Metastatic Resistant Prostate Cancer Research Articles

Isolation and genomic analysis of circulating tumor cells from castration resistant metastatic prostate cancer

BackgroundThe number of circulating tumor cells (CTCs) in metastatic prostate cancer patients provides prognostic and predictive information. However, it is the molecular characterization of CTCs that offers insight into the biology of these tumor cells in the context of personalized treatment.MethodsWe developed a novel approach to isolate CTCs away from hematopoietic cells with high purity, enabling genomic analysis of these cells. The isolation protocol involves immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS). To evaluate the feasibility of isolation of CTCs by IE/FACS and downstream genomic profiling, we conducted a pilot study in patients with metastatic castration resistant prostate cancer (CRPC). Twenty (20) sequential CRPC patients were assayed using CellSearch™. Twelve (12) patients positive for CTCs were subjected to immunomagnetic enrichment and fluorescence activated cell sorting (IE/FACS) to isolate CTCs. Genomic DNA of CTCs was subjected to whole genome amplification (WGA) followed by gene copy number analysis via array comparative genomic hybridization (aCGH).ResultsCTCs from nine (9) patients successfully profiled were observed to have multiple copy number aberrations including those previously reported in primary prostate tumors such as gains in 8q and losses in 8p. High-level copy number gains at the androgen receptor (AR) locus were observed in 7 (78%) cases. Comparison of genomic profiles between CTCs and archival primary tumors from the same patients revealed common lineage. However, high-level copy number gains in the AR locus were observed in CTCs, but not in the matched archival primary tumors.ConclusionsWe developed a new approach to isolate prostate CTCs without significant leukocyte admixture, and to subject them to genome-wide copy number analysis. Our assay may be utilized to explore genomic events involved in cancer progression, e.g. development of castration resistance and to monitor therapeutic efficacy of targeted therapies in clinical trials in a relatively non-invasive manner.

Castrate Resistant Metastatic Prostate Cancer: Options for a Patient in 2012

Castrate resistant metastatic prostate cancer remains a fatal disease. Through preclinical studies and clinical trials, a multitude of options have been made available to prolong the life of these patients, as well as improve quality of life. First line treatment options following tumor progression after androgen deprivation therapy include Provenge and docetaxel. Several options are available as second line treatment, including cabazitaxel, abiraterone, and enzalutamide. Many drugs currently being studied are very promising, such as alpharadin. Here we review treatment options for patients suffering from disease progression after androgen deprivation therapy, and offer a review of the current available options for the clinician.

Efficacy and toxicity of docetaxel in elderly men with castrate-resistant metastatic prostate cancer.

4687 Background: Docetaxel is currently the standard cytotoxic therapy for patients (pts) with castrate resistant metastatic prostate cancer. As the number of very elderly men in the population ris...

Does Ethnicity Influence Response To Docetaxel Based-Chemotherapy For Patients With Castration Resistant Prostate Cancer? The New Mexico Perspective.

INTRODUCTION: Metastatic prostate cancer is lethal in 15 % of the patients. Ethnic variations in response to docetaxel in patients with metastatic prostate cancer have not been studied. The aim of this study was to identify ethnic differences in the response to docetaxel, among patients with castration resistant metastatic prostate cancer.PATIENTS AND METHODS: We queried the New Mexico Cancer Registry then the electronic charts of all castration resistant metastatic prostate cancer patients who were treated with docetaxel between 1999 and 2010 at the University of New Mexico Cancer Center. Patient characteristics that might influence the response to docetaxel such as age, prior treatment including hormones, chemotherapy, radiotherapy, and surgery, concurrent chemotherapy, site of disease, baseline PSA, and number of docetaxel courses were recorded. Progression of disease after start of treatment was defined as identification of new lesions or a biochemical recurrence. The primary end point was overall survival. Secondary end points were progression-free survival and PSA response to docetaxel. RESULTS: Despite a lower incidence of prostate cancer in NM, the death rate is higher than the national average. Although not statistically significant, the overall survival for patients treated with docetaxel is highest among Non Hispanic Whites, followed by Native Americans and worst among the Hispanic population. The progression free survival was greatest in the Native American population followed by Non Hispanic Whites, followed by Hispanics. Compared to published data, the survival of New Mexicans with prostate cancer treated with docetaxel is worse.CONCLUSION: Hispanic males with castration resistant metastatic prostate cancer on docetaxel, tended to have the lowest overall survival and progression free survival, but overall the differences between New Mexican ethnicities were not statistically significant.

The relationship of body mass index and serum testosterone with disease outcomes in men with castration-resistant metastatic prostate cancer

5074 Background: We sought to evaluate the relationship of baseline body mass index (BMI), NIH-defined presence of obesity, and serum testosterone levels with disease-specific outcomes and prognosis in men with castration resistant metastatic prostate cancer (CRPC). Methods: BMI and testosterone level were evaluated for their ability to predict overall survival (OS) and progression-free survival (PFS) in multivariable analysis using data from the TAX327 clinical trial. This was an international phase III randomized controlled trial of one of two schedules of docetaxel and prednisone compared with mitoxantrone and prednisone. BMI and testosterone were additionally examined for prognostic significance in determining PSA declines with chemotherapy as well as the relationship to other prognostic factors. Results: In this study of 1006 men with CRPC, the median serum testosterone level was 14.5 ng/dl (range 0–270), the median BMI was 27 kg/m2 (range 15.7–46.5), and 26% of men were obese or morbidly obese (BMI > 30). Obese men were significantly more likely to be younger, have fewer visceral metastases, lower PSA and alkaline phosphatase, and have higher performance status, primary Gleason sum, testosterone, and hemoglobin levels as compared to non-obese men. In multivariable analysis, neither BMI nor the presence of obesity was significantly associated with PSA declines with therapy, progression-free survival, or overall survival. Baseline testosterone in the castrate range was also not associated with disease outcome, including PSA declines, PFS, or OS. Conclusions: In this multicenter international trial of men with CRPC, neither BMI nor serum testosterone in the castrate range were associated with prostate cancer outcomes. The cut-off threshold for castrate levels of serum testosterone should remain ≤50 ng/dl. Higher levels of serum testosterone among obese men suggest incomplete gonadal suppression with current therapies, but these differences may not be clinically relevant in men with CRPC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis

A Phase II Trial of Bortezomib and Prednisone for Castration Resistant Metastatic Prostate Cancer

We defined the antitumor effects of bortezomib alone and in combination with prednisone in patients with progressive, castration resistant metastatic prostate cancer. A total of 30 men with progressive castration resistant disease were treated in 2 groups. Cohort 1 received 1.5 mg/m2 bortezomib intravenously twice weekly for 2 cycles (2 weeks on and 1 week off), followed by 1.6 mg/m2 weekly (4 weeks on and 2 weeks off). Prednisone (10 mg) was given orally throughout. Cohort 2 comprised patients with limited chemotherapy exposure who received a decreased dose of bortezomib (1.3 mg/m2) during the induction period with prednisone added only at disease progression. The primary end point was no evidence of disease progression at 12 weeks, defined as no increase in prostate specific antigen from baseline and no radiographic progression. Interleukin-6 was assessed to correlate with antitumor effects. One of 24 evaluable patients (4%) achieved the primary end point. In cohort 1, 18 patients were treated, 13 were evaluable for response and 4 discontinued treatment due to toxicities, including 3 before attaining the point of being evaluable. No patient achieved the primary end point. In cohort 2, 12 patients were treated and 11 were evaluable for response. Toxicity was slightly mitigated compared with that in cohort 1. One patient achieved the primary end point. Interleukin-6 did not correlate with posttreatment prostate specific antigen changes in either cohort. Although interleukin-6 and other pathways regulated by nuclear factor-kappa B may be legitimate targets, treatment with bortezomib alone and with prednisone does not appear to have significant antitumor effects in patients with castration resistant metastatic prostate cancer.

Castration Resistant, Taxane Naïve Metastatic Prostate Cancer: Current Clinical Approaches and Future Directions

With the wide use of prostate specific antigen to detect response and disease progression resistance to androgen deprivation is being detected at an increasingly earlier stage. We focused on the current management and novel investigational strategies for the chemonaïve patient population with castration resistant metastatic disease. We reviewed standard and investigational hormonal, chemotherapeutic, biological and immune based strategies for patients with castration resistant metastatic prostate cancer who have not yet received taxane based chemotherapy. Our understanding of the natural history of this group of patients is evolving. A variety of standard and experimental treatment options are available for this group of patients. Manipulating the androgen receptor signaling axis, targeting antiapoptotic pathways, using antiangiogenic strategies, harnessing the immune system and optimizing docetaxel based regimens and novel cytotoxic agents are under investigation. Multiple agents currently under development offer a promise of palliation and prolongation of survival above and beyond that of docetaxel. In the absence of guidance from randomized trials with regard to chemotherapy timing, and considering the modest effects of docetaxel on survival, decisions regarding choice of therapy (standard chemotherapy or experimental therapies) must be based on careful consideration of the functional status of each individual, presence of symptoms, comorbidities and overall therapeutic objectives.

Mitomycin C Versus Estramustine in the Treatment of Hormone Resistant Metastatic Prostate Cancer: Thefinal Analysis of the European Organization Forresearch and Treatment of Cancer, Genitourinarygroup Prospective Randomized Phase III Study (30865)

A total of 171 patients with progressive metastatic prostate cancer following hormonal therapy was randomized to receive either 560 to 700mg. estramustine orally per day or 15mg./m.2 mitomycin C by intravenous infusion every 6 weeks. The patients were recruited during a 2.5-year period, and 70% had undergone more than 1 previous therapy for prostate cancer, with some having received as many as 5 different previous treatments. The overall results were disappointing. The median time to progression was 5 months and 50% of the patients died within 10 months. There was no difference in efficacy between the 2 treatment arms. Toxicity was severe in both arms but appeared earlier in those patients receiving estramustine, leading to a tendency for earlier deterioration in performance status. In this group of heavily pretreated patients there appears to be no justification for the use of either of these agents at the present time.

Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer

Purpose : A large proportion of the practice of radiotherapy in the management of metastatic adenocarcinoma of the prostate is associated with palliation of pain from osseous metastases and improving quality of life. Radiation therapy is well known to be effective in treating painful sites and may also be effective in reducing the propensity for adjuvantly treated disease to become symptomatic. Strontium-89 is a systemic radionuclide that has clinical efficacy in the palliation of pain from bony metastases. Methods and Materials : The study was a Phase-III randomized placebo control trial performed in eight Canadian Cancer Centers to evaluate the effectiveness of strontium-89 as an adjunct to local field radiotherapy. Patients with endocrine refractory metastatic prostate cancer received local field radiotherapy and either strontium-89 as a single injection of 10.8 mCi or placebo. Results : One hundred twenty-six patients were recruited. No significant differences in survival or in relief of pain at the index site where noted. Intake of analgesics over time demonstrated a significant reduction in the arm treated with strontium-89. Progression of pain as measured by sites of new pain or the requirement for radiotherapy showed statistically significant differences between the arms in favor of strontium-89. Tumor markers including prostate specific antigen, acid phosphatase, and alkaline phosphatase were also reduced in patients receiving strontium-89. A Quality-of-Life analysis was performed as a multivariate data set and demonstrated an overall superiority of strontium-89 with alleviation of pain and improvement in physical activity being statistically significant. Toxicity was evaluated and demonstrated increased hematological toxicity in the group receiving strontium-89. Conclusions : It is concluded that the addition of strontium-89 is an effective adjuvant therapy to local field radiotherapy reducing progression of disease as evidenced by new sites of pain and the requirement of further radiotherapy and improving quality-of-life and need for analgesic support in this group of patients.

Piparubicin and 5 fluorouracil in the treatment of hormone resistant metastatic prostate cancer

Piparubicin and 5 fluorouracil in the treatment of hormone resistant metastatic prostate cancer

Suramin in advanced platinum-resistant ovarian cancer

10 patients with ovarian cancer, whose disease had progressed while receiving platinum-based therapy, were entered onto a phase II clinical trial of the antiproliferative agent suramin. Suramin was administered in a fashion that is associated with durable objective disease response in patients with hormonally resistant metastatic prostate cancer. No individual had an objective response to therapy in this study, but 3 of 9 evaluable patients (33%) experienced disease stabilisation and subjective clinical improvement for periods ranging from 2 to 5 months. Disease stabilisation was associated with prolonged periods of comparatively high plasma levels of drug, which appeared to be determined primarily by reduced drug clearance. We conclude that suramin has potential activity in platinum-resistant ovarian cancer, and we have initiated a second clinical trial using pharmacological information derived from this study.

Results of a phase III study evaluating the use of strontium 89 therapy as an adjubant to local external beam radiotherapyy in patients with endocrine resistant metastatic prostate cancer — first results of the trans-Canada study

Results of a phase III study evaluating the use of strontium 89 therapy as an adjubant to local external beam radiotherapyy in patients with endocrine resistant metastatic prostate cancer — first results of the trans-Canada study

Phase I/II study of suramin in hormone resistant metastatic prostate cancer

Phase I/II study of suramin in hormone resistant metastatic prostate cancer