Genomic Testing in Localized Prostate Cancer Can Identify Subsets of African Americans With Aggressive Disease.

BACKGROUND: Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting. METHODS: This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non-African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score. RESULTS: The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non-African American men). A higher proportion of African American men with National Comprehensive Cancer Network-classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non-African American men. Self-identified African American men were twice more likely than non-African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes. CONCLUSIONS: Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions.

Substantial Gleason reclassification in Black men with national comprehensive cancer network low-risk prostate cancer - A propensity score analysis.

BACKGROUND: Emerging evidence suggests that a subset of Black men with National Comprehensive Cancer Network (NCCN) low-risk prostate cancer (PCa) may harbor high volume and genomically aggressive disease. However, limited, and ambiguous research exist to evaluate the risk of extreme Gleason reclassification in Black men with low-risk PCa. METHODS: This retrospective cohort study included 45,674 low-risk PCa patients who underwent prostatectomy and were not on active surveillance, from National Cancer Database (NCDB). A propensity score matched-pair design was employed, and the final cohort was limited to 1:1 matched 12,340 patients. Gleason score reclassification was used as primary endpoint. As such, any migration to pathologic Gleason score ≥7(3 + 4) was identified as overall, whereas migration to ≥7(4 + 3) was defined as extreme reclassification. A conditional Poisson regression model was used to estimate the risk of reclassification. Whereas spline model was used to estimate the impact of increasing time to treatment as a non-linear function on Gleason reclassification between race group. RESULTS: Upon matching there were no differences in the baseline characteristics between race groups. In a matched cohort, higher proportion of low-risk Black men (6.6%) reported extreme reclassification to pathologic Gleason score than White men (5.0%), p < 0.001. In a conditional Poisson regression model adjusted for time to treatment, the risk of overall (RR = 1.09, 95% CI, 1.05-1.13, p < 0.001) and extreme (RR = 1.30, 95% CI, 1.12-1.50, p = 0.004) reclassification was significantly higher in Black men as compared to their White counterpart. In spline model, the probability of Gleason reclassification in Black men was elevated with increasing time to treatment, especially after 180 days (53% vs. 43% between Black and White men). CONCLUSION: Risk of Gleason score reclassification is disparately elevated in Black men with low-risk PCa. Furthermore, time to treatment can non-linearly impact Gleason reclassification in Black men.

Change in Management Based on Pathologic Second Opinion Among Bladder Cancer Patients Presenting to a Comprehensive Cancer Center: Implications for Clinical Practice.

OBJECTIVE: To evaluate the incidence and degree of change from a pathologic second opinion of bladder biopsies at a Comprehensive Cancer Center that were initially performed at referring community hospitals. The secondary objective was to determine the impact the potential changes would have on a patient's treatment. MATERIALS AND METHODS: Dedicated genitourinary pathologists reviewed 1191 transurethral biopsies of the bladder and/or prostatic urethra from 2008 to 2013. Major and minor treatment changes were defined as altering recommendations for cystectomy, systemic chemotherapy, or primary cancer diagnosis, and alterations in intravesical regimens, respectively. RESULTS: There were 326/1191 patients (27.4%) with a pathologic change on second opinion: grade (62/1191, 5.2%), stage (115/1191, 9.7%), muscle in the specimen (29/1191, 2.4%), presence or absence of carcinoma in situ (34/1191, 2.9%). Outside pathology did not address the presence or absence of lymphovascular invasion in 620/759 (81.7%) of invasive cases (≥cT1), of which 35/620 (5.6%) had lymphovascular invasion. There were 212 mixed, variant, or nonurothelial histologies detected in 199/1191 (16.7%) patients, with 114/212 (53.7%) resulting in reclassification by our pathologists. Potential treatment alterations accounted for 182/1191 (15.3%) of cases, with 141/1191 (11.8%) imparting major changes. There were 82/1191 (6.8%) changes in recommendation for a radical cystectomy, 38/1191 (3.2%) had a complete change in primary tumor type, and 21/1191 (1.8%) for change in chemotherapy regimen. CONCLUSION: The amount and degree of pathologic changes and its potential impact on treatment emphasize the importance of bladder cancer patients having their histology reviewed by genitourinary-dedicated pathologists. In our cohort, 15.3% of patients could see a treatment alteration, with 11.8% being a major change.

Randomized, placebo-controlled trial evaluating the safety of one-year administration of green tea catechins.

PURPOSE: Although preclinical, epidemiological and prior clinical trial data suggest that green tea catechins (GTCs) may reduce prostate cancer (PCa) risk, several preclinical studies and case reports have reported liver toxicities and acute gastrointestinal bleeding. Based on these observations, regulatory bodies have required stringent inclusion criteria with frequent, excessive toxicity monitoring and early stopping rules in clinical trials. These requirements have impeded recruitment and retention of subjects in chemoprevention trials and subsequent progress in agent development efforts. EXPERIMENTAL DESIGN: We conducted a placebo-controlled, randomized clinical trial of Polyphenon E® (PolyE®), a proprietary mixture of decaffeinated GTCs, containing 400 mg (-)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). PolyE® containing 200 mg EGCG was administered with food, BID. A secondary study endpoint in this trial was a comparison of the overall one-year treatment related adverse events and grade 3 or higher adverse event on the two study arms. Monthly assessments of toxicity (CTCAE 4.0), concomitant medications and organ function, including hepatic panel, PT/PTT and LDH, were performed. RESULTS: Daily intake of a standardized, decaffeinated, catechin mixture containing 200 mg EGCG BID taken with food for 1 year accumulated in plasma and was well tolerated and did not produce treatment related adverse effects in men with baseline HGPIN or ASAP. CONCLUSION: The current data provides evidence of safety of decaffeinated, catechin mixture containing 200 mg EGCG BID to be further tested for prostate cancer prevention or other indications.

Randomized, Placebo-Controlled Trial of Green Tea Catechins for Prostate Cancer Prevention.

Preclinical, epidemiologic, and prior clinical trial data suggest that green tea catechins (GTC) may reduce prostate cancer risk. We conducted a placebo-controlled, randomized clinical trial of Polyphenon E (PolyE), a proprietary mixture of GTCs, containing 400 mg (-)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). The primary study endpoint was a comparison of the cumulative one-year prostate cancer rates on the two study arms. No differences in the number of prostate cancer cases were observed: 5 of 49 (PolyE) versus 9 of 48 (placebo), P = 0.25. A secondary endpoint comparing the cumulative rate of prostate cancer plus ASAP among men with HGPIN without ASAP at baseline, revealed a decrease in this composite endpoint: 3 of 26 (PolyE) versus 10 of 25 (placebo), P < 0.024. This finding was driven by a decrease in ASAP diagnoses on the Poly E (0/26) compared with the placebo arm (5/25). A decrease in serum prostate-specific antigen (PSA) was observed on the PolyE arm [-0.87 ng/mL; 95% confidence intervals (CI), -1.66 to -0.09]. Adverse events related to the study agent did not significantly differ between the two study groups. Daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year accumulated in plasma and was well tolerated but did not reduce the likelihood of prostate cancer in men with baseline HGPIN or ASAP.

Improving treatment strategies for patients with metastatic castrate resistant prostate cancer through personalized computational modeling.

Metastatic castrate resistant prostate cancer (mCRPC) is responsible for the majority of prostate cancer deaths with the median survival after diagnosis being 2 years. The metastatic lesions often arise in the skeleton, and current treatment options are primarily palliative. Using guidelines set forth by the National Comprehensive Cancer Network (NCCN), the medical oncologist has a number of choices available to treat the metastases. However, the sequence of those treatments is largely dependent on the patient history, treatment response and preferences. We posit that the utilization of personalized computational models and treatment optimization algorithms based on patient specific parameters could significantly enhance the oncologist's ability to choose an optimized sequence of available therapies to maximize overall survival. In this perspective, we used an integrated team approach involving clinicians, researchers, and mathematicians, to generate an example of how computational models and genetic algorithms can be utilized to predict the response of heterogeneous mCRPCs in bone to varying sequences of standard and targeted therapies. The refinement and evolution of these powerful models will be critical for extending the overall survival of men diagnosed with mCRPC.

Understanding the psychosocial issues of African American couples surviving prostate cancer.

African Americans are disproportionately affected by prostate cancer, yet less is known about the most salient psychosocial dimensions of quality of life. The purpose of this study was to explore the perceptions of African American prostate cancer survivors and their spouses of psychosocial issues related to quality of life. Twelve African American couples were recruited from a National Cancer Institute Comprehensive Cancer Center registry and a state-based non-profit organization to participate in individual interviews. The study was theoretically based on Ferrell's Quality of Life Conceptual Model. Common themes emerged regarding the psychosocial needs of African American couples. These themes were categorized into behavioral, social, psychological, and spiritual domains. Divergent perspectives were identified between male prostate cancer survivors and their female spouses. This study delineated unmet needs and areas for future in-depth investigations into psychosocial issues. The differing perspectives between patients and their spouses highlight the need for couple-centered interventions.

Results of a randomized phase I dose-finding trial of several doses of isoflavones in men with localized prostate cancer: administration prior to radical prostatectomy.

The purpose of this phase I dose-finding randomized controlled trial was to evaluate the safe and effective dose of isoflavones to be used in future clinical trials for prostate cancer prevention. Forty-five eligible men were supplemented with 40, 60, and 80 mg of purified isoflavones or no supplement from biopsy to prostatectomy. Compliance with the study agent, toxicity, and changes in plasma isoflavones, serum steroid hormones, prostate-specific antigen (PSA), and tissue Ki-67 were analyzed from baseline to completion of the study. Forty-four subjects completed the study with a duration of intervention of 30 (+/- 3) days. We observed significant increases in plasma isoflavones with treatment for all doses compared with controls without producing any toxicity. Significant increases in serum total estradiol were observed in the 40 and 60 mg isoflavone-treated arms. However, a significant increase in serum free testosterone was observed in the 60 mg isoflavone-treated arm. Changes in serum sex hormone-binding globulin, PSA, and percentage of tissue Ki-67 were not statistically significant with treatment for this sample size and duration of intervention. Our results identify a safe dose of purified isoflavones for future clinical trials and establish the need for further definitive, well-powered trials to examine the role of isoflavones in prostate carcinogenesis.

A Phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer.

Our purpose was to evaluate the safety and effectiveness of purified isoflavones in producing an increase in plasma isoflavones and a corresponding change in serum sex hormone binding globulin (SHBG) and steroid hormone levels in men diagnosed with early stage prostate cancer. In this Phase II randomized, double-blinded, placebo-controlled trial, 53 prostate cancer patients with a Gleason score of 6 or below were supplemented with 80 mg purified isoflavones or placebo for 12 weeks. Changes in plasma isoflavones, serum steroid hormones, and safety markers were analyzed from baseline to 12 wk. A total of 50 subjects completed the study. Although significant increases in plasma isoflavones (P < 0.001) was observed with no clinical toxicity, the corresponding modulation of serum SHBG, total estradiol, and testosterone in the isoflavone-treated group compared to men receiving placebo was nonsignificant. Increasing plasma isoflavones failed to produce a corresponding modulation of serum steroid hormone levels in men with localized prostate cancer. The study establishes the need to explore other potential mechanisms by which prolonged and consistent purified isoflavone consumption may modulate prostate cancer risk.

Safety of purified isoflavones in men with clinically localized prostate cancer.

Our purpose was to evaluate the safety of 80 mg of purified isoflavones administered to men with early stage prostate cancer. A total of 53 men with clinically localized prostate cancer, Gleason score of 6 or below, were supplemented with 80 mg purified isoflavones or placebo for 12 wk administered in 2 divided doses of 40 mg to provide a continuous dose of isoflavones. Compliance, changes in plasma isoflavones, and clinical toxicity were analyzed at baseline, 4, and 12 wk. A total of 50 subjects completed the 12-wk intervention. A continuous, divided-dose administration of 80 mg/day of purified isoflavones at amounts that exceeded normal American dietary intakes significantly increased (P < 0.001) plasma isoflavones in the isoflavone-treated group compared to placebo and produced no clinical toxicity. With the current evidence on the cancer preventive properties of isoflavones, these results are significant and offer promise for these phytochemicals to be developed as potent agents to prevent cancer progression.

Treatment of intermediate-risk prostate cancer with brachytherapy without supplemental pelvic radiotherapy: a review of the H. Lee Moffitt Cancer Center experience.

PURPOSE: To determine the biochemical outcomes of patients with intermediate-risk prostate cancer treated at the H. Lee Moffitt Cancer Center with an I-125 permanent seed implant without supplemental pelvic radiotherapy. METHODS AND MATERIALS: Under an institutional review board approved protocol, the charts of 88 patients with intermediate-risk prostate cancer and a minimum follow-up of 36 months treated with brachytherapy without supplemental pelvic radiotherapy were reviewed. Median follow-up for the whole cohort was 57 months (range 37-121). Biochemical failure was defined using the American Society for Therapeutic Radiology and Oncology definition. RESULTS: The 5-year biochemical failure-free survival for the cohort was 83%. Patients with perineural invasion had a worse biochemical outcome, which was statistically significant (perineural invasion vs. no perineural invasion, 5-year biochemical failure-free survival 64% vs. 89%, P = 0.004). None of the following factors were found significant in this subset of patients: Gleason scores 6 versus 7, primary Gleason grades 3 versus 4, percentage of core positive <20% versus >20%, number of cores positive <2 versus 2 versus >2, hormonal therapy versus no hormonal therapy, T1 versus T2, prostate-specific antigen <10 versus >10, or > or =2 intermediate risk factors versus 1 intermediate risk factor. CONCLUSIONS: Our data suggest that patients with intermediate-risk prostate cancer may be treated effectively with brachytherapy without supplemental pelvic radiotherapy. However, because of the limited nature of our study, we cannot exclude that patients with intermediate-risk prostate cancer may benefit from supplemental external beam radiotherapy.

The specific role of isoflavones in reducing prostate cancer risk.

AIMS: To evaluate the effectiveness of supplementing a group of early stage prostate cancer patients, with 60 mg of soy isoflavones in producing a change in hormonal and proliferative risk parameters that are implicated in prostate cancer promotion. METHODS: Seventy six eligible prostate cancer patients with a Gleason score of 6 or below, between ages 50 and 80 were admitted and supplemented with soy isoflavones or placebo for a 12 week period and changes in PSA and steroid hormones were analyzed at baseline and post intervention. RESULTS: Fifty-nine patients completed the 12-week intervention. Serum free testosterone was reduced or showed no change in 61% of subjects in the isoflavone group compared to 33% in the placebo group. Serum total PSA decreased or was unchanged in 69% of the subjects in the isoflavone treated group compared to 55% in the placebo group. However, we did not see an increase in SHBG levels. Nineteen percent of subjects receiving soy isoflavones reduced total PSA by two points or more during the intervention period. CONCLUSIONS: These data suggest that supplementing early stage prostate cancer patients with soy isoflavones, even in a study of short duration, altered surrogate markers of proliferation such as serum PSA and free testosterone in a larger number of subjects in the isoflavone supplemented group than the group receiving placebo. The study establishes the need to explore further the effects of prolonged and consistent soy consumption, which could potentially delay onset of histologic disease in this patient population.