Mechanisms of resistance in castration-resistant prostate cancer (CRPC)

PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

Randomized clinical trials have recently examined the benefit of adding docetaxel or abiraterone to androgen deprivation therapy (ADT) in hormone-naïve advanced prostate cancer (PCa). To perform a systematic review and network meta-analysis of randomized clinical trials, indirectly evaluating overall survival (OS) for men treated with abiraterone acetate plus prednisone/prednisolone with ADT (Abi-ADT) versus docetaxel with ADT (Doce-ADT) in hormone-naïve high-risk and metastatic PCa. Medline, Embase, Web of Science, Scopus, and Clinicaltrials.gov databases were searched in August 2017. We pooled results using the inverse variance technique and random-effects models. The Bucher technique for indirect treatment comparison was used to compare Abi-ADT with Doce-ADT. A priori subgroup and sensitivity analyses were performed. Overall, 6067 patients from five trials were included: 1181 (19.5%) patients who received Doce-ADT, 1557 (25.7%) patients who received Abi-ADT, and 3329 (54.9%) patients who received ADT-alone. There was a total of 1921 deaths: 391 in the Doce-ADT group, 353 in the Abi-ADT group, and 1177 in the ADT-only group. The pooled hazard ratio (HR) for OS was 0.75 (95% confidence interval [CI]: 0.63-0.91, I2=51%, 3 trials, 2951 patients) for Doce-ADT versus ADT-alone and 0.63 (95% CI: 0.55-0.72, I2=0%, 2 trials, 3116 patients) for Abi-ADT versus ADT-alone. The indirect comparison of Abi-ADT to Doce-ADT demonstrated no statistically significant difference in OS between these approaches (HR: 0.84, 95% CI: 0.67-1.06). Findings were similar in various a priori subset analyses, including patients with metastatic disease. Bayesian analyses demonstrated comparable results (HR: 0.83, 95% CI: 0.63-1.16). Despite the lack of statistical significance, Surface Under the Cumulative Ranking Analysis demonstrated an 89% probability that Abi-ADT was preferred. We did not identify a significant difference in OS between Abi-ADT and Doce-ADT for men with hormone-naïve high-risk or metastatic PCa, although Bayesian analysis demonstrates a high likelihood that Abi-ADT was preferred. We synthesized the evidence available from studies examining the administration of docetaxel or abiraterone in combination with hormonal therapy for patients with newly diagnosed, advanced prostate cancer. While these studies did not directly compare these agents, we used methodological techniques to indirectly compare them and found no significant difference in overall survival.

We evaluated intervention rates, progression and cancer specific survival outcomes in patients with complex renal cysts in a single center experience. We used the Montage™ radiology data mining system to retrospectively identify all reported cases of complex renal cyst at our institution from 2001 to 2013. The primary study end points were overall and cancer specific survival. The secondary end points included radiographic progression and upgrading, clinical progression and final histology on surgical pathology. We identified 336 patients with a complex renal cyst, of whom 185 (55.1%), 122 (36.3%) and 29 (8.6%) had Bosniak IIF, III and IV cysts, respectively. Median followup was 67.1 months (range 34.4 to 101.6). In the 332 patients with followup there was 1 cancer specific death (0.3%) and overall mortality was 6.2%. Ten (5.4%), 37 (30.3%) and 18 patients (62.1%) with Bosniak IIF, III and IV, respectively, underwent surgical or ablative intervention. The indication for intervention was predominantly age (intervention vs no intervention mean ± SD age 50.1 ± 15.9 vs 62.5 ± 13.9 years) and complexity. Surgery with radical and partial nephrectomy (23 patients or 35% and 37 or 57%, respectively) was most common and favorable final pathology was identified. Two treated patients experienced recurrence during followup. When excluding patients with von Hippel-Lindau syndrome, the cancer specific survival rate was 100%. Cancer survival and overall survival in patients with Bosniak IIF to IV renal cysts was high with only 1 cancer specific death. No cancer deaths were recorded in patients who did not undergo intervention. Reconsidering management guidelines for complex renal cysts is warranted, particularly consideration for initial surveillance of Bosniak III cysts.