Menchi, Ilario; Mungai, Francesco; Ricardi, Umberto; Bombardieri, Emilio

2016-07-01

Different therapeutic options for the management of prostate cancer (PC) have been developed, and some are successful in providing crucial improvement in both survival and quality of life, especially in patients with metastatic castration-resistant PC. In this scenario, diverse combinations of radiopharmaceuticals (for targeting bone, cancer cells and receptors) and nuclear medicine modalities (e.g. bone scan, SPECT, SPECT/CT, PET and PET/CT) are now available for imaging bone metastases. Some radiopharmaceuticals are approved, currently available and used in the routine clinical setting, while others are not registered and are still under evaluation, and should therefore be considered experimental. On the other hand, radiologists have other tools, in addition to CT, that can better visualize bone localization and medullary involvement, such as multimodal MRI. In this review, the authors provide an overview of current management of advanced PC and discuss the choice of diagnostic modality for the detection of metastatic skeletal lesions in different phases of the disease. In addition to detection of bone metastases, the evaluation of response to therapy is another critical issue, since it remains one of the most important open questions that a multidisciplinary team faces when optimizing the management of PC. The authors emphasize the role of nuclear modalities that can presently be used in clinical practice, and also look at future perspectives based on relevant clinical data with novel radiopharmaceuticals.

Advances in systemic delivery of anti-cancer agents for the treatment of metastatic cancer.

PubMed

Grundy, Megan; Coussios, Constantin; Carlisle, Robert

2016-07-01

The successful treatment of metastatic cancer is refractory to strategies employed to treat confined, primary lesions, such as surgical resection and radiation therapy, and thus must be addressed by systemic delivery of anti-cancer agents. Conventional systemically administered chemotherapeutics are often ineffective and come with severe dose-limiting toxicities. This review focuses on the recent developments in systemic therapy for metastatic cancer. Firstly, the strategies employed to improve the efficacy of conventional chemotherapeutics by 'passively' and 'actively' targeting them to tumors are discussed. Secondly, recent advances in the use of biologics to better target cancer and to instigate anti-tumor immunity are reviewed. Under the label of 'biologics', antibody-therapies, T cell engaging therapies, oncolytic virotherapies and cell-based therapies are examined and evaluated. Improving specificity of action, and engaging the immune system appear to be key goals in the development of novel or reformulated anti-cancer agents for the treatment of metastatic cancer. One of the largest areas of opportunity in this field will be the identification of robust predictive biomarkers for use in conjunction with these agents. Treatment regimens that combine an agent to elicit an immune response (such as an oncolytic virus), and an agent to potentiate/mediate that immune response (such as immune checkpoint inhibitors) are predicted to be more effective than treatment with either agent alone.

Biocompatible, Biodegradable, and Enzymatic-Cleavable MRI Contrast Agents for Early Detection of Bone Metastatic Breast Cancer

DTIC Science & Technology

2012-04-01

detection of bone metastasis from breast cancer. The proposed imaging agent is consist of bone targeting moiety of Asp8 and MRI imaging moiety of DOTA ...peptide onto DOTA followed by Gd complexation was performed to achieve the proposed imaging agent. Non-targeting and CTSK-insensitive controls were...synthesis (SPPS) strategy, and purified by preparative HPLC. The chemical structures of peptides were shown below. Peptides reacted with DOTA -NHS

The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers

PubMed Central

Morris, Luc G. T.; Chandramohan, Raghu; West, Lyndsay; Zehir, Ahmet; Chakravarty, Debyani; Pfister, David G.; Wong, Richard J.; Lee, Nancy Y.; Sherman, Eric J.; Baxi, Shrujal S.; Ganly, Ian; Singh, Bhuvanesh; Shah, Jatin P.; Shaha, Ashok R.; Boyle, Jay O.; Patel, Snehal G.; Roman, Benjamin R.; Barker, Christopher A.; McBride, Sean M.; Chan, Timothy A.; Dogan, Snjezana; Hyman, David M.; Berger, Michael F.; Solit, David B.; Riaz, Nadeem; Ho, Alan L.

2016-01-01

IMPORTANCE Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies. OBJECTIVE To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease. DESIGN, SETTING, AND PARTICIPANTS After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis. INTERVENTIONS Next-generation sequencing of tumors and matched normal DNA. MAIN OUTCOMES AND MEASURES Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease. RESULTS Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV

Comparison of [68Ga]Ga-PSMA-11 PET/CT with [18F]NaF PET/CT in the evaluation of bone metastases in metastatic prostate cancer patients prior to radionuclide therapy.

PubMed

Uprimny, Christian; Svirydenka, Anna; Fritz, Josef; Kroiss, Alexander Stephan; Nilica, Bernhard; Decristoforo, Clemens; Haubner, Roland; von Guggenberg, Elisabeth; Buxbaum, Sabine; Horninger, Wolfgang; Virgolini, Irene Johanna

2018-05-16

The purpose of this study was to investigate the diagnostic performance of 68 Ga-PSMA-11 PET/CT in the evaluation of bone metastases in metastatic prostate cancer (PC) patients scheduled for radionuclide therapy in comparison to [ 18 F]sodium fluoride ( 18 F-NaF) PET/CT. Sixteen metastatic PC patients with known skeletal metastases, who underwent both 68 Ga-PSMA-11 PET/CT and 18 F-NaF PET/CT for assessment of metastatic burden prior to radionuclide therapy, were analysed retrospectively. The performance of both tracers was calculated on a lesion-based comparison. Intensity of tracer accumulation of pathologic bone lesions on 18 F-NaF PET and 68 Ga-PSMA-11 PET was measured with maximum standardized uptake values (SUV max ) and compared to background activity of normal bone. In addition, SUV max values of PET-positive bone lesions were analysed with respect to morphologic characteristics on CT. Bone metastases were either confirmed by CT or follow-up PET scan. In contrast to 468 PET-positive lesions suggestive of bone metastases on 18 F-NaF PET, only 351 of the lesions were also judged positive on 68 Ga-PSMA-11 PET (75.0%). Intensity of tracer accumulation of pathologic skeletal lesions was significantly higher on 18 F-NaF PET compared to 68 Ga-PSMA-11 PET, showing a median SUV max of 27.0 and 6.0, respectively (p < 0.001). Background activity of normal bone was lower on 68 Ga-PSMA-11 PET, with a median SUV max of 1.0 in comparison to 2.7 on 18 F-NaF PET; however, tumour to background ratio was significantly higher on 18 F-NaF PET (9.8 versus 5.9 on 68 Ga-PSMA-11 PET; p = 0.042). Based on morphologic lesion characterisation on CT, 18 F-NaF PET revealed median SUV max values of 23.6 for osteosclerotic, 35.0 for osteolytic, and 19.0 for lesions not visible on CT, whereas on 68 Ga-PSMA-11 PET median SUV max values of 5.0 in osteosclerotic, 29.5 in osteolytic, and 7.5 in lesions not seen on CT were measured. Intensity of tracer accumulation between 18 F-NaF PET

High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Transplantation in Metastatic Breast Cancer: Overview of Six Randomized Trials

PubMed Central

Berry, Donald A.; Ueno, Naoto T.; Johnson, Marcella M.; Lei, Xiudong; Caputo, Jean; Smith, Dori A.; Yancey, Linda J.; Crump, Michael; Stadtmauer, Edward A.; Biron, Pierre; Crown, John P.; Schmid, Peter; Lotz, Jean-Pierre; Rosti, Giovanni; Bregni, Marco; Demirer, Taner

2011-01-01

Purpose High doses of effective chemotherapy are compelling if they can be delivered safely. Substantial interest in supporting high-dose chemotherapy with bone marrow or autologous hematopoietic stem-cell transplantation in the 1980s and 1990s led to the initiation of randomized trials to evaluate its effect in the treatment of metastatic breast cancer. Methods We identified six randomized trials in metastatic breast cancer that evaluated high doses of chemotherapy with transplant support versus a control regimen without stem-cell support. We assembled a single database containing individual patient information from these trials. The primary analysis of overall survival was a log-rank test comparing high dose versus control. We also used Cox proportional hazards regression, adjusting for known covariates. We addressed potential treatment differences within subsets of patients. Results The effect of high-dose chemotherapy on overall survival was not statistically different (median, 2.16 v 2.02 years; P = .08). A statistically significant advantage in progression-free survival (median, 0.91 v 0.69 years) did not translate into survival benefit. Subset analyses found little evidence that there are groups of patients who might benefit from high-dose chemotherapy with hematopoietic support. Conclusion Overall survival of patients with metastatic breast cancer in the six randomized trials was not significantly improved by high-dose chemotherapy; any benefit from high doses was small. No identifiable subset of patients seems to benefit from high-dose chemotherapy. PMID:21768454

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

PubMed Central

Peinado, Héctor; Alečković, Maša; Lavotshkin, Simon; Matei, Irina; Costa-Silva, Bruno; Moreno-Bueno, Gema; Hergueta-Redondo, Marta; Williams, Caitlin; García-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Hoffman, Caitlin; Badal, Karen; Garcia, Benjamin A.; Callahan, Margaret K.; Yuan, Jianda; Martins, Vilma R.; Skog, Johan; Kaplan, Rosandra N.; Brady, Mary S.; Wolchok, Jedd D.; Chapman, Paul B.; Kang, Yibin; Bromberg, Jacqueline; Lyden, David

2013-01-01

Tumor-derived exosomes are emerging mediators of tumorigenesis with tissue-specific addresses and messages. We explored the function of melanoma-derived exosomes in the formation of primary tumor and metastases in mouse and human subjects. Exosomes from highly metastatic melanoma increased the metastatic behavior of primary tumors by permanently “educating” bone marrow (BM) progenitors via the MET receptor. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitors towards a c-Kit+Tie2+Met+ pro-vasculogenic phenotype. Reducing Met expression in exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was elevated in circulating CD45−C-KITlow/+TIE2+ BM progenitors from metastatic melanoma subjects. RAB1a, RAB5b, RAB7, and RAB27a were highly expressed in melanoma cells and Rab27a RNA interference decreased exosome production, preventing BM education, tumor growth and metastasis. Finally, we identified an exosome-specific “melanoma signature” with prognostic and therapeutic potential, comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. PMID:22635005

Metastatic pattern and DNA ploidy in stage IV breast cancer at initial diagnosis. Relation to response and survival.

PubMed

De Lena, M; Romero, A; Rabinovich, M; Leone, B; Vallejo, C; Machiavelli, M; Cuevas, M; Rodriguez, R; Lacava, J; Perez, J

1993-06-01

Sixty-nine patients with metastatic breast cancer (MBC) at initial diagnosis were analyzed to verify if metastatic pattern and clinical outcome are related to DNA ploidy determined by flow cytometry (FCM). Characteristics of 55 fully evaluable patients were as follows: median age: 61 years; postmenopausal: 75%; bone-only metastases (BM): 60%; extraosseous-only metastases (EM): 40%. Overall response rates (CR + PR) obtained with different chemotherapies and/or hormonal therapies were 58% and 68% for patients with BM and EM, respectively. Sixty percent of specimens resulted aneuploid, and the mean coefficient of variation of the complete series was 5.1%. In the whole group of patients DNA ploidy of primary tumor did not predict the metastatic pattern and had no influence upon response to treatment, duration of response, time to progression, and overall survival. When analyses were carried out according to metastatic pattern, those patients with BM showed similar results. However, within the group with EM, those with diploid tumors presented a significantly better survival (median 18 vs 13 months, p = .04). FCM-DNA analysis seems to identify a subgroup of patients with poor prognosis constituted by those who had aneuploid primary tumors and metastases to extraosseous sites.

APN401 in Treating Patients With Recurrent or Metastatic Pancreatic Cancer, Colorectal Cancer, or Other Solid Tumors That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-03-29

Metastatic Malignant Neoplasm in the Brain; Metastatic Solid Neoplasm; Recurrent Colorectal Carcinoma; Recurrent Pancreatic Carcinoma; Recurrent Solid Neoplasm; Stage IV Colorectal Cancer; Stage IV Pancreatic Cancer; Stage IVA Colorectal Cancer; Stage IVA Pancreatic Cancer; Stage IVB Colorectal Cancer; Stage IVB Pancreatic Cancer; Unresectable Solid Neoplasm

FSensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions and cell free DNA of breast cancer patients

PubMed Central

Wang, Peilu; Bahreini, Amir; Gyanchandani, Rekha; Lucas, Peter C.; Hartmaier, Ryan J.; Watters, Rebecca J.; Jonnalagadda, Amruth R.; Trejo Bittar, Humberto E.; Berg, Aaron; Hamilton, Ronald L.; Kurland, Brenda F.; Weiss, Kurt R.; Mathew, Aju; Leone, Jose Pablo; Davidson, Nancy E; Nikiforova, Marina N.; Brufsky, Adam M.; Ambros, Tadeu F.; Stern, Andrew M.; Puhalla, Shannon L.; Lee, Adrian V.; Oesterreich, Steffi

2015-01-01

Purpose Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell free DNA (cfDNA). Patients and Methods Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n=43), bone (n=12) and brain metastases (n=38), and cfDNA (n=29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. Results ESR1 mutations were detected for D538G (n=13), Y537S (n=3) and Y537C (n=1), and not for K303R, S463P or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3 to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n=5), mutations were detected in both (n=3) or in cfDNA only (n=2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. Conclusions ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1 mutant clones are enriched by endocrine therapy. Further studies should address if sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease. PMID:26500237

Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

PubMed Central

Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

2018-01-01

ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents.

PubMed

Sarabia-Estrada, Rachel; Ruiz-Valls, Alejandro; Guerrero-Cazares, Hugo; Ampuero, Ana M; Jimenez-Estrada, Ismael; De Silva, Samantha; Bernhardt, Lydia J; Goodwin, Courtney Rory; Ahmed, Ali Karim; Li, Yuxin; Phillips, Neil A; Gokaslan, Ziya L; Quiñones-Hinojosa, Alfredo; Sciubba, Daniel M

2017-09-01

posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis. Copyright © 2017 Elsevier Inc. All rights reserved.

Nine-year prostate cancer survival differences between aggressive versus conservative therapy in men with advanced and metastatic prostate cancer.

PubMed

Dall'Era, Marc A; Lo, Mary J; Chen, Jaclyn; Cress, Rosemary; Hamilton, Ann S

2018-05-01

To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP). Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer-specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival. For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9-year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment. The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption

Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis.

PubMed

Dumont, Bruno; Castronovo, Vincent; Peulen, Olivier; Blétard, Noëlla; Clézardin, Philippe; Delvenne, Philippe; De Pauw, Edwin A; Turtoi, Andrei; Bellahcène, Akeila

2012-04-06

The classical fate of metastasizing breast cancer cells is to seed and form secondary colonies in bones. The molecules closely associated with these processes are predominantly present at the cell surface and in the extracellular space, establishing the first contacts with the target tissue. In this study, we had the rare opportunity to analyze a bone metastatic lesion and its corresponding breast primary tumor obtained simultaneously from the same patient. Using mass spectrometry, we undertook a proteomic study on cell surface and extracellular protein-enriched material. We provide a repertoire of significantly modulated proteins, some with yet unknown roles in the bone metastatic process as well as proteins notably involved in cancer cell invasiveness and in bone metabolism. The comparison of these clinical data with those previously obtained using a human osteotropic breast cancer cell line highlighted an overlapping group of proteins. Certain differentially expressed proteins are validated in the present study using immunohistochemistry on a retrospective collection of breast tumors and matched bone metastases. Our exclusive set of selected proteins supports the setup of further investigations on both clinical samples and experimental bone metastasis models that will help to reveal the finely coordinated expression of proteins that favor the development of metastases in the bone microenvironment.

Nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer

Cancer.gov

A summary of results from a phase III trial that compared the combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane®]) and gemcitabine (Gemzar®) versus gemcitabine alone in patients with metastatic pancreatic cancer.

Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients.

PubMed

Wang, Peilu; Bahreini, Amir; Gyanchandani, Rekha; Lucas, Peter C; Hartmaier, Ryan J; Watters, Rebecca J; Jonnalagadda, Amruth R; Trejo Bittar, Humberto E; Berg, Aaron; Hamilton, Ronald L; Kurland, Brenda F; Weiss, Kurt R; Mathew, Aju; Leone, Jose Pablo; Davidson, Nancy E; Nikiforova, Marina N; Brufsky, Adam M; Ambros, Tadeu F; Stern, Andrew M; Puhalla, Shannon L; Lee, Adrian V; Oesterreich, Steffi

2016-03-01

Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease. See related commentary by Gu and Fuqua, p. 1034. ©2015 American Association for Cancer Research.

Targeting mast cells in gastric cancer with special reference to bone metastases

PubMed Central

Leporini, Christian; Ammendola, Michele; Marech, Ilaria; Sammarco, Giuseppe; Sacco, Rosario; Gadaleta, Cosmo Damiano; Oakley, Caroline; Russo, Emilio; De Sarro, Giovambattista; Ranieri, Girolamo

2015-01-01

Bone metastases from gastric cancer (GC) are considered a relatively uncommon finding; however, they are related to poorer prognosis. Both primary GC and its metastatic progression rely on angiogenesis. Several lines of evidence from GC patients strongly support the involvement of mast cells (MCs) positive to tryptase (MCPT) in primary gastric tumor angiogenesis. Recently, we analyzed infiltrating MCs and neovascularization in bone tissue metastases from primary GC patients, and observed a significant correlation between infiltrating MCPT and angiogenesis. Such a finding suggested the involvement of peritumoral MCPT by infiltrating surrounding tumor cells, and in bone metastasis angiogenesis from primary GC. Thus, an MCPT-stimulated angiogenic process could support the development of metastases in bone tissue. From this perspective, we aim to review the hypothetical involvement of tumor-infiltrating, peritumoral MCPT in angiogenesis-mediated GC cell growth in the bone microenvironment and in tumor-induced osteoclastic bone resorption. We also focus on the potential use of MCPT targeting agents, such as MCs tryptase inhibitors (gabexate mesylate, nafamostat mesylate) or c-KitR tyrosine kinase inhibitors (imatinib, masitinib), as possible new anti-angiogenic and anti-resorptive strategies for the treatment of GC patients affected by bone metastases. PMID:26457010

Engineering a humanized bone organ model in mice to study bone metastases.

PubMed

Martine, Laure C; Holzapfel, Boris M; McGovern, Jacqui A; Wagner, Ferdinand; Quent, Verena M; Hesami, Parisa; Wunner, Felix M; Vaquette, Cedryck; De-Juan-Pardo, Elena M; Brown, Toby D; Nowlan, Bianca; Wu, Dan Jing; Hutmacher, Cosmo Orlando; Moi, Davide; Oussenko, Tatiana; Piccinini, Elia; Zandstra, Peter W; Mazzieri, Roberta; Lévesque, Jean-Pierre; Dalton, Paul D; Taubenberger, Anna V; Hutmacher, Dietmar W

2017-04-01

Current in vivo models for investigating human primary bone tumors and cancer metastasis to the bone rely on the injection of human cancer cells into the mouse skeleton. This approach does not mimic species-specific mechanisms occurring in human diseases and may preclude successful clinical translation. We have developed a protocol to engineer humanized bone within immunodeficient hosts, which can be adapted to study the interactions between human cancer cells and a humanized bone microenvironment in vivo. A researcher trained in the principles of tissue engineering will be able to execute the protocol and yield study results within 4-6 months. Additive biomanufactured scaffolds seeded and cultured with human bone-forming cells are implanted ectopically in combination with osteogenic factors into mice to generate a physiological bone 'organ', which is partially humanized. The model comprises human bone cells and secreted extracellular matrix (ECM); however, other components of the engineered tissue, such as the vasculature, are of murine origin. The model can be further humanized through the engraftment of human hematopoietic stem cells (HSCs) that can lead to human hematopoiesis within the murine host. The humanized organ bone model has been well characterized and validated and allows dissection of some of the mechanisms of the bone metastatic processes in prostate and breast cancer.

Phytochemicals potently inhibit migration of metastatic breast cancer cells†

PubMed Central

Ham, Stephanie Lemmo; Nasrollahi, Samila; Shah, Kush N.; Soltisz, Andrew; Paruchuri, Sailaja; Yun, Yang H.; Luker, Gary D.; Bishayee, Anupam; Tavana, Hossein

2017-01-01

Cell migration is a major process that drives metastatic progression of cancers, the major cause of cancer death. Existing chemotherapeutic drugs have limited efficacy to prevent and/or treat metastasis, emphasizing the need for new treatments. We focus on triple negative breast cancer (TNBC), the subtype of breast cancer with worst prognosis and no standard chemotherapy protocols. Here we demonstrate that a group of natural compounds, known as phytochemicals, effectively block migration of metastatic TNBC cells. Using a novel cell micropatterning technology, we generate consistent migration niches in standard 96-well plates where each well contains a cell-excluded gap within a uniform monolayer of cells. Over time, cells migrate into and occupy the gap. Treating TNBC cells with non-toxic concentrations of phytochemicals significantly blocks motility of cells. Using a molecular analysis approach, we show that anti-migratory property of phytochemicals is partly due to their inhibitory effects on phosphorylation of ERK1/2. This study provides a framework for future studies to understand molecular targets of phytochemicals and evaluate their effectiveness in inhibiting metastasis in animal models of cancer. PMID:26120051

Gene expression markers in circulating tumor cells may predict bone metastasis and response to hormonal treatment in breast cancer.

PubMed

Wang, Haiying; Molina, Julian; Jiang, John; Ferber, Matthew; Pruthi, Sandhya; Jatkoe, Timothy; Derecho, Carlo; Rajpurohit, Yashoda; Zheng, Jian; Wang, Yixin

2013-11-01

Circulating tumor cells (CTCs) have recently attracted attention due to their potential as prognostic and predictive markers for the clinical management of metastatic breast cancer patients. The isolation of CTCs from patients may enable the molecular characterization of these cells, which may help establish a minimally invasive assay for the prediction of metastasis and further optimization of treatment. Molecular markers of proven clinical value may therefore be useful in predicting disease aggressiveness and response to treatment. In our earlier study, we identified a gene signature in breast cancer that appears to be significantly associated with bone metastasis. Among the genes that constitute this signature, trefoil factor 1 (TFF1) was identified as the most differentially expressed gene associated with bone metastasis. In this study, we investigated 25 candidate gene markers in the CTCs of metastatic breast cancer patients with different metastatic sites. The panel of the 25 markers was investigated in 80 baseline samples (first blood draw of CTCs) and 30 follow-up samples. In addition, 40 healthy blood donors (HBDs) were analyzed as controls. The assay was performed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) with RNA extracted from CTCs captured by the CellSearch system. Our study indicated that 12 of the genes were uniquely expressed in CTCs and 10 were highly expressed in the CTCs obtained from patients compared to those obtained from HBDs. Among these genes, the expression of keratin 19 was highly correlated with the CTC count. The TFF1 expression in CTCs was a strong predictor of bone metastasis and the patients with a high expression of estrogen receptor β in CTCs exhibited a better response to hormonal treatment. Molecular characterization of these genes in CTCs may provide a better understanding of the mechanism underlying tumor metastasis and identify gene markers in CTCs for predicting disease progression and

Emerging therapeutic targets in metastatic progression: a focus on breast cancer

PubMed Central

Li, Zhuo; Kang, Yibin

2016-01-01

Metastasis is the underlying cause of death for the majority of breast cancer patients. Despite significant advances in recent years in basic research and clinical development, therapies that specifically target metastatic breast cancer remain inadequate, and represents the single greatest obstacle to reducing mortality of late-stage breast cancer. Recent efforts have leveraged genomic analysis of breast cancer and molecular dissection of tumor-stromal cross-talk to uncover a number of promising candidates for targeted treatment of metastatic breast cancer. Rational combinations of therapeutic agents targeting tumor-intrinsic properties and microenvironmental components provide a promising strategy to develop precision treatments with higher specificity and less toxicity. In this review, we discuss the emerging therapeutic targets in breast cancer metastasis, from tumor-intrinsic pathways to those that involve the host tissue components, including the immune system. PMID:27000769

Primary tumor resection in metastatic breast cancer: A propensity-matched analysis, 1988-2011 SEER data base.

PubMed

Vohra, Nasreen A; Brinkley, Jason; Kachare, Swapnil; Muzaffar, Mahvish

2018-03-02

Primary tumor resection (PTR) in metastatic breast cancer is not a standard treatment modality, and its impact on survival is conflicting. The primary objective of this study was to analyze impact of PTR on survival in metastatic patients with breast cancer. A retrospective study of metastatic patients with breast cancer was conducted using the 1988-2011 Surveillance, Epidemiology, and End Results (SEER) data base. Cox proportional hazards regression models were used to evaluate the relationship between PTR and survival and to adjust for the heterogeneity between the groups, and a propensity score-matched analysis was also performed. A total of 29 916 patients with metastatic breast cancer were included in the study, and 15 129 (51%) of patients underwent primary tumor resection, and 14 787 (49%) patients did not undergo surgery. Overall, decreasing trend in PTR for metastatic breast cancer in last decades was noted. Primary tumor resection was associated with a longer median OS (34 vs 18 months). In a propensity score-matched analysis, prognosis was also more favorable in the resected group (P = .0017). Primary tumor resection in metastatic breast cancer was associated with survival improvement, and the improvement persisted in propensity-matched analysis. © 2018 Wiley Periodicals, Inc.

Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer

PubMed Central

Simone, Brittany A.; Dan, Tu; Palagani, Ajay; Jin, Lianjin; Han, Sunny Y.; Wright, Christopher; Savage, Jason E.; Gitman, Robert; Lim, Meng Kieng; Palazzo, Juan; Mehta, Minesh P.; Simone, Nicole L.

2016-01-01

ABSTRACT Purpose: Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease. Methods: An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model. Results: CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR. Conclusions: CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer. PMID:27027731

Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer.

PubMed

Simone, Brittany A; Dan, Tu; Palagani, Ajay; Jin, Lianjin; Han, Sunny Y; Wright, Christopher; Savage, Jason E; Gitman, Robert; Lim, Meng Kieng; Palazzo, Juan; Mehta, Minesh P; Simone, Nicole L

2016-09-01

Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease. An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model. CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR. CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer.

Changes in cytoskeletal dynamics and nonlinear rheology with metastatic ability in cancer cell lines

NASA Astrophysics Data System (ADS)

Coughlin, Mark F.; Fredberg, Jeffrey J.

2013-12-01

Metastatic outcome is impacted by the biophysical state of the primary tumor cell. To determine if changes in cancer cell biophysical properties facilitate metastasis, we quantified cytoskeletal biophysics in well-characterized human skin, bladder, prostate and kidney cell line pairs that differ in metastatic ability. Using magnetic twisting cytometry with optical detection, cytoskeletal dynamics was observed through spontaneous motion of surface bound marker beads and nonlinear rheology was characterized through large amplitude forced oscillations of probe beads. Measurements of cytoskeletal dynamics and nonlinear rheology differed between strongly and weakly metastatic cells. However, no set of biophysical parameters changed systematically with metastatic ability across all cell lines. Compared to their weakly metastatic counterparts, the strongly metastatic kidney cancer cells exhibited both increased cytoskeletal dynamics and stiffness at large deformation which are thought to facilitate the process of vascular invasion.

Stable and high expression of Galectin-8 tightly controls metastatic progression of prostate cancer

PubMed Central

Gentilini, Lucas Daniel; Pérez, Ignacio González; Kotler, Monica Lidia; Chauchereau, Anne; Laderach, Diego Jose; Compagno, Daniel

2017-01-01

Two decades ago, Galectin-8 was described as a prostate carcinoma biomarker since it is only expressed in the neoplastic prostate, but not in the healthy tissue. To date, no biological function has been attributed to Galectin-8 that could explain this differential expression. In this study we silenced Galectin-8 in two human prostate cancer cell lines, PC3 and IGR-CaP1, and designed a pre-clinical experimental model that allows monitoring the pathology from its early steps to the long-term metastatic stages. We show for the first time that the natural and conserved expression of Gal-8 in tumour cells is responsible for the metastatic evolution of prostate cancer. In fact, Gal-8 controls the rearrangement of the cytoskeleton and E-Cadherin expression, with a major impact on anoikis and homotypic aggregation of tumour cells, both being essential processes for the survival of circulating tumour cells during metastasis. While localized prostate cancer can be cured, metastatic and advanced disease remains a significant therapeutic challenge, urging for the identification of prognostic markers of the metastatic process. Collectively, our results highlight Galectin-8 as a potential target for anti-metastatic therapy against prostate cancer. PMID:28591719

Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer

PubMed Central

Rampurwala, Murtuza; Wisinski, Kari B; Burkard, Mark E; Ehsani, Sima; O’Regan, Ruth M; Carmichael, Lakeesha; Kim, KyungMann; Kolesar, Jill; Tevaarwerk, Amye J

2017-01-01

Intro Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3+3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47–73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to orteronel included grade 1–2 nausea (n=4) and bone pain (n=3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n=2). The only grade 3 AE was hypertension (n=2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer. PMID:27826831

Icotinib plus gemcitabine for metastatic pancreatic cancer: A case report

PubMed Central

Zhao, Jing; Shen, Hong; Hu, Han-Guang; Huang, Jian-Jin

2015-01-01

A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative. PMID:25805958

Icotinib plus gemcitabine for metastatic pancreatic cancer: a case report.

PubMed

Zhao, Jing; Shen, Hong; Hu, Han-Guang; Huang, Jian-Jin

2015-03-21

A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative.

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. ©2015 Frontline Medical Communications.

Characterizing the efficacy of cancer therapeutics in patient-derived xenograft models of metastatic breast cancer.

PubMed

Turner, Tia H; Alzubi, Mohammad A; Sohal, Sahib S; Olex, Amy L; Dozmorov, Mikhail G; Harrell, J Chuck

2018-03-12

Basal-like breast cancers are aggressive and often metastasize to vital organs. Treatment is largely limited to chemotherapy. This study aims to characterize the efficacy of cancer therapeutics in vitro and in vivo within the primary tumor and metastatic setting, using patient-derived xenograft (PDX) models. We employed two basal-like, triple-negative PDX models, WHIM2 and WHIM30. PDX cells, obtained from mammary tumors grown in mice, were treated with twelve cancer therapeutics to evaluate their cytotoxicity in vitro. Four of the effective drugs-carboplatin, cyclophosphamide, bortezomib, and dacarbazine-were tested in vivo for their efficacy in treating mammary tumors, and metastases generated by intracardiac injection of tumor cells. RNA sequencing showed that global gene expression of PDX cells grown in the mammary gland was similar to those tested in culture. In vitro, carboplatin was cytotoxic to WHIM30 but not WHIM2, whereas bortezomib, dacarbazine, and cyclophosphamide were cytotoxic to both lines. Yet, these drugs were ineffective in treating both primary and metastatic WHIM2 tumors in vivo. Carboplatin and cyclophosphamide were effective in treating WHIM30 mammary tumors and reducing metastatic burden in the brain, liver, and lungs. WHIM2 and WHIM30 metastases showed distinct patterns of cytokeratin and vimentin expression, regardless of treatment, suggesting that different tumor cell subpopulations may preferentially seed in different organs. This study highlights the utility of PDX models for studying the efficacy of therapeutics in reducing metastatic burden in specific organs. The differential treatment responses between two PDX models of the same intrinsic subtype, in both the primary and metastatic setting, recapitulates the challenges faced in treating cancer patients and highlights the need for combination therapies and predictive biomarkers.

Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer.

PubMed

Adjei, Isaac M; Sharma, Blanka; Peetla, Chiranjeevi; Labhasetwar, Vinod

2016-06-28

Advanced-stage prostate cancer usually metastasizes to bone and is untreatable due to poor biodistribution of intravenously administered anticancer drugs to bone. In this study, we modulated the surface charge/composition of biodegradable nanoparticles (NPs) to sustain their blood circulation time and made them small enough to extravasate through the openings of the bone's sinusoidal capillaries and thus localize into marrow. NPs with a neutral surface charge, achieved by modulating the NP surface-associated emulsifier composition, were more effective at localizing to bone marrow than NPs with a cationic or anionic surface charge. These small neutral NPs (~150nm vs. the more usual ~320nm) were also ~7-fold more effective in localizing in bone marrow than large NPs. We hypothesized that NPs that effectively localize to marrow could improve NP-mediated anticancer drug delivery to sites of bone metastasis, thereby inhibiting cancer progression and preventing bone loss. In a PC-3M-luc cell-induced osteolytic intraosseous model of prostate cancer, these small neutral NPs demonstrated greater accumulation in bone within metastatic sites than in normal contralateral bone as well as co-localization with the tumor mass in marrow. Significantly, a single-dose intravenous administration of these small neutral NPs loaded with paclitaxel (PTX-NPs), but not anionic PTX-NPs, slowed the progression of bone metastasis. In addition, neutral PTX-NPs prevented bone loss, whereas animals treated with the rapid-release drug formulation Cremophor EL (PTX-CrEL) or saline (control) showed >50% bone loss. Neutral PTX-NPs did not cause acute toxicity, whereas animals treated with PTX-CrEL experienced weight loss. These results indicate that NPs with appropriate physical and sustained drug-release characteristics could be explored to treat bone metastasis, a significant clinical issue in prostate and other cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Concomitant endometrial and gallbladder metastasis in advanced multiple metastatic invasive lobular carcinoma of the breast: A rare case report.

PubMed

Bezpalko, Kseniya; Mohamed, Mohamed A; Mercer, Leo; McCann, Michael; Elghawy, Karim; Wilson, Kenneth

2015-01-01

At time of presentation, fewer than 10% of patients have metastatic breast cancer. The most common sites of metastasis in order of frequency are bone, lung, pleura, soft tissue, and liver. Breast cancer metastasis to the uterus or gallbladder is rare and has infrequently been reported in the English literature. A 47 year old female with a recent history of thrombocytopenia presented with abnormal vaginal bleeding. Pelvic ultrasound revealed multiple uterine fibroids and endometrial curettings revealed cells consistent with lobular carcinoma of the breast. Breast examination revealed edema and induration of the lower half of the right breast. Biopsy of the right breast revealed invasive lobular carcinoma. Bone marrow aspiration obtained at a previous outpatient visit revealed extensive involvement by metastatic breast carcinoma. Shortly after discharge, the patient presented with acute cholecystitis and underwent cholecystectomy. Microscopic examination of the gallbladder revealed metastatic infiltrating lobular carcinoma. The final diagnosis was invasive lobular carcinoma of the right breast with metastasis to the bone marrow, endometrium, gallbladder, regional lymph nodes, and peritoneum. The growth pattern of invasive lobular carcinoma of the breast is unique and poses a challenge in diagnosing the cancer at an early stage. Unlike other types of breast cancer, it tends to metastasize more to the peritoneum, ovary, and gastrointestinal tract. Metastasis to the endometrium or gallbladder is rare. Metastatic spread should be considered in the differential diagnosis of patients with invasive lobular breast carcinoma presenting with abnormal vaginal bleeding or acute cholecystitis. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Salvage Lenvatinib Therapy in Metastatic Anaplastic Thyroid Cancer.

PubMed

Iñiguez-Ariza, Nicole M; Ryder, Mabel M; Hilger, Crystal R; Bible, Keith C

2017-07-01

Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required

Heat shock protein 27 regulates human prostate cancer cell motility and metastatic progression

PubMed Central

Voll, Eric A; Ogden, Irene M; Pavese, Janet M; Huang, XiaoKe; Xu, Li; Jovanovic, Borko D; Bergan, Raymond C

2014-01-01

Prostate cancer (PCa) is the most common form of cancer in American men. Mortality from PCa is caused by the movement of cancer cells from the primary organ to form metastatic tumors at distant sites. Heat shock protein 27 (HSP27) is known to increase human PCa cell invasion and its overexpression is associated with metastatic disease. The role of HSP27 in driving PCa cell movement from the prostate to distant metastatic sites is unknown. Increased HSP27 expression increased metastasis as well as primary tumor mass. In vitro studies further examined the mechanism of HSP27-induced metastatic behavior. HSP27 did not affect cell detachment, adhesion, or migration, but did increase cell invasion. Cell invasion was dependent upon matrix metalloproteinase 2 (MMP-2), whose expression was increased by HSP27. In vivo, HSP27 induced commensurate changes in MMP-2 expression in tumors. These findings demonstrate that HSP27 drives metastatic spread of cancer cells from the prostate to distant sites, does so across a continuum of expression levels, and identifies HSP27-driven increases in MMP-2 expression as functionally relevant. These findings add to prior studies demonstrating that HSP27 increases PCa cell motility, growth and survival. Together, they demonstrate that HSP27 plays an important role in PCa progression. PMID:24798191

Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions.

PubMed

Brannon, A Rose; Vakiani, Efsevia; Sylvester, Brooke E; Scott, Sasinya N; McDermott, Gregory; Shah, Ronak H; Kania, Krishan; Viale, Agnes; Oschwald, Dayna M; Vacic, Vladimir; Emde, Anne-Katrin; Cercek, Andrea; Yaeger, Rona; Kemeny, Nancy E; Saltz, Leonard B; Shia, Jinru; D'Angelica, Michael I; Weiser, Martin R; Solit, David B; Berger, Michael F

2014-08-28

Colorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of response to anti-EGFR therapy has become standard practice in the treatment of metastatic colorectal cancer; however, the quantity and type of tissue available for testing is frequently limited. Further, the degree to which the primary tumor is a faithful representation of metastatic disease has been questioned. As next-generation sequencing technology becomes more widely available for clinical use and additional molecularly targeted agents are considered as treatment options in colorectal cancer, it is important to characterize the extent of tumor heterogeneity between primary and metastatic tumors. We performed deep coverage, targeted next-generation sequencing of 230 key cancer-associated genes for 69 matched primary and metastatic tumors and normal tissue. Mutation profiles were 100% concordant for KRAS, NRAS, and BRAF, and were highly concordant for recurrent alterations in colorectal cancer. Additionally, whole genome sequencing of four patient trios did not reveal any additional site-specific targetable alterations. Colorectal cancer primary tumors and metastases exhibit high genomic concordance. As current clinical practices in colorectal cancer revolve around KRAS, NRAS, and BRAF mutation status, diagnostic sequencing of either primary or metastatic tissue as available is acceptable for most patients. Additionally, consistency between targeted sequencing and whole genome sequencing results suggests that targeted sequencing may be a suitable strategy for clinical diagnostic applications.

Gene expression profiles help identify the tissue of origin for metastatic brain cancers.

PubMed

Wu, Alan H B; Drees, Julia C; Wang, Hangpin; VandenBerg, Scott R; Lal, Anita; Henner, William D; Pillai, Raji

2010-04-26

Metastatic brain cancers are the most common intracranial tumor and occur in about 15% of all cancer patients. In up to 10% of these patients, the primary tumor tissue remains unknown, even after a time consuming and costly workup. The Pathwork Tissue of Origin Test (Pathwork Diagnostics, Redwood City, CA, USA) is a gene expression test to aid in the diagnosis of metastatic, poorly differentiated and undifferentiated tumors. It measures the expression pattern of 1,550 genes in these tumors and compares it to the expression pattern of a panel of 15 known tumor types. The purpose of this study was to evaluate the performance of the Tissue of Origin Test in the diagnosis of primary sites for metastatic brain cancer patients. Fifteen fresh-frozen metastatic brain tumor specimens of known origins met specimen requirements. These specimens were entered into the study and processed using the Tissue of Origin Test. Results were compared to the known primary site and the agreement between the two results was assessed. Fourteen of the fifteen specimens produced microarray data files that passed all quality metrics. One originated from a tissue type that was off-panel. Among the remaining 13 cases, the Tissue of Origin Test accurately predicted the available diagnosis in 12/13 (92.3%) cases. This study demonstrates the accuracy of the Tissue of Origin Test when applied to predict the tissue of origin of metastatic brain tumors. This test could be a very useful tool for pathologists as they classify metastatic brain cancers.

Gene expression profiles help identify the Tissue of Origin for metastatic brain cancers

PubMed Central

2010-01-01

Background Metastatic brain cancers are the most common intracranial tumor and occur in about 15% of all cancer patients. In up to 10% of these patients, the primary tumor tissue remains unknown, even after a time consuming and costly workup. The Pathwork® Tissue of Origin Test (Pathwork Diagnostics, Redwood City, CA, USA) is a gene expression test to aid in the diagnosis of metastatic, poorly differentiated and undifferentiated tumors. It measures the expression pattern of 1,550 genes in these tumors and compares it to the expression pattern of a panel of 15 known tumor types. The purpose of this study was to evaluate the performance of the Tissue of Origin Test in the diagnosis of primary sites for metastatic brain cancer patients. Methods Fifteen fresh-frozen metastatic brain tumor specimens of known origins met specimen requirements. These specimens were entered into the study and processed using the Tissue of Origin Test. Results were compared to the known primary site and the agreement between the two results was assessed. Results Fourteen of the fifteen specimens produced microarray data files that passed all quality metrics. One originated from a tissue type that was off-panel. Among the remaining 13 cases, the Tissue of Origin Test accurately predicted the available diagnosis in 12/13 (92.3%) cases. Discussion This study demonstrates the accuracy of the Tissue of Origin Test when applied to predict the tissue of origin of metastatic brain tumors. This test could be a very useful tool for pathologists as they classify metastatic brain cancers. PMID:20420692

US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments.

PubMed

Wedam, Suparna B; Beaver, Julia A; Amiri-Kordestani, Laleh; Bloomquist, Erik; Tang, Shenghui; Goldberg, Kirsten B; Sridhara, Rajeshwari; Ibrahim, Amna; Kim, Geoffrey; Kluetz, Paul; McKee, Amy; Pazdur, Richard

2018-04-20

Purpose The outcome and proportion of patients with bone-only (BO) metastatic breast cancer (MBC) has not been well described. We sought to describe the differential outcomes of patients with BO MBC in clinical trials and explore whether there was a discrepancy in radiographic reads between investigator and blinded independent central review. Methods We pooled and analyzed data on 10,521 patients from 13 prospective trials submitted for MBC treatment in initial or supplemental New Drug or Biologics License Applications from 2005. Three subsets were evaluated: BO, bone with other metastases (BWO), and no bone metastases (NBM). Early discordance rate and late discordance rate were calculated from 3,733 and 2,813 patients subject to a blinded independent central review, respectively. Results Bone metastases were identified in 49% (range: 42% to 73%) of patients across trials. BO disease was present in 12.5% (range: 4% to 26%), dependent on subtype. Investigator-assessed progression-free survival (PFS) and overall survival (OS) for the pooled trials demonstrated improved outcomes for the BO subgroup compared with other subgroups (BO v BWO PFS hazard ratio [HR], 0.64; 95% CI, 0.591 to 0.696; BO v NBM PFS HR, 0.70; 95% CI, 0.65 to 0.76; BO v BWO OS HR, 0.56; 95% CI, 0.50 to 0.61; BO v NBM OS HR, 0.68; 95% CI, 0.61 to 0.76). The BO subgroup has a higher early discordance rate and lower late discordance rate than the BWO and NBM subgroups. Conclusion To our knowledge, this review is the largest analysis to date of the BO subgroup of MBC and suggests this subgroup may have a distinct natural history. There also seems to be a difference in how the local investigators assessed progression events in the BO subgroup when compared with the other two groups.

Predicting survival of de novo metastatic breast cancer in Asian women: systematic review and validation study.

PubMed

Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G M; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M

2014-01-01

In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48-0.53) to 0.63 (95% CI, 0.60-0.66). The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making.

Breast Cancer and Bone Loss

MedlinePlus

... Resource Find an Endocrinologist Search Breast Cancer and Bone Loss July 2010 Download PDFs English Espanol Editors ... What is the link between breast cancer and bone loss? Certain treatments for breast cancer can lead ...

Evidence of Prostate-Specific Membrane Antigen Expression in Metastatic Differentiated Thyroid Cancer Using 68Ga-PSMA-HBED-CC PET/CT.

PubMed

Verma, Priyanka; Malhotra, Gaurav; Agrawal, Ritesh; Sonavane, Sunita; Meshram, Vilas; Asopa, Ramesh V

2018-06-12

Prostate-specific membrane antigen (PSMA) overexpression is not restricted to prostate cancer, but it has also been demonstrated in gliomas, lung cancer, and in tumor neovasculature. Systematic studies exploring PSMA uptake in thyroid tumors are lacking. The aim of this pilot study was to assess PSMA expression in patients with metastatic differentiated thyroid cancer (mDTC). Ten patients of mDTC harboring 32 lesions (5 men; age range, 38-65 years; mean age, 50 years) underwent prospective evaluation with radioiodine (I), F-FDG PET, and Ga-PSMA-HBED-CC PET scans as per the institution protocol. PSMA expression (SUVmax) was compared with F-FDG and I scan findings in all patients. Lesions were radioiodine avid in 8 patients, whereas 2 were classified as thyroglobulin elevation with negative iodide scintigraphy (TENIS) patients. All patients with iodine-avid metastatic disease showed substantial PSMA uptake. PSMA PET detected 30/32 total lesions (93.75%; SUVmax ranging from 4.86 to 101.81 with median SUVmax of 31.35), whereas FDG PET/CT was positive in 23/32 lesions (81.85%). Twenty-one (70%) of 30 lesions that showed PSMA expression were localized to the bones. PSMA localized a lesion in each of the 2 TENIS patients similar to FDG PET scan. Ga-PSMA-HBED-CC PET/CT is a potentially useful imaging modality in patients of mDTC with most (70%) of PSMA expressing metastasis being localized to the bones. PSMA PET/CT could be useful for identifying patients with limited therapeutic options (eg, TENIS) who might benefit from PSMA-targeted radionuclide therapy.

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer

PubMed Central

Rao, S R; Snaith, A E; Marino, D; Cheng, X; Lwin, S T; Orriss, I R; Hamdy, F C; Edwards, C M

2017-01-01

Background: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. Methods: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. Results: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. Conclusions: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression. PMID:28006818

Imaging tests in staging and surveillance of non-metastatic breast cancer: changes in routine clinical practice and cost implications.

PubMed

De Placido, S; De Angelis, C; Giuliano, M; Pizzi, C; Ruocco, R; Perrone, V; Bruzzese, D; Tommasielli, G; De Laurentiis, M; Cammarota, S; Arpino, G; Arpino, G

2017-03-14

Although guidelines do not recommend computerised tomography (CT), positron emission tomography (PET) or magnetic resonance imaging (MRI) for the staging or follow-up of asymptomatic patients with non-metastatic breast cancer, they are often requested in routine clinical practice. The aim of this study was to determine the staging and follow-up patterns, and relative costs in a large population of breast cancer patients living and treated in a Southern Italian region. We analysed the clinical computerised information recorded by 567 primary-care physicians assisting about 650 000 inhabitants in the Campania region. Patients with non-metastatic breast cancer were identified and divided into calendar years from 2001 to 2010. The number of diagnostic tests prescribed per 100 patients (N/Pts) and the mean cost per patient was determined 3 months before diagnosis and up to 1 year after diagnosis. Costs are expressed in constant 2011 euros. We identified 4680 newly diagnosed cases of asymptomatic non-metastatic breast cancer. N/Pts increased significantly (P<0.0001) from 2001 to 2010. The mean number of prescribed mammograms, bone scans, abdominal ultrasound and chest X-rays ('routine tests'), and costs was unchanged. However, the number of CT, PET scans and MRI ('new tests')prescriptions almost quadrupled and the mean cost per patient related to these procedures significantly increased from [euro ]357 in 2001 to [euro ]830 in 2010 (P<0.0001). New test prescriptions and relative costs significantly and steadily increased throughout the study period. At present there is no evidence that the delivery of new tests to asymptomatic patients improves breast cancer outcome. Well-designed clinical trials are urgently needed to shed light on the impact of these tests on clinical outcome and overall survival.

Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

PubMed Central

Santio, Niina M.; Eerola, Sini K.; Paatero, Ilkka; Yli-Kauhaluoma, Jari; Anizon, Fabrice; Moreau, Pascale; Tuomela, Johanna; Härkönen, Pirkko; Koskinen, Päivi J.

2015-01-01

Background and methods Pim family proteins are oncogenic kinases implicated in several types of cancer and involved in regulation of cell proliferation, survival as well as motility. Here we have investigated the ability of Pim kinases to promote metastatic growth of prostate cancer cells in two xenograft models for human prostate cancer. We have also evaluated the efficacy of Pim-selective inhibitors to antagonize these effects. Results We show here that tumorigenic growth of both subcutaneously and orthotopically inoculated prostate cancer xenografts is enhanced by stable overexpression of either Pim-1 or Pim-3. Moreover, Pim-overexpressing orthotopic prostate tumors are highly invasive and able to migrate not only to the nearby prostate-draining lymph nodes, but also into the lungs to form metastases. When the xenografted mice are daily treated with the Pim-selective inhibitor DHPCC-9, both the volumes as well as the metastatic capacity of the tumors are drastically decreased. Interestingly, the Pim-promoted metastatic growth of the orthotopic xenografts is associated with enhanced angiogenesis and lymphangiogenesis. Furthermore, forced Pim expression also increases phosphorylation of the CXCR4 chemokine receptor, which may enable the tumor cells to migrate towards tissues such as the lungs that express the CXCL12 chemokine ligand. Conclusions Our results indicate that Pim overexpression enhances the invasive properties of prostate cancer cells in vivo. These effects can be reduced by the Pim-selective inhibitor DHPCC-9, which can reach tumor tissues without serious side effects. Thus, Pim-targeting therapies with DHPCC-9-like compounds may help to prevent progression of local prostate carcinomas to fatally metastatic malignancies. PMID:26075720

Outcomes in Patients with Obstructive Jaundice from Metastatic Colorectal Cancer and Implications for Management

PubMed Central

Nichols, Shawnn D.; Albert, Scott; Shirley, Lawrence; Schmidt, Carl; Abdel-Misih, Sherif; El-Dika, Samer; Groce, J. Royce; Wu, Christina; Goldberg, Richard M.; Bekaii-Saab, Tanios; Bloomston, Mark

2016-01-01

Introduction Patients with metastatic colorectal cancer can develop jaundice from intrahepatic or extrahepatic causes. Currently, there is little data on the underlying causes and overall survival after onset of jaundice. The purpose of this study was to characterize the causes of jaundice and determine outcomes. Methods Six hundred twenty-nine patients treated for metastatic colorectal cancer between 2004 and 2010 were retrospectively reviewed. Those developing jaundice were grouped as having intrahepatic or extrahepatic obstruction. Demographics, clinicopathologic, and outcome data were analyzed. Results Sixty-two patients with metastatic colorectal cancer developed jaundice. Intrahepatic biliary obstruction was most common, occurring in younger patients. Time from metastatic diagnosis to presentation of jaundice was similar between groups, as was the mean number of prior lines of chemotherapy. Biliary decompression was successful 41.7 % of the time and was attempted more commonly for extrahepatic causes. Median overall survival after onset of jaundice was 1.5 months and it was similar between groups, but improved to 9.6 months in patients who were able to receive further chemotherapy. Conclusions Jaundice due to metastatic colorectal cancer is an ominous finding, representing aggressive tumor biology or exhaustion of therapies. Biliary decompression is often difficult and should only be pursued when additional treatment options are available. PMID:25300799

What's New in Bone Cancer Research and Treatment?

MedlinePlus

... Cancer Research? Bone Cancer About Bone Cancer What’s New in Bone Cancer Research? Research on bone cancer ... treat these cancers. Chemotherapy Some studies are testing new chemo drugs. Researchers are also looking for new, ...

Enzalutamide Improves Survival in Patients with Metastatic Prostate Cancer

Cancer.gov

A summary of results from an international phase III trial that compared enzalutamide (Xtandi®) and placebo for the treatment of metastatic prostate cancer that had progressed during treatment with androgen deprivation therapy.

Repeatability of quantitative parameters of 18F-fluoride PET/CT and biochemical tumour and specific bone remodelling markers in prostate cancer bone metastases.

PubMed

Wassberg, Cecilia; Lubberink, Mark; Sörensen, Jens; Johansson, Silvia

2017-12-01

18F-fluoride PET/CT exhibits high sensitivity to delineate and measure the extent of bone metastatic disease in patients with prostate cancer. 18F-fluoride PET/CT could potentially replace traditional bone scintigraphy in clinical routine and trials. However, more studies are needed to assess repeatability and biological uptake variation. The aim of this study was to perform test-retest analysis of quantitative PET-derived parameters and blood/serum bone turnover markers at the same time point. Ten patients with prostate cancer and verified bone metastases were prospectively included. All underwent two serial 18F-fluoride PET/CT at 1 h post-injection. Up to five dominant index lesions and whole-body 18F-fluoride skeletal tumour burden were recorded per patient. Lesion-based PET parameters were SUVmax, SUVmean and functional tumour volume applying a VOI with 50% threshold (FTV 50% ). The total skeletal tumour burden, total lesion 18F-fluoride (TLF), was calculated using a threshold of SUV of ≥15. Blood/serum biochemical bone turnover markers obtained at the time of each PET were PSA, ALP, S-osteocalcin, S-beta-CTx, 1CTP and BAP. A total of 47 index lesions and a range of 2-122 bone metastases per patient were evaluated. Median time between 18F-fluoride PET/CT was 7 days (range 6-8 days). Repeatability coefficients were for SUVmax 26%, SUVmean 24%, FTV 50% for index lesions 23% and total skeletal tumour burden (TLF) 35%. Biochemical bone marker repeatability coefficients were for PSA 19%, ALP 23%, S-osteocalcin 18%, S-beta-CTx 22%, 1CTP 18% and BAP 23%. Quantitative 18F-fluoride uptake and simultaneous biochemical bone markers measurements are reproducible for prostate cancer metastases and show similar magnitude in test-retest variation.

Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential.

PubMed

Coughlin, Mark F; Bielenberg, Diane R; Lenormand, Guillaume; Marinkovic, Marina; Waghorne, Carol G; Zetter, Bruce R; Fredberg, Jeffrey J

2013-03-01

We quantified mechanical properties of cancer cells differing in metastatic potential. These cells included normal and H-ras-transformed NIH3T3 fibroblast cells, normal and oncoprotein-overexpressing MCF10A breast cancer cells, and weakly and strongly metastatic cancer cell line pairs originating from human cancers of the skin (A375P and A375SM cells), kidney (SN12C and SN12PM6 cells), prostate (PC3M and PC3MLN4 cells), and bladder (253J and 253JB5 cells). Using magnetic twisting cytometry, cytoskeletal stiffness (g') and internal friction (g″) were measured over a wide frequency range. The dependencies of g' and g″ upon frequency were used to determine the power law exponent x which is a direct measure of cytoskeletal fluidity and quantifies where the cytoskeleton resides along the spectrum of solid-like (x = 1) to fluid-like (x = 2) states. Cytoskeletal fluidity x increased following transformation by H-ras oncogene expression in NIH3T3 cells, overexpression of ErbB2 and 14-3-3-ζ in MCF10A cells, and implantation and growth of PC3M and 253J cells in the prostate and bladder, respectively. Each of these perturbations that had previously been shown to enhance cancer cell motility and invasion are shown here to shift the cytoskeleton towards a more fluid-like state. In contrast, strongly metastatic A375SM and SN12PM6 cells that disseminate by lodging in the microcirculation of peripheral organs had smaller x than did their weakly metastatic cell line pairs A375P and SN12C, respectively. Thus, enhanced hematological dissemination was associated with decreased x and a shift towards a more solid-like cytoskeleton. Taken together, these results are consistent with the notion that adaptations known to enhance metastatic ability in cancer cell lines define a spectrum of fluid-like versus solid-like states, and the position of the cancer cell within this spectrum may be a determinant of cancer progression.

Survival of metastatic colorectal cancer patients treated with chemotherapy in Alberta (1995-2004).

PubMed

Chen, Yiqun; Qiu, Zhenguo; Kamruzzaman, Anmmd; Snodgrass, Tom; Scarfe, Andrew; Bryant, Heather E

2010-02-01

Clinical trials have suggested that advances in chemotherapy significantly improve the survival of patients with metastatic colorectal cancer. Comparable evidence from clinical practice is scarce. This study aims to investigate the survival of patients with metastatic colorectal cancer treated with chemotherapy in Alberta, Canada. Trends of relative survival of patients diagnosed in 1994-2003 were assessed using Alberta Cancer Registry (ACR) data. The median overall survival (OS) of patients diagnosed in 2004 was determined by linking Cancer Registry data with Electronic Medical Records (EMR). Cox regression models were fitted to calculate the hazard ratio for patients treated with chemotherapy. The 2-year relative survival for patients with metastatic colorectal cancer who received chemotherapy increased significantly from 29% to 41% over the 10 years (1994-2003, p < 0.015). A 69% reduction in the risk of mortality was observed in the 168 patients who received chemotherapy compared to the 87 patients who did not, after adjusting for age, gender, and number of metastases. The median OS of patients who received chemotherapy was 17.5 months. This is comparable to the 18-20 months seen in recently published clinical trials, considering the patients in this study were from the real clinical practice, nearly half of them were older than 70, and many of them might have important co-morbidities. The survival of patients diagnosed with metastatic colorectal cancer in Alberta has improved in recent years; this is most likely attributable in large part to the use of chemotherapy.

TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells.

PubMed

Bartucci, M; Dattilo, R; Moriconi, C; Pagliuca, A; Mottolese, M; Federici, G; Benedetto, A Di; Todaro, M; Stassi, G; Sperati, F; Amabile, M I; Pilozzi, E; Patrizii, M; Biffoni, M; Maugeri-Saccà, M; Piccolo, S; De Maria, R

2015-02-05

Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.

Radium-223 in the treatment of bone metastasis in patients with castration-resistant prostate cancer. Review and procedure.

PubMed

Orcajo-Rincon, J; Caresia-Aróztegui, A P; Del Puig Cózar-Santiago, M; García-Garzón, J R; de Arcocha-Torres, M; Delgado-Bolton, R C; García-Velloso, M J; Alvarez-Ruiz, S; García-Vicente, A M

2018-04-13

Bone metastatic disease is the main cause of morbidity / mortality in patients with prostate cancer, presenting frequently as bone pain, pathological fractures or spinal cord compression, which requires early and timely therapy. Although, for the moment, the therapeutic window for its use has not been definitively established, radium-223 ( 223 Ra), an alpha particle emitter, has proved to be an effective therapeutic tool, pre or post-chemotherapy, in patients with castration-resistant prostate cancer with symptomatic bone metastases and absence of visceral metastases, significantly modifying the prognosis of the disease. It is therefore imperative to define the ideal scenarios and the correct protocol for the use of this therapy and thus offer the greatest possible clinical benefit to the patient. Copyright © 2018 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.

Predicting Survival of De Novo Metastatic Breast Cancer in Asian Women: Systematic Review and Validation Study

PubMed Central

Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G. M.; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M.

2014-01-01

Background In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. Materials and Methods We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). Results We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48–0.53) to 0.63 (95% CI, 0.60–0.66). Conclusion The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making. PMID:24695692

Patient and implant survival following joint replacement because of metastatic bone disease

PubMed Central

2013-01-01

Background Patients suffering from a pathological fracture or painful bony lesion because of metastatic bone disease often benefit from a total joint replacement. However, these are large operations in patients who are often weak. We examined the patient survival and complication rates after total joint replacement as the treatment for bone metastasis or hematological diseases of the extremities. Patients and methods 130 patients (mean age 64 (30–85) years, 76 females) received 140 joint replacements due to skeletal metastases (n = 114) or hematological disease (n = 16) during the period 2003–2008. 21 replaced joints were located in the upper extremities and 119 in the lower extremities. Clinical and survival data were extracted from patient files and various registers. Results The probability of patient survival was 51% (95% CI: 42–59) after 6 months, 39% (CI: 31–48) after 12 months, and 29% (CI: 21–37) after 24 months. The following surgical complications were seen (8 of which led to additional surgery): 2–5 hip dislocations (n = 8), deep infection (n = 3), peroneal palsy (n = 2), a shoulder prosthesis penetrating the skin (n = 1), and disassembly of an elbow prosthesis (n = 1). The probability of avoiding all kinds of surgery related to the implanted prosthesis was 94% (CI: 89–99) after 1 year and 92% (CI: 85–98) after 2 years. Conclusion Joint replacement operations because of metastatic bone disease do not appear to have given a poorer rate of patient survival than other types of surgical treatment, and the reoperation rate was low. PMID:23530874

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.

Ribociclib as First-Line Treatment for Metastatic Breast Cancer

Cancer.gov

A summary of interim results from a phase III trial testing ribociclib plus letrozole (Femara®) as a first-line treatment for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.

Management of locally advanced and metastatic colon cancer in elderly patients.

PubMed

Kurniali, Peter C; Hrinczenko, Borys; Al-Janadi, Anas

2014-02-28

Colon cancer is the second leading cause of cancer mortality in the United States with a median age at diagnosis of 69 years. Sixty percent are diagnosed over the age of 65 years and 36% are 75 years or older. At diagnosis, approximately 58% of patients will have locally advanced and metastatic disease, for which systemic chemotherapy has been shown to improve survival. Treatment of cancer in elderly patients is more challenging due to multiple factors, including disabling co-morbidities as well as a decline in organ function. Cancer treatment of elderly patients is often associated with more toxicities that may lead to frequent hospitalizations. In locally advanced disease, fewer older patients receive adjuvant chemotherapy despite survival benefit and similar toxicity when compared to their younger counterparts. A survival benefit is also observed in the palliative chemotherapy setting for elderly patients with metastatic disease. When treating elderly patients with colon cancer, one has to consider drug pharmacokinetics and pharmacodynamics. Since chronological age is a poor marker of a patient's functional status, several methods of functional assessment including performance status and activities of daily living (ADL) or instrumental ADL, or even a comprehensive geriatric assessment, may be used. There is no ideal chemotherapy regimen that fits all elderly patients and so a regimen needs to be tailored for each individual. Important considerations when treating elderly patients include convenience and tolerability. This review will discuss approaches to the management of elderly patients with locally advanced and metastatic colon cancer.

Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma

ClinicalTrials.gov

2018-06-28

Metastatic Ewing Sarcoma; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Bone Marrow; Metastatic Malignant Neoplasm in the Lung; Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone; Peripheral Primitive Neuroectodermal Tumor of Soft Tissues

Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds.

PubMed

Tungsukruthai, Sucharat; Petpiroon, Nalinrat; Chanvorachote, Pithi

2018-05-01

Throughout the world, breast cancer is among the major causes of cancer-related death and is the most common cancer found in women. The development of cancer molecular knowledge has surpassed the novel concept of cancer biology and unraveled principle targets for anticancer drug developments and treatment strategies. Metastatic breast cancer cells acquire their aggressive features through several mechanisms, including augmentation of survival, proliferation, tumorigenicity, and motility-related cellular pathways. Clearly, natural product-derived compounds have since long been recognized as an important source for anticancer drugs, several of which have been shown to have promising anti-metastasis activities by suppressing key molecular features supporting such cell aggressiveness. This review provides the essential details of breast cancer, the molecular-based insights into metastasis, as well as the effects and mechanisms of potential compounds for breast cancer therapeutic approaches. As the abilities of cancer cells to invade and metastasize are addressed as the hallmarks of cancer, compounds possessing anti-metastatic effects, together with their defined molecular drug action could benefit the development of new drugs as well as treatment strategies. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Combining Src inhibitors and aromatase inhibitors: a novel strategy for overcoming endocrine resistance and bone loss.

PubMed

Hiscox, Stephen; Barrett-Lee, Peter; Borley, Annabel C; Nicholson, Robert I

2010-08-01

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes. Copyright 2010 Elsevier Ltd. All rights reserved.

Impact of Bone-targeted Therapies in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer Patients Treated with Abiraterone Acetate: Post Hoc Analysis of Study COU-AA-302

PubMed Central

Saad, Fred; Shore, Neal; Van Poppel, Hendrik; Rathkopf, Dana E.; Smith, Matthew R.; de Bono, Johann S.; Logothetis, Christopher J.; de Souza, Paul; Fizazi, Karim; Mulders, Peter F.A.; Mainwaring, Paul; Hainsworth, John D.; Beer, Tomasz M.; North, Scott; Fradet, Yves; Griffin, Thomas A.; De Porre, Peter; Londhe, Anil; Kheoh, Thian; Small, Eric J.; Scher, Howard I.; Molina, Arturo; Ryan, Charles J.

2016-01-01

Background Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy. Objective Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients. Design, setting, and participants This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial. Intervention Patients were grouped by concomitant BTT use or no BTT use. Outcome measurements and statistical analysis Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models. Results and limitations While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p = 0.01) and increased the time to ECOG deterioration (HR 0.75; p < 0.001) and time to opiate use for cancer-related pain (HR 0.80; p = 0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients. Conclusions AA with concomitant BTT was safe and well tolerated in men with chemotherapy

[Metastatic breast cancer to the stomach: An uncommon evolution of breast carcinoma].

PubMed

Hild, C; Talha-Vautravers, A; Hoefler, P; Zirabe, S; Bellocq, J-P; Mathelin, C

2014-01-01

Breast carcinoma exceptionally leads to metastatic linitis plastica. Distinguishing a breast cancer metastasis to the stomach from a primary gastric cancer on the basis of clinical and radiological signs is very challenging. Thanks to being cognizant of the previous history of invasive lobular carcinoma and the gastric biopsy followed by immunohistochemical analysis, gastric metastasis can be diagnosed. Despite the use of chemotherapy and hormonal therapy, gastric metastasis remains often associated with poor prognosis. We present a case where gastric biopsy allowed a metastatic breast cancer to the stomach to be diagnosed and we discuss its clinical, diagnostic, pathological and therapeutic particularities. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Cell-Penetrating Peptide-Modified Gold Nanoparticles for the Delivery of Doxorubicin to Brain Metastatic Breast Cancer.

PubMed

Morshed, Ramin A; Muroski, Megan E; Dai, Qing; Wegscheid, Michelle L; Auffinger, Brenda; Yu, Dou; Han, Yu; Zhang, Lingjiao; Wu, Meijing; Cheng, Yu; Lesniak, Maciej S

2016-06-06

As therapies continue to increase the lifespan of patients with breast cancer, the incidence of brain metastases has steadily increased, affecting a significant number of patients with metastatic disease. However, a major barrier toward treating these lesions is the inability of therapeutics to penetrate into the central nervous system and accumulate within intracranial tumor sites. In this study, we designed a cell-penetrating gold nanoparticle platform to increase drug delivery to brain metastatic breast cancer cells. TAT peptide-modified gold nanoparticles carrying doxorubicin led to improved cytotoxicity toward two brain metastatic breast cancer cell lines with a decrease in the IC50 of at least 80% compared to free drug. Intravenous administration of these particles led to extensive accumulation of particles throughout diffuse intracranial metastatic microsatellites with cleaved caspase-3 activity corresponding to tumor foci. Furthermore, intratumoral administration of these particles improved survival in an intracranial MDA-MB-231-Br xenograft mouse model. Our results demonstrate the promising application of gold nanoparticles for improving drug delivery in the context of brain metastatic breast cancer.

Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer.

PubMed

Al Murri, A M; Bartlett, J M S; Canney, P A; Doughty, J C; Wilson, C; McMillan, D C

2006-01-30

Prediction of outcome in patients with metastatic breast cancer remains problematical. The present study evaluated the value of an inflammation-based score (Glasgow Prognostic Score, GPS) in patients with metastatic breast cancer. The GPS was constructed as follows: patients with both an elevated C-reactive protein (>10 mg l(-1)) and hypoalbuminaemia (<35 g l(-1)) were allocated a score of 2. Patients in whom only one or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively. In total, 96 patients were studied. During follow-up 51 patients died of their cancer. On multivariate analysis of the GPS and treatment received, only the GPS (HR 2.26, 95% CI 1.45-3.52, P<0.001) remained significantly associated with cancer-specific survival. The presence of a systemic inflammatory response (the GPS) appears to be a useful indicator of poor outcome independent of treatment in patients with metastatic breast cancer.

Rare expression of high-molecular-weight cytokeratin in adenocarcinoma of the prostate gland: a study of 100 cases of metastatic and locally advanced prostate cancer.

PubMed

Yang, X J; Lecksell, K; Gaudin, P; Epstein, J I

1999-02-01

Immunohistochemistry with antibodies for high-molecular-weight cytokeratin labels basal cells and is used as an ancillary study in diagnosing prostate carcinoma, which reportedly lacks expression of high-molecular-weight cytokeratin. A recent report questioned the specificity of this marker, describing immunopositivity for high-molecular-weight cytokeratin in a small series of metastatic prostate cancer. We have also noted rare cases of prostate lesions on biopsy with typical histological features of adenocarcinoma showing immunopositivity for high-molecular-weight cytokeratin, either in tumor cells or in patchy cells with the morphology of basal cells. In some of these cases, it was difficult to distinguish cancer from out-pouching of high-grade prostatic intraepithelial neoplasia. To investigate whether prostate cancer cells express high-molecular-weight cytokeratin, we studied 100 cases of metastatic prostate carcinoma and 10 cases of prostate cancer invading the seminal vesicles from surgical specimens. Metastatic sites included regional lymph nodes (n = 67), bone (n = 19), and miscellaneous (n = 14). Cases with any positivity for high-molecular-weight cytokeratin antibody (34betaE12) were verified as being of prostatic origin with immunohistochemistry for prostate-specific antigen and prostate-specific acid phosphatase. Only four cases were detected positive for high-molecular-weight cytokeratin. In two cases (one metastasis, one seminal vesicle invasion) there was weakly diffuse positivity above background level. Two metastases in lymph nodes showed scattered strong staining of clusters of tumor cells, which represented <0.2% of tumor cells in the metastatic deposits. These positive cells did not have the morphology of basal cells. We conclude that prostate cancer, even high grade, only rarely expresses high-molecular-weight cytokeratin. This marker remains a very useful adjunct in the diagnosis of prostate cancer.

Sorafenib in Treating Patients With Advanced or Metastatic Cancer of the Urinary Tract

ClinicalTrials.gov

2015-08-04

Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder

Genomic Sequencing in Determining Treatment in Patients With Metastatic Cancer or Cancer That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-01-22

Metastatic Neoplasm; Recurrent Neoplasm; Recurrent Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer; Unresectable Malignant Neoplasm

A case of rectal carcinoma with skin and bone marrow metastasis with concurrent extensive visceral involvement; unusual and dismal co-incidence.

PubMed

Arslan, Cagatay; Sen, Cenk Ahmet; Ortac, Ragip

2015-06-01

Novel systemic therapies and modern surgical and ablative approaches have improved the survival rates for the patients with metastatic colorectal cancer. However, there are still patients with poor prognosis and underlying mechanisms that could not be defined clearly. Metastatic colorectal cancer patients with skin metastasis have a poor prognosis. A 45-year-old man, who presented with large bowel obstruction, was diagnosed with metastatic rectal adenocarcinoma. Unresectable liver metastases were found at diagnosis. FOLFOX plus bevacizumab treatment was started, but the patient developed bowel obstruction after the third cycle. Therefore, ileostomy was performed. Multiple skin, lung, liver and bone metastases appeared during that time. Bone marrow biopsy demonstrated diffuse infiltration by adenocarcinoma cells. Even though partial remission was achieved after 4 cycles of FOLFIRI-cetuximab, the disease progressed after the 8th cycle. The patient lost his life due to disease progression 8 months after the diagnosis. Bone marrow and skin are unusual sites of metastasis for colorectal carcinoma. Metastases in bone marrow and skin develop at later stages of metastatic disease. This patient lived only 4 months after the development of skin and bone marrow metastases. Skin and bone marrow metastases may be the harbingers of short survival. Biopsy of metastatic sites is crucial for diagnosis and detailed molecular analysis. Molecular pathway alterations underlying worse disease course may be found, and hence probable targets for drug improvement may be indicated.

Fasting Enhances the Contrast of Bone Metastatic Lesions in 18F-Fluciclovine-PET: Preclinical Study Using a Rat Model of Mixed Osteolytic/Osteoblastic Bone Metastases

PubMed Central

Oka, Shuntaro; Kanagawa, Masaru; Doi, Yoshihiro; Schuster, David M.; Goodman, Mark M.; Yoshimura, Hirokatsu

2017-01-01

18F-fluciclovine (trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid) is an amino acid positron emission tomography (PET) tracer used for cancer staging (e.g., prostate and breast). Patients scheduled to undergo amino acid-PET are usually required to fast before PET tracer administration. However, there have been no reports addressing whether fasting improves fluciclovine-PET imaging. In this study, the authors investigated the influence of fasting on fluciclovine-PET using triple-tracer autoradiography with 14C-fluciclovine, [5,6-3H]-2-fluoro-2-deoxy-d-glucose (3H-FDG), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) in a rat breast cancer model of mixed osteolytic/osteoblastic bone metastases in which the animals fasted overnight. Lesion accumulation of each tracer was evaluated using the target-to-background (muscle) ratio. The mean ratios of 14C-fluciclovine in osteolytic lesions were 4.6 ± 0.8 and 2.8 ± 0.6, respectively, with and without fasting, while those for 3H-FDG were 6.9 ± 2.5 and 5.1 ± 2.0, respectively. In the peri-tumor bone formation regions (osteoblastic), where 99mTc-HMDP accumulated, the ratios of 14C-fluciclovine were 4.3 ± 1.4 and 2.4 ± 0.7, respectively, and those of 3H-FDG were 6.2 ± 3.8 and 3.3 ± 2.2, respectively, with and without fasting. These results suggest that fasting before 18F-fluciclovine-PET improves the contrast between osteolytic and osteoblastic bone metastatic lesions and background, as well as 18F-FDG-PET. PMID:28468238

Metastatic Breast Cancer in Uterine Cervix: A Rare Presentation.

PubMed

Proença, Sara; Reis, Maria Inês; Cominho, Joana; Conde, Pedro Casado; Santos E Pereira, Helena; Ribeiro, Filipa Castro

2016-01-01

Uterine cervix involvement by a distant primary tumor is a rare event. We report the following 2 cases of breast tumor metastasis to the uterine cervix with different presentations: case 1 is an isolated cervix metastasis and case 2 is a disseminated metastatic disease with cervix involvement. In both, clinical examination raised the suspicion of cervical tumor, which was confirmed to be a metastatic adenocarcinoma.The poor outcome and lack of symptoms suggest that although its rareness, all patients with breast cancer should undergo a careful routine gynecologic examination.

What Is Breast in the Bone?

PubMed

Shemanko, Carrie S; Cong, Yingying; Forsyth, Amanda

2016-10-22

The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%-50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural "recycling" of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle.

Radiation Therapy and MK-3475 for Patients With Recurrent/Metastatic Head and Neck Cancer, Renal Cell Cancer, Melanoma, and Lung Cancer

ClinicalTrials.gov

2017-10-25

Head and Neck Squamous Cell Carcinoma; Metastatic Renal Cell Cancer; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IV Lung Cancer; Stage IV Skin Melanoma

How MMPs Impact Bone Responses to Metastatic Prostate Cancer

DTIC Science & Technology

2009-02-01

STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Using an animal model of prostate tumor...prostate tumor progression in the bone since no difference in osteolytic or osteoblastic responses between wild type and MMP-9 deficient animals were...described as the ‘vicious cycle’ (4). Using an animal model of 4 tumor progression in the bone, we have previously identified a group of enzymes known as

How MMPs Impact Bone Responses to Metastatic Prostate Cancer

DTIC Science & Technology

2010-02-01

13. SUPPLEMENTARY NOTES 14. ABSTRACT Using an animal model of prostate tumor progression in the bone we have previously shown that MMPs...in osteolytic or osteoblastic responses between wild type and MMP-9 deficient animals were detected by Faxitron, CT, SPECT and histomorphometry...as the ‘vicious cycle’ (4). Using an animal model of 2 tumor progression in the bone, we have previously identified a group of enzymes known as

Feature genes in metastatic breast cancer identified by MetaDE and SVM classifier methods.

PubMed

Tuo, Youlin; An, Ning; Zhang, Ming

2018-03-01

The aim of the present study was to investigate the feature genes in metastatic breast cancer samples. A total of 5 expression profiles of metastatic breast cancer samples were downloaded from the Gene Expression Omnibus database, which were then analyzed using the MetaQC and MetaDE packages in R language. The feature genes between metastasis and non‑metastasis samples were screened under the threshold of P<0.05. Based on the protein‑protein interactions (PPIs) in the Biological General Repository for Interaction Datasets, Human Protein Reference Database and Biomolecular Interaction Network Database, the PPI network of the feature genes was constructed. The feature genes identified by topological characteristics were then used for support vector machine (SVM) classifier training and verification. The accuracy of the SVM classifier was then evaluated using another independent dataset from The Cancer Genome Atlas database. Finally, function and pathway enrichment analyses for genes in the SVM classifier were performed. A total of 541 feature genes were identified between metastatic and non‑metastatic samples. The top 10 genes with the highest betweenness centrality values in the PPI network of feature genes were Nuclear RNA Export Factor 1, cyclin‑dependent kinase 2 (CDK2), myelocytomatosis proto‑oncogene protein (MYC), Cullin 5, SHC Adaptor Protein 1, Clathrin heavy chain, Nucleolin, WD repeat domain 1, proteasome 26S subunit non‑ATPase 2 and telomeric repeat binding factor 2. The cyclin‑dependent kinase inhibitor 1A (CDKN1A), E2F transcription factor 1 (E2F1), and MYC interacted with CDK2. The SVM classifier constructed by the top 30 feature genes was able to distinguish metastatic samples from non‑metastatic samples [correct rate, specificity, positive predictive value and negative predictive value >0.89; sensitivity >0.84; area under the receiver operating characteristic curve (AUROC) >0.96]. The verification of the SVM classifier in an

[Advanced and Metastatic Lung Cancer – What is new in the Diagnosis and Therapy?].

PubMed

Rothschild, Sacha I

2015-07-01

Lung cancer is one of the most common types of malignancies worldwide. The majority of patients are diagnosed with an incurable advanced/metastatic stage disease. Palliative treatment approaches improve the survival and the quality of life of these patients. Lung cancer is subdivided according to histology and molecular biology. The most important classification separates small cell from non-small cell lung cancer. In the subgroup of non-small cell lung cancer novel treatment approaches coming along with an improved prognosis have been established during the last decade. The current manuscript provides an overview on current treatment options for metastatic lung cancer. Furthermore, an outlook on promising future treatment options is provided.

Prostate Specific Membrane Antigen (PSMA) Targeted Bio-orthogonal Therapy for Metastatic Prostate Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-16-1-0595 TITLE: Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate Cancer...Sep 2016 - 14 Sep 2017 4. TITLE AND SUBTITLE Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate

Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives

PubMed Central

2014-01-01

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome, and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations, the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future, advances in targeted therapy will depend on the availability of metastatic tissue. PMID:25032257

A Randomized Controlled Trial of Emotionally Expressive Writing for Women With Metastatic Breast Cancer

PubMed Central

Low, Carissa A.; Stanton, Annette L.; Bower, Julienne E.; Gyllenhammer, Lauren

2011-01-01

Objective To test the effects of emotionally expressive writing in a randomized controlled trial of metastatic breast cancer patients and to determine whether effects of the intervention varied as a function of perceived social support or time since metastatic diagnosis. Design Women (N = 62) living with Stage IV breast cancer were randomly assigned to write about cancer-related emotions (EMO; n = 31) or the facts of their diagnosis and treatment (CTL; n = 31). Participants wrote at home for four 20-min sessions within a 3-week interval. Main Outcome Measures Depressive symptoms, cancer-related intrusive thoughts, somatic symptoms, and sleep quality at 3 months postintervention. Results No significant main effects of experimental condition were observed. A significant condition × social support interaction emerged on intrusive thoughts; EMO writing was associated with reduced intrusive thoughts for women reporting low emotional support (η2 = .15). Significant condition × time since metastatic diagnosis interactions were also observed for somatic symptoms and sleep disturbances. Relative to CTL, EMO participants who were more recently diagnosed had fewer somatic symptoms (η2 = .10), whereas EMO participants with longer diagnosis duration exhibited increases in sleep disturbances (η2 = .09). Conclusion Although there was no main effect of expressive writing on health among the current metastatic breast cancer sample, expressive writing may be beneficial for a subset of metastatic patients (including women with low levels of emotional support or who have been recently diagnosed) and contraindicated for others (i.e., those who have been living with the diagnosis for years). PMID:20658835

Gene expression markers in circulating tumor cells may predict bone metastasis and response to hormonal treatment in breast cancer

PubMed Central

WANG, HAIYING; MOLINA, JULIAN; JIANG, JOHN; FERBER, MATTHEW; PRUTHI, SANDHYA; JATKOE, TIMOTHY; DERECHO, CARLO; RAJPUROHIT, YASHODA; ZHENG, JIAN; WANG, YIXIN

2013-01-01

Circulating tumor cells (CTCs) have recently attracted attention due to their potential as prognostic and predictive markers for the clinical management of metastatic breast cancer patients. The isolation of CTCs from patients may enable the molecular characterization of these cells, which may help establish a minimally invasive assay for the prediction of metastasis and further optimization of treatment. Molecular markers of proven clinical value may therefore be useful in predicting disease aggressiveness and response to treatment. In our earlier study, we identified a gene signature in breast cancer that appears to be significantly associated with bone metastasis. Among the genes that constitute this signature, trefoil factor 1 (TFF1) was identified as the most differentially expressed gene associated with bone metastasis. In this study, we investigated 25 candidate gene markers in the CTCs of metastatic breast cancer patients with different metastatic sites. The panel of the 25 markers was investigated in 80 baseline samples (first blood draw of CTCs) and 30 follow-up samples. In addition, 40 healthy blood donors (HBDs) were analyzed as controls. The assay was performed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) with RNA extracted from CTCs captured by the CellSearch system. Our study indicated that 12 of the genes were uniquely expressed in CTCs and 10 were highly expressed in the CTCs obtained from patients compared to those obtained from HBDs. Among these genes, the expression of keratin 19 was highly correlated with the CTC count. The TFF1 expression in CTCs was a strong predictor of bone metastasis and the patients with a high expression of estrogen receptor β in CTCs exhibited a better response to hormonal treatment. Molecular characterization of these genes in CTCs may provide a better understanding of the mechanism underlying tumor metastasis and identify gene markers in CTCs for predicting disease progression and

Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy

PubMed Central

Phoenix, Kathryn N.; Vumbaca, Frank; Fox, Melissa M.; Evans, Rebecca

2010-01-01

Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reduce cancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow-derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events. PMID:20204498

Evaluation of an inflammation-based prognostic score in patients with metastatic renal cancer.

PubMed

Ramsey, Sara; Lamb, Gavin W A; Aitchison, Michael; Graham, John; McMillan, Donald C

2007-01-15

Recently, it was shown that an inflammation-based prognostic score, the Glasgow Prognostic Score (GPS), provides additional prognostic information in patients with advanced cancer. The objective of the current study was to examine the value of the GPS compared with established scoring systems in predicting cancer-specific survival in patients with metastatic renal cancer. One hundred nineteen patients who underwent immunotherapy for metastatic renal cancer were recruited. The Memorial Sloan-Kettering Cancer Center (MSKCC) score and the Metastatic Renal Carcinoma Comprehensive Prognostic System (MRCCPS) score were calculated as described previously. Patients who had both an elevated C-reactive protein level (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a GPS of 2. Patients who had only 1 of those 2 biochemical abnormalities were allocated a GPS of 1. Patients who had neither abnormality were allocated a GPS of 0. On multivariate analysis of significant individual factors, only calcium (hazard ratio [HR], 3.21; 95% confidence interval [95% CI], 1.51-6.83; P = .002), white cell count (HR, 1.66; 95% CI, 1.17-2.35; P = .004), albumin (HR, 2.63; 95% CI, 1.38-5.03; P = .003), and C-reactive protein (HR, 2.85; 95% CI; 1.49-5.45; P = .002) were associated independently with cancer-specific survival. On multivariate analysis of the different scoring systems, the MSKCC (HR, 1.88; 95% CI, 1.22-2.88; P = .004), the MRCCPS (HR, 1.42; 95% CI, 0.97-2.09; P = .071), and the GPS (HR, 2.35; 95% CI, 1.51-3.67; P < .001) were associated independently with cancer-specific survival. An inflammation-based prognostic score (GPS) predicted survival independent of established scoring systems in patients with metastatic renal cancer.

Metastatic gastric carcinoma from breast cancer mimicking primary linitis plastica: A case report.

PubMed

Yagi, Yasumichi; Sasaki, Shozo; Yoshikawa, Akemi; Tsukioka, Yuji; Fukushima, Wataru; Fujimura, Takashi; Hirosawa, Hisashi; Izumi, Ryohei; Saito, Katsuhiko

2015-12-01

Metastases to the gastrointestinal tract rarely occur in breast cancer except in invasive lobular carcinoma. The present study reports a rare case of metastatic gastric cancer from invasive ductal carcinoma (IDC) of the breast mimicking primary gastric linitis plastica. A 51-year-old premenopausal female, who had a history of partial mastectomy for right breast cancer at the age of 40, was referred to Toyama City Hospital (Toyoma, Japan) for an endoscopic diagnosis of gastric linitis plastica. Abdominal computed tomography (CT) revealed left hydronephrosis, while peritoneal metastasis and malignant ascites were not detected. Chest CT detected a left lung tumor, which had invaded the left upper bronchus. Biopsy specimens were obtained and the histopathological findings on both the gastric tumor and lung tumor demonstrated poorly differentiated adenocarcinoma, whereas the histology of the original breast cancer was IDC with a solid-tubular type. Immunohistochemistry revealed that the biopsied specimens of the gastric and lung tumors were positive for estrogen receptor (ER), progesterone receptor (PgR) and negative for human epithelial growth factor receptor-2 (HER2). These molecular characteristics indicated the case was metastatic gastric carcinoma from the breast cancer with lung metastasis, since the statuses of ER, PgR and HER2 were concordant with those of the original breast cancer. However, the possibility of primary gastric cancer could not be completely ruled out. Therefore, a total gastrectomy was performed for the purpose of both diagnosis and treatment. Pathological examination of the resected specimen provided a definite diagnosis of multiple metastatic gastric carcinomas from the breast. To the best of our knowledge, metastatic gastric cancer derived from the breast presenting as linitis plastica 11 years following the surgical removal of IDC has not been described previously.

Diagnostic performance of 11C-choline PET/CT and bone scintigraphy in the detection of bone metastases in patients with prostate cancer.

PubMed

Kitajima, Kazuhiro; Fukushima, Kazuhito; Yamamoto, Shingo; Kato, Takashi; Odawara, Soichi; Takaki, Haruyuki; Fujiwara, Masayuki; Yamakado, Koichiro; Nakanishi, Yukako; Kanematsu, Akihiro; Nojima, Michio; Hirota, Shozo

2017-08-01

The aim of this study was to compare 11C-choline PET/CT and bone scintigraphy (BS) for detection of bone metastases in patients with prostate cancer. Twenty-one patients with histologically proven prostate cancer underwent 11C-choline PET/CT and BS before (n = 4) or after (n = 17) treatment. Patient-, region-, and lesion-based diagnostic performances of bone metastasis of both 11C-choline PET/CT and BS were evaluated using a five-point scale by two experienced readers. Bone metastases were present in 11 (52.4%) of 21 patients and 48 (32.7%) of 147 regions; 111 lesions were found to have bone metastases. Region-based analysis showed that the sensitivity, specificity, accuracy, and area under the receiver-operating-characteristic curves (AUC) of 11C-choline PET/CT were 97.9%, 99.0%, 98.6%, and 0.9989, respectively; those of BS were 72.9%, 99.0%, 90.5%, and 0.8386, respectively. Sensitivity, accuracy, and AUC significantly differed between the two methods (McNemar test, p = 0.0015, p = 0.0015, and p < 0.0001, respectively). 11C-choline PET/CT detected 110/111 metastatic lesions (99.1%); BS detected 85 (76.6%) (p < 0.0001). According to the CT morphological type, the visualization rates of 11C-choline-PET/BS were 100%/90.3% for the blastic type, 91.7%/8.3% for the lytic type, 100%/100% for the mixed type, and 100%/53.3% for the invisible type, respectively. Significant differences in blastic, lytic, and invisible types were observed between the two methods (p = 0.013, p = 0.0044, and p = 0.023, respectively). In conclusion, 11C-choline PET/CT had greater sensitivity and accuracy than BS for detection of bone involvement in patients with prostate cancer.

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

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

PubMed

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

2015-11-04

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.

Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer.

PubMed

Soekmadji, Carolina; Corcoran, Niall M; Oleinikova, Irina; Jovanovic, Lidija; Ramm, Grant A; Nelson, Colleen C; Jenster, Guido; Russell, Pamela J

2017-10-01

The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation. © 2017 Wiley Periodicals, Inc.

The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the “Seed” and the “Soil”?

PubMed Central

Chu, Jenny E.; Allan, Alison L.

2012-01-01

Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic microenvironments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic microenvironments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation. PMID:22295241

ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients.

PubMed

Chu, David; Paoletti, Costanza; Gersch, Christina; VanDenBerg, Dustin A; Zabransky, Daniel J; Cochran, Rory L; Wong, Hong Yuen; Toro, Patricia Valda; Cidado, Justin; Croessmann, Sarah; Erlanger, Bracha; Cravero, Karen; Kyker-Snowman, Kelly; Button, Berry; Parsons, Heather A; Dalton, W Brian; Gillani, Riaz; Medford, Arielle; Aung, Kimberly; Tokudome, Nahomi; Chinnaiyan, Arul M; Schott, Anne; Robinson, Dan; Jacks, Karen S; Lauring, Josh; Hurley, Paula J; Hayes, Daniel F; Rae, James M; Park, Ben Ho

2016-02-15

Mutations in the estrogen receptor (ER)α gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Because of limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from patients with metastatic breast cancer. We retrospectively obtained plasma samples from eight patients with known ESR1 mutations and three patients with wild-type ESR1 identified by next-generation sequencing (NGS) of biopsied metastatic tissues. Three common ESR1 mutations were queried for using droplet digital PCR (ddPCR). In a prospective cohort, metastatic tissue and plasma were collected contemporaneously from eight ER-positive and four ER-negative patients. Tissue biopsies were sequenced by NGS, and ptDNA ESR1 mutations were analyzed by ddPCR. In the retrospective cohort, all corresponding mutations were detected in ptDNA, with two patients harboring additional ESR1 mutations not present in their metastatic tissues. In the prospective cohort, three ER-positive patients did not have adequate tissue for NGS, and no ESR1 mutations were identified in tissue biopsies from the other nine patients. In contrast, ddPCR detected seven ptDNA ESR1 mutations in 6 of 12 patients (50%). We show that ESR1 mutations can occur at a high frequency and suggest that blood can be used to identify additional mutations not found by sequencing of a single metastatic lesion. ©2015 American Association for Cancer Research.

Sorafenib in Treating Patients With Regional or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2014-05-20

Adenocarcinoma of the Bladder; Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Squamous Cell Carcinoma of the Bladder; Stage III Bladder Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

Macrophage Efferocytosis and Prostate Cancer Bone Metastasis

DTIC Science & Technology

2016-10-01

mediator of prostate cancer tumor growth. Specifically, phagocytic macrophages and efferocytosis were found to be upregulated in the blood of...patients with metastatic prostate cancer. Moreover, inhibiting phagocytic macrophages with the chemotherapeutic trabectedin reduced efferocytosis and

Challenging metastatic breast cancer with the natural defensin PvD1.

PubMed

Figueira, Tiago N; Oliveira, Filipa D; Almeida, Inês; Mello, Érica O; Gomes, Valdirene M; Castanho, Miguel A R B; Gaspar, Diana

2017-11-09

Metastatic breast cancer is a very serious life threatening condition that poses many challenges for the pharmaceutical development of effective chemotherapeutics. As the therapeutics targeted to the localized masses in breast improve, metastatic lesions in the brain slowly increase in their incidence compromising successful treatment outcomes overall. The blood-brain-barrier (BBB) is one important obstacle for the management of breast cancer brain metastases. New therapeutic approaches are in demand for overcoming the BBB's breaching by breast tumor cells. In this work we demonstrate the potential dual role of a natural antimicrobial plant defensin, PvD 1 : it interferes with the formation of solid tumors in the breast and concomitantly controls adhesion of breast cancer cells to human brain endothelial cells. We have used a combination of techniques that probe PvD 1 's effect at the single cell level and reveal that this peptide can effectively damage breast tumor cells, leaving healthy breast and brain cells unaffected. Results suggest that PvD1 quickly internalizes in cancer cells but remains located in the membrane of normal cells with no significant damage to its structure and biomechanical properties. These interactions in turn modulate cell adhesiveness between tumor and BBB cells. PvD 1 is a potential template for the design of innovative pharmacological approaches for metastatic breast cancer treatment: the manipulation of the biomechanical properties of tumor cells that ultimately prevent their attachment to the BBB.

Hypnotizability, posttraumatic stress, and depressive symptoms in metastatic breast cancer.

PubMed

Keuroghlian, Alex S; Butler, Lisa D; Neri, Eric; Spiegel, David

2010-01-01

This study assessed whether high hypnotizability is associated with posttraumatic stress and depressive symptoms in a sample of 124 metastatic breast cancer patients. Hypnotic Induction Profile Scores were dichotomized into low and high categories; posttraumatic intrusion and avoidance symptoms were measured with the Impact of Events Scale (IES); hyperarousal symptoms with items from the Profile of Mood States; and depressive symptoms with the Center for Epidemiologic Studies-Depression Scale. High hypnotizability was significantly related to greater IES total, IES intrusion symptoms, and depressive symptoms. A logistic regression model showed that IES total predicts high hypnotizability after adjusting for depressive symptoms and hyperarousal. The authors relate these results to findings in other clinical populations and discuss implications for the psychosocial treatment of metastatic breast cancer.

Osthole inhibits bone metastasis of breast cancer

PubMed Central

Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

2017-01-01

Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-β/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases. PMID:28938572

Increasing Receipt of High-Tech/High-Cost Imaging and Its Determinants in the Last Month of Taiwanese Patients With Metastatic Cancer, 2001–2010

PubMed Central

Liu, Tsang-Wu; Hung, Yen-Ni; Soong, Thomas C.; Tang, Siew Tzuh

2015-01-01

Abstract One strategy for controlling the skyrocketing costs of cancer care may be to target high-tech/high-cost imaging at the end of life (EOL). This population-based study investigated receipt of high-tech/high-cost imaging and its determinants for Taiwanese patients with metastatic cancer in their last month of life. Individual patient-level data were linked with encrypted identification numbers from computerized administrative data in Taiwan, that is, the National Register of Deaths Database, Cancer Registration System database, and National Health Insurance claims datasets, Database of Medical Care Institutions Status, and national census statistics (population/household income). We identified receipt of computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and radionuclide bone scans (BSs) for 236,911 Taiwanese cancer decedents with metastatic disease, 2001 to 2010. Associations of patient, physician, hospital, and regional factors with receiving CT, MRI, and bone scan in the last month of life were evaluated by multilevel generalized linear-mixed models. Over one-third (average [range]: 36.11% [33.07%–37.31%]) of patients with metastatic cancer received at least 1 high-tech/high-cost imaging modality in their last month (usage rates for CT, MRI, PET, and BS were 31.05%, 5.81%, 0.25%, and 8.15%, respectively). In 2001 to 2010, trends of receipt increased for CT (27.96–32.22%), MRI (4.34–6.70%), and PET (0.00–0.62%), but decreased for BS (9.47–6.57%). Facilitative determinants with consistent trends for at least 2 high-tech/high-cost imaging modalities were male gender, younger age, married, rural residence, lung cancer diagnosis, dying within 1 to 2 years of diagnosis, not under medical oncology care, and receiving care at a teaching hospital with a larger volume of terminally ill cancer patients and greater EOL care intensity. Undergoing high-tech/high-cost imaging at EOL generally was not associated

EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides.

PubMed

Handkiewicz-Junak, Daria; Poeppel, Thorsten D; Bodei, Lisa; Aktolun, Cumali; Ezziddin, Samer; Giammarile, Francesco; Delgado-Bolton, Roberto C; Gabriel, Michael

2018-05-01

The skeleton is the most common metastatic site in patients with advanced cancer. Pain is a major healthcare problem in patients with bone metastases. Bone-seeking radionuclides that selectively accumulate in the bone are used to treat cancer-induced bone pain and to prolong survival in selected groups of cancer patients. The goals of these guidelines are to assist nuclear medicine practitioners in: (a) evaluating patients who might be candidates for radionuclide treatment of bone metastases using beta-emitting radionuclides such as strontium-89 ( 89 Sr), samarium-153 ( 153 Sm) lexidronam ( 153 Sm-EDTMP), and phosphorus-32 ( 32 P) sodium phosphate; (b) performing the treatments; and ©) understanding and evaluating the treatment outcome and side effects.

Wnt Signaling in Prostate Cancer Bone Metastases

DTIC Science & Technology

2015-09-01

Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Ace-1-Dkk-1, a canine prostate cancer overexpressing Dkk-1 is used in this study to investigate how...Dkk-1 expression in prostate cancer could change the metastatic phenotype and tumor growth in vivo. Ace-1-Dkk-1, a canine prostate cancer

Cancer stem cells with increased metastatic potential as a therapeutic target for esophageal cancer.

PubMed

Wang, D; Plukker, J Th M; Coppes, R P

2017-06-01

Esophageal cancers (EC) are highly aggressive tumors, commonly presented in a locally advanced stage with a poor prognosis and survival. Up to 50% of the patients are eligible for treatment with curative intent and receive the standard treatment with neoadjuvant chemoradiotherapy (nCRT) and surgery. Currently, pathologic complete response to nCRT is 20-30%, with a partial or no response in about 50% and 20%, respectively. EC recurrences occur frequently even after successful anti-cancer treatment, suggesting high aggressiveness with increased metastatic potential. A tumor sub-population of so-called cancer stem cells (CSCs), is known to display a high metastatic potential and resistance to conventional anti-cancer therapy, hereby being responsible for the unbeneficial clinical features. In this review, a concise overview will be given of the current literature on esophageal CSCs and related metastases. Esophageal CSC markers will be discussed followed by the pathways that initiate and sustain these cells. In addition, the cellular processes, epithelial-mesenchymal transition (EMT), hypoxia and autophagy, known to contribute to cancer stemness and metastasis will be explained. Finally, potential options for treatment also related to cancer genome atlas (TCGA) data on EC will be discussed. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Local control of metastatic lung tumors treated with SBRT of 48 Gy in four fractions: in comparison with primary lung cancer.

PubMed

Hamamoto, Yasushi; Kataoka, Masaaki; Yamashita, Motohiro; Shinkai, Tetsu; Kubo, Yoshiro; Sugawara, Yoshifumi; Inoue, Takeshi; Sakai, Shinya; Aono, Shoji; Takahashi, Tadaaki; Semba, Takatoshi; Uwatsu, Kotaro

2010-02-01

The optimal dose of stereotactic body radiotherapy (SBRT) for metastatic lung tumors has not been clarified. Local control rates of metastatic lung tumors treated with SBRT of 48 Gy in four fractions, which is one of the common dose schedules for Stage I primary lung cancer in Japan, were examined. Between 2006 and 2008, 12 metastatic lung tumors (colorectal cancer, 7; others, 5) in 10 patients and 56 lesions of Stage I primary lung cancer (T1, 43; T2, 13) in 52 patients were treated with SBRT of 48 Gy in four fractions at the isocenter. Two-year overall survival rates were 86% for patients with metastatic lung tumors and 96% for patients with Stage I primary lung cancer (P = 0.4773). One- and 2-year local control rates were 48% and 25% for metastatic lung tumors, and 91% and 88% for Stage I primary lung cancer, respectively (P < 0.0001). The local control rates after SBRT of 48 Gy in four fractions were significantly worse in metastatic lung tumors compared with Stage I primary lung cancer. In SBRT, metastatic lung tumors should be clearly differentiated from primary lung cancer and should be given higher doses.

Travel distance and use of salvage palliative chemotherapy in patients with metastatic colorectal cancer.

PubMed

Ahmed, Shahid; Iqbal, Mahjabeen; Le, Duc; Iqbal, Nayyer; Pahwa, Punam

2018-04-01

Salvage palliative chemotherapy in metastatic colorectal cancer has been associated with significant improvement in survival. However, not all patients receive all available therapies. Travel burden can affect patient access and use of future therapy. The present study aims to determine relationship between travel distance (TD) and salvage palliative chemotherapy in patients with metastatic colorectal cancer. A patient cohort diagnosed with metastatic colorectal cancer during 2006-2010 in the province of Saskatchewan, Canada was studied. Logistic regression analyses were performed to assess relationship between travel distance and subsequent line therapies. The median age of 264 eligible patients was 62 years [interquartile range (IQR): 53-72]. The patients who received salvage systemic therapy had a median distance to travel of 60.0 km (IQR: 4.7-144) compared with 88.1 km (IQR: 4.8-189) if they did not receive second- or third-line therapy (P=0.06). In multivariate analysis distance to the cancer center <100 km, odds ratio (OR) 1.69 (95% CI: 1.003-2.84), no metastasectomy, OR 1.89 (95% CI: 1.03-3.46), and absence of comorbid illness as per Charlson comorbid index, OR 1.45 (95% CI: 1.19-1.77) were correlated with the use of second- and subsequent line therapies. Our result revealed that travel distance to the cancer center greater than 100 km was associated less frequent use of second or subsequent line therapies in patients with metastatic colorectal cancer.

Paget's disease of bone resembling bone metastasis from gastric cancer.

PubMed

Shimoyama, Yasuyuki; Kusano, Motoyasu; Shimoda, Yoko; Ishihara, Shingo; Toyomasu, Yoshitaka; Ohno, Tetsuro; Mochiki, Erito; Sano, Takaaki; Hirato, Junko; Mori, Masatomo

2011-08-01

A 74-year-old man had an endoscopic type 0'-IIc tumor in the upper gastric body on the greater curvature and biopsy showed the tumor to be a well-differentiated adenocarcinoma (Group 5). He was referred to us for endoscopic submucosal dissection (ESD). Endoscopy revealed fold convergency, fold swelling, and fusion of the fold, indicating tumor invasion into the submucosa, which was outside the indications for ESD. In addition, there was an increase of serum bone-type alkaline phosphatase (ALP-III and ALP-IV) and urinary cross-linked N-terminal telopeptide of type I collagen (a bone metabolism marker), while (18)F-fluorodeoxyglucose positron emission tomography showed increased uptake in the left pelvis and Th10, suggesting bone metastases. We first diagnosed gastric cancer with bone metastases; however, the symptoms suggested pathological bone fracture and no bone pain. Therefore, a computed tomography-guided aspiration bone biopsy was performed to exclude the possibility of Paget's disease of bone. Biopsy specimens revealed no tumor and a mosaic pattern. No increased uptake of (18)F-FAMT (L-[3-(18)F] α-methyltyrosine) supported a diagnosis of no bone metastases from gastric cancer. We finally diagnosed gastric cancer accompanied by Paget's disease of bone and performed a laparoscopy-assisted proximal gastrectomy. The pathological diagnosis was U less 0-IIb, and U post 0-IIc ypT1a (M) N0H0P0M0 yp stage IA. In gastric cancer patients with suspected bone metastasis, we also need to consider Paget's disease of bone.

Occurrence and outcome of de novo metastatic breast cancer by subtype in a large, diverse population.

PubMed

Tao, Li; Chu, Laura; Wang, Lisa I; Moy, Lisa; Brammer, Melissa; Song, Chunyan; Green, Marjorie; Kurian, Allison W; Gomez, Scarlett L; Clarke, Christina A

2016-09-01

To examine the occurrence and outcomes of de novo metastatic (Stage IV) breast cancer, particularly with respect to tumor HER2 expression. We studied all 6,268 de novo metastatic breast cancer cases diagnosed from 1 January 2005 to 31 December 2011 and reported to the California Cancer Registry. Molecular subtypes were classified according to HER2 and hormone receptor (HR, including estrogen and/or progesterone receptor) expression. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) of Stage IV versus Stage I-III breast cancer; Cox proportional hazards regression was used to assess relative hazard (RH) of mortality. Five percent of invasive breast cancer was metastatic at diagnosis. Compared to patients with earlier stage disease, patients with de novo metastatic disease were significantly more likely to have HER2+ tumors (HR+/HER2+: OR 1.29, 95 % CI 1.17-1.42; HR-/HER2+: OR 1.40, 95 %CI 1.25-1.57, vs. HR+/HER2-). Median survival improved over time, but varied substantially across race/ethnicity (Asians: 34 months; African Americans: 6 months), neighborhood socioeconomic status (SES) (highest: 34 months, lowest: 20 months), and molecular subtype (HR+/HER2+: 45 months; triple negative: 12 months). In a multivariable model, triple negative (RH 2.85, 95 % CI 2.50-3.24) and HR-/HER2+ (RH 1.60, 95 % CI 1.37-1.87) had worse, while HR+/HER2+ had similar, risk of all-cause death compared to HR+/HER2- breast cancer. De novo metastatic breast cancer was more likely to be HER2+. Among metastatic tumors, those that were HER2+ had better survival than other subtypes.

A comparison of bone-related biomarkers and CA27.29 to assess response to treatment of osseous metastatic breast cancer.

PubMed

Lüfter, D; Richter, A; Günther, S; Flath, B; Akrivakis, C; Geppert, R; Wernecke, K D; Possinger, K

2000-01-01

The assessment of bone metastases by clinical examination or imaging techniques is still considered unreliable. We compared a specific marker of bone resorption, urinary deoxypyridinoline (DPD)-crosslinks, with serum calcium (Ca), alkaline phosphatase (AP) and CA27.29, to evaluate the status of bone metastases in patients with breast cancer. Second morning voided urine was collected from 2 groups of patient (pts), those without evidence of disease (n = 118), and those with bone metastases (n = 85) under specific therapy plus pamidronate. DPD and CA27.29 were measured on the automated ACS180 system (Bayer Diagnostics, Tarrytown, NY, USA). Receiver operating characteristics (ROC) curves were established for each of the 4 biomarkers to determine whether they could distinguish the 2 subsets of pts with clinically sufficient validity, and to establish the corresponding cut-off values. Neither Ca nor AP was useful in discriminating the 2 subgroups. At a DPD cut-off of 13 nmol/mmol, we found a specificity of 69% and a sensitivity of 53% for diagnosing bone metastases. Best results, however, were seen for CA27.29. A cut-off value of 30 U/ml resulted in a specificity of 62% and a sensitivity of 81%. CA27.29 was the best parameter for the discrimination of stage IV breast cancer with bone metastases. The primary advantage of DPD lies in the monitoring of bone metastases under specific therapy.

Expression of potential target antigens for immunotherapy on primary and metastatic prostate cancers.

PubMed

Zhang, S; Zhang, H S; Reuter, V E; Slovin, S F; Scher, H I; Livingston, P O

1998-02-01

Defining the expression of tumor-associated antigens on primary and metastatic prostate cancer is the crucial first step in selecting appropriate targets for immune attack. In this study, the distribution of the tumor-associated antigens GM2, Tn, sTn, Thompson-Friedenreich antigen (TF), Globo H, Le(y), MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC7, carcinoembryonic antigen, beta chain of human chorionic gonadotropin (hCG beta), HER2/neu, PSMA, and KSA on primary and metastatic prostate cancer and 16 types of normal tissues was compared by immunohistochemistry, using a panel of well-characterized monoclonal antibodies. Our results show that GM2, KSA, and MUC2 were strongly expressed on 8 or 9 of 9 metastatic prostate cancer biopsy specimens and, with PSMA, hCG beta, TF, Tn, and sTn, on 8 or more of 11 primary prostate cancer specimens. Tn, MUC1, and PSMA were expressed on 4-6 of 9 metastatic specimens. The remaining antigens were expressed on no more than three of nine metastatic specimens. Normal tissues were also tested with all antibodies. With regard to the eight antigens most widely expressed on prostate cancers, PSMA was not expressed significantly on any of the normal tissues except prostate epithelium. Tn, sTn, hCG beta, and MUC2 were detected on up to 3 of 10 types of normal epithelia. GM2, TF, MUC1, and KSA were more broadly distributed on normal epithelia, all primarily at the secretory borders. STn, KSA, and hCG beta were also detected in the testis, and GM2 was expressed on gray matter of brain. From the 30 antigens that we have screened, this study provides the basis for selecting GM2, TF, Tn, sTn, hCG beta, MUC1, MUC2, KSA, and PSMA as target antigens for specific immunotherapy of prostate cancer.

Vectors for Treatment of Metastatic Breast Cancer

DTIC Science & Technology

2005-08-01

from human carcinomas of the breast, ovary and mouse breast cancer. In this study, in vitro cytotoxicity tests were carried out with the replication...injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas . J...see Figure IC) in carcinomas of the breast, lung, prostate, ovary, cervix, endometrium, esophagous, stomach and colon is associated with metastasis

Effects of tamoxifen on bone mineral density and metabolism in postmenopausal women with early-stage breast cancer.

PubMed

Zidan, Jamal; Keidar, Zohar; Basher, Walid; Israel, Ora

2004-01-01

At the present time, tamoxifen is the most widely used anti-estrogen for adjuvant therapy and metastatic disease in postmenopausal women with breast cancer, a population at high risk for osteoporosis. This prospective study was designed to evaluate the effect of adjuvant tamoxifen on bone mineral density and all biochemical markers concomitantly in women with early-stage breast cancer in one study. Using dual-energy X-ray absorptiometry, prior to and 12 mo after tamoxifen treatment, bone mineral density in lumbar spine and femoral neck was measured in 44 women with T1-T2N0M0 estrogen-receptor-positive breast cancer receiving adjuvant treatment with tamoxifen 20 mg/d. Biomarkers that can affect bone mineral metabolism were measured before and after 3 and 12 mo of tamoxifen treatment. Bone mineral density was minimally increased in lumbar spine and femoral neck after 12 mo treatment with tamoxifen (p = 0.79 and 0.55, respectively). No differences were found in serum levels of calcium, phosphate, creatinine, ALAT, albumin, LDH, calcitonin, or estradiol. A significant decrease in osteocalcin levels was found after 3 and 12 mo (p < or = 0.01). TSH and PTH levels were increased (p < or = 0.05) after 3 mo, returning to baseline after 12 mo. In conclusion, tamoxifen has an estrogen-like effect on bone metabolism in postmenopausal women and is associated with preservation of bone mineral density in lumbar spine and femoral neck. Changes in serum concentration of biochemical markers may reflect decreased bone turnover or bone remodeling and add to the understanding of tamoxifen's effect on bone mineral density.

Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer.

PubMed

Tania, Mousumi; Khan, Md Asaduzzaman; Fu, Junjiang

2014-08-01

The epithelial to mesenchymal transition (EMT) is an important step for the developmental process. Recent evidences support that EMT allows the tumor cells to acquire invasive properties and to develop metastatic growth characteristics. Some of the transcription factors, which are actively involved in EMT process, have a significant role in the EMT-metastasis linkage. A number of studies have reported that EMT-inducing transcription factors (EMT-TFs), such as Twist, Snail, Slug, and Zeb, are directly or indirectly involved in cancer cell metastasis through a different signaling cascades, including the Akt, signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK) and Wnt pathways, with the ultimate consequence of the downregulation of E-cadherin and upregulation of metastatic proteins, such as N-cadherin, vimentin, matrix metalloproteinase (MMP)-2, etc. This review summarizes the update information on the association of EMT-TFs with cancer metastasis and the possible cancer therapeutics via targeting the EMT-TFs.

Enzalutamide in metastatic prostate cancer before chemotherapy.

PubMed

Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana E; Loriot, Yohann; Sternberg, Cora N; Higano, Celestia S; Iversen, Peter; Bhattacharya, Suman; Carles, Joan; Chowdhury, Simon; Davis, Ian D; de Bono, Johann S; Evans, Christopher P; Fizazi, Karim; Joshua, Anthony M; Kim, Choung-Soo; Kimura, Go; Mainwaring, Paul; Mansbach, Harry; Miller, Kurt; Noonberg, Sarah B; Perabo, Frank; Phung, De; Saad, Fred; Scher, Howard I; Taplin, Mary-Ellen; Venner, Peter M; Tombal, Bertrand

2014-07-31

Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy

Imaging Nuclear-Cytoplasmic Dynamics in Primary and Metastatic Colon Cancer in Nude Mice.

PubMed

Hasegawa, Kosuke; Suetsugu, Atsushi; Nakamura, Miki; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Bouvet, Michael; Shimizu, Masahito; Hoffman, Robert M

2016-05-01

Colon cancer frequently results in metastasis to the liver, where it becomes the main cause of death. However, the cell cycle in primary tumors and metastases is poorly understood. We developed a mouse model of liver metastasis using the human colon cancer cell line HCT-116, which expresses green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm (HCT-116-GFP-RFP). HCT-116 GFP-RFP cells were injected into the spleen of nu/nu nude mice. HCT-116-GFP-RFP cells subsequently formed primary tumors in the spleen, as well as metastatic colonies in the liver and retroperitoneum by 28 days after cell transplantation. Using an Olympus FV1000 confocal microscope, it was possible to clearly image mitosis of the dual-colored colon cancer cells in the primary tumor as well as liver and other metastases. Multi-nucleate cancer cells, in addition to mono-nucleate cancer cells and their mitosis, were observed in the primary tumor and metastasis. Multi-nucleate HCT-116-GFP-RFP cells were also observed after culture of the primary and metastatic tumors. A similar ratio of mono-nucleate, multi-nucleate, and mitotic cells grew from the primary and metastatic tumors in culture, suggesting similarity of the nuclear-cytoplasmic dynamics of primary and metastatic cancer cells, further emphasizing the stochastic nature of metastasis. Our results demonstrate a similar heterogeneity of nuclear-cytoplasmic dynamics within primary tumors and metastases, which may be an important factor in the stochastic nature of metastasis. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Metastatic cancer stem cells: from the concept to therapeutics.

PubMed

Liao, Wen-Ting; Ye, Ya-Ping; Deng, Yong-Jian; Bian, Xiu-Wu; Ding, Yan-Qing

2014-01-01

Metastatic cancer stem cells (MCSCs) refer to a subpopulation of cancer cells with both stem cell properties and invasion capabilities that contribute to cancer metastasis. MCSCs have capability of self-renewal, potentials of multiple differentiation and development and/or reconstruction of cancer tissues. As compared with stationary cancer stem cells, MCSCs are capable of invasion to normal tissues such as vasculatures, resistance to chemo- and/or radio-therapies, escape from immune surveillance, survival in circulation and formation of metastasis. MCSCs are derived from invasive cancer stem cells (iCSCs) due to the plasticity of cancer stem cells, which is one of the characteristics of cancer cell heterogeneity. Both stages of iCSCs and MSCSs are the potential therapeutic targets for cancer metastasis in the future strategies of personalized cancer therapy.

Vorinostat in Treating Patients With Locally Recurrent or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2015-01-28

Localized Transitional Cell Cancer of the Renal Pelvis and Ureter; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Transitional Cell Carcinoma of the Bladder

Is Prophylactic Intervention More Cost-effective Than the Treatment of Pathologic Fractures in Metastatic Bone Disease?

PubMed

Blank, Alan T; Lerman, Daniel M; Patel, Neeraj M; Rapp, Timothy B

2016-07-01

Metastatic bone disease is a substantial burden to patients and the healthcare system as a whole. Metastatic disease can be painful, is associated with decreased survival, and is emotionally traumatic to patients when they discover their disease has progressed. In the United States, more than 250,000 patients have metastatic bone disease, with an estimated annual cost of USD 12 billion. Prior studies suggest that patients who receive prophylactic fixation for impending pathologic fractures, compared with those treated for realized pathologic fractures, have decreased pain levels, faster postoperative rehabilitation, and less in-hospital morbidity. However, to our knowledge, the relative economic utility of these treatment options has not been examined. We asked: (1) Is there a cost difference between a cohort of patients treated surgically for pathologic fractures compared with a cohort of patients treated prophylactically for impending pathologic lesions? (2) Do these cohorts differ in other ways regarding their utilization of healthcare resources? We performed a retrospective study of 40 patients treated our institution. Between 2011 and 2014, we treated 46 patients surgically for metastatic lesions of long bones. Of those, 19 (48%) presented with pathologic fractures; the other 21 patients (53%) underwent surgery for impending fractures. Risk of impending fracture was determined by one surgeon based on appearance of the lesion, subjective symptoms of the patient, cortical involvement, and location of the lesion. At 1 year postoperative, four patients in each group had died. Six patients (13%) were treated for metastatic disease but were excluded from the retrospective data because of a change in medical record system and inability to obtain financial records. Variables of interest included total and direct costs per episode of care, days of hospitalization, discharge disposition, 1-year postoperative mortality, and descriptive demographic data. All costs were

In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.

PubMed

Lobbezoo, D J A; van Kampen, R J W; Voogd, A C; Dercksen, M W; van den Berkmortel, F; Smilde, T J; van de Wouw, A J; Peters, F P J; van Riel, J M G H; Peters, N A J B; de Boer, M; Peer, P G M; Tjan-Heijnen, V C G

2016-02-01

The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Bone microenvironment-mediated resistance of cancer cells to bisphosphonates and impact on bone osteocytes/stem cells.

PubMed

Alasmari, Abeer; Lin, Shih-Chun; Dibart, Serge; Salih, Erdjan

2016-08-01

Anti-resorptive bisphosphonates (BPs) have been clinically used to prevent cancer-bone metastasis and cancer-induced bone pathologies despite the fact that the phenotypic response of the cancer-bone interactions to BP exposure is "uncharted territory". This study offers unique insights into the interplay between cancer stem cells and osteocytes/osteoblasts and mesenchymal stem cells using a three-dimensional (3D) live cancer-bone interactive model. We provide extraordinary cryptic details of the biological events that occur as a result of alendronate (ALN) treatment using 3D live cancer-bone model systems under specific bone remodeling stages. While cancer cells are susceptible to BP treatment in the absence of bone, they are totally unaffected in the presence of bone. Cancer cells colonize live bone irrespective of whether the bone is committed to bone resorption or formation and hence, cancer-bone metastasis/interactions are though to be "independent of bone remodeling stages". In our 3D live bone model systems, ALN inhibited bone resorption at the osteoclast differentiation level through effects of mineral-bound ALN on osteocytes and osteoblasts. The mineral-bound ALN rendered bone incapable of osteoblast differentiation, while cancer cells colonize the bone with striking morphological adaptations which led to a conclusion that a direct anti-cancer effect of BPs in a "live or in vivo" bone microenvironment is implausible. The above studies were complemented with mass spectrometric analysis of the media from cancer-bone organ cultures in the absence and presence of ALN. The mineral-bound ALN impacts the bone organs by limiting transformation of mesenchymal stem cells to osteoblasts and leads to diminished endosteal cell population and degenerated osteocytes within the mineralized bone matrix.

Therapeutic Angiotensin-(1-7) in Treating Patients With Metastatic Sarcoma That Cannot Be Removed By Surgery

ClinicalTrials.gov

2018-02-27

Bone Cancer; Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Osteosarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone.

PubMed

Roca, Hernan; Jones, Jacqueline D; Purica, Marta C; Weidner, Savannah; Koh, Amy J; Kuo, Robert; Wilkinson, John E; Wang, Yugang; Daignault-Newton, Stephanie; Pienta, Kenneth J; Morgan, Todd M; Keller, Evan T; Nör, Jacques E; Shea, Lonnie D; McCauley, Laurie K

2018-01-02

During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-κB(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5-mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics.

Oncology Nursing Support for Safe and Effective Use of Eribulin in Metastatic Breast Cancer

PubMed Central

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

A novel framework for the temporal analysis of bone mineral density in metastatic lesions using CT images of the femur

NASA Astrophysics Data System (ADS)

Knoop, Tom H.; Derikx, Loes C.; Verdonschot, Nico; Slump, Cornelis H.

2015-03-01

In the progressive stages of cancer, metastatic lesions in often develop in the femur. The accompanying pain and risk of fracture dramatically affect the quality of life of the patient. Radiotherapy is often administered as palliative treatment to relieve pain and restore the bone around the lesion. It is thought to affect the bone mineralization of the treated region, but the quantitative relation between radiation dose and femur remineralization remains unclear. A new framework for the longitudinal analysis of CT-scans of patients receiving radiotherapy is presented to investigate this relationship. The implemented framework is capable of automatic calibration of Hounsfield Units to calcium equivalent values and the estimation of a prediction interval per scan. Other features of the framework are temporal registration of femurs using elastix, transformation of arbitrary Regions Of Interests (ROI), and extraction of metrics for analysis. Build in Matlab, the modular approach aids easy adaptation to the pertinent questions in the explorative phase of the research. For validation purposes, an in-vitro model consisting of a human cadaver femur with a milled hole in the intertrochanteric region was used, representing a femur with a metastatic lesion. The hole was incrementally stacked with plates of PMMA bone cement with variable radiopaqueness. Using a Kolmogorov-Smirnov (KS) test, changes in density distribution due to an increase of the calcium concentration could be discriminated. In a 21 cm3 ROI, changes in 8% of the volume from 888 ± 57mg • ml-1 to 1000 ± 80mg • ml-1 could be statistically proven using the proposed framework. In conclusion, the newly developed framework proved to be a useful and flexible tool for the analysis of longitudinal CT data.

Metastatic Bone Pain Palliation using (177)Lu-Ethylenediaminetetramethylene Phosphonic Acid.

PubMed