Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.

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.

Effects of Time to Treatment on Biochemical and Clinical Outcomes for Patients With Prostate Cancer Treated With Definitive Radiation.

INTRODUCTION: The purpose of this study was to evaluate if time to treatment (TTT) has an effect on outcomes for patients with localized prostate cancer treated with definitive external beam radiation therapy (EBRT). PATIENTS AND METHODS: We included 4064 patients (1549 low-risk, 1612 intermediate-risk, and 903 high-risk) treated with EBRT. For each National Comprehensive Cancer Network (NCCN) risk group, TTT (defined as the time between initial positive prostate biopsy and start of RT) was analyzed in 4 intervals: < 3, 3-6, 6-9, and 9-24 months. We recorded the use of androgen deprivation therapy among patients with intermediate-risk and high-risk disease. RESULTS: The median TTT was 3.3 months (range, 0.6-23.5 months), and it was similar for each risk group (range, 3.3-3.4 months). The median follow up was 64 months. There were no significant differences in biochemical failure, distant metastasis, or overall survival for patients with TTT < 3, 3-6, 6-9, or 9-24 months for each risk group. There were also no significant differences in the outcomes at 5 years when patients with TTT > 3.3 months were compared with those with TTT ≤ 3.3 months for each risk group. For high-risk men, 328 of 450 (72.9%) with TTT > 3.3 months were on androgen deprivation therapy (ADT) versus 299 of 453 (66%) with TTT ≤ 3.3 months. Among men with high-risk cancer treated without ADT, there remained no significant difference in outcomes between TTT > 3.3 months and TTT ≤ 3.3 months. CONCLUSION: TTT was not associated with significant differences in outcomes among each risk group of men with localized prostate cancer treated with EBRT. Among the high-risk patients, there were no observed detriments in outcomes with TTT > 3.3 months regardless of androgen deprivation therapy use.

Residual Parenchymal Volume, Not Warm Ischemia Time, Predicts Ultimate Renal Functional Outcomes in Patients Undergoing Partial Nephrectomy.

OBJECTIVE: To examine relative contributions of functional parenchymal preservation and renal ischemia following nephron-sparing surgery (NSS). While residual functional parenchymal volume (FPV) is proposed as the key factor in predicting functional outcomes following NSS, efforts to curtail ischemia time continue to add technical complexity to partial nephrectomy. METHODS: Our kidney cancer database was queried for patients who underwent NSS with warm ischemia time (WIT). Patients with cross-sectional imaging for FPV calculation were included. Cylindrical volume approximation methodology was used to calculate FPV, accounting for the volume of tumor's endophytic component. Percent estimated glomerular filtration rate (eGFR) preservation, perioperatively and at 6 months, was the outcome metric. Spearman correlation and linear regression analyses were used to evaluate associations of WIT and %FPV preservation with renal function preservation. RESULTS: Of the 179 patients included, median preoperative eGFR was 88.4 (9.5% chronic kidney disease III or IV), tumor size was 2.7 cm (interquartile range [IQR] 2.0-3.6 cm), and R.E.N.A.L. nephrometry was low in 34%, intermediate in 57%, and high in 9%. Median WIT was 30 minutes (IQR 24-36), resulting in 97.4% FPV preservation. Median postoperative eGFR at 6.4 months was 80.5 (19.1% chronic kidney disease III or IV), a median of 93.1% eGFR preservation (IQR 85.1-101.7). At discharge, WIT (P <.001), not %FPV (P = .112), was associated with %eGFR preservation. However, 6 months following surgery, on multivariable analysis, both preoperative eGFR (linear regression coefficient = -0.208, P = .006) and %FPV preservation (linear regression coefficient = 0.491, P = .001), but not WIT (P = .946), demonstrated statistically significant association with %eGFR preservation. CONCLUSION: Residual FPV, and not WIT, appears to be the main predictor of ultimate renal function following NSS.

PSA Doubling Time Predicts for the Development of Distant Metastases for Patients Who Fail 3DCRT Or IMRT Using the Phoenix Definition.

PURPOSE: PSA doubling time (PSADT) is commonly used as an indication for salvage androgen deprivation therapy (ADT) for PSA failure following RT. Previously, we had shown that PSADT of <12 months is an important predictor of distant metastasis following 3DCRT using the ASTRO definition of BF. We sought to determine if this approach is still valid using the Phoenix definition. METHODS: Eligible patients included 432 men with T1-3N0M0 prostate cancer who demonstrated PSA failure after completing definitive 3DCRT or IMRT from 1989-2005. Endpoints included freedom from distant metastasis (FDM), cause-specific survival (CSS) and overall survival (OS). PSADT was stratified by 0-6, 6-12, 12-18, 18-24, and >24 months. The median follow-up was 95 months (6-207 months). RESULTS: The 7 year FDM, CSS, and OS rates for the entire group were 73%, 77% and 52%, respectively. 7 year FDM was 50% for PSADT <6 months vs. 83% for PSADT >6 months (p=0.0001). 7 year CSS was 61% for PSADT <6 and 85% for PSADT >6 (p=0.0001). 7 year OS was 47% for PSADT <6 and 53% for PSADT >6 (p=0.04). The proportion of men with BF receiving salvage ADT with a PSADT <6 months was 59%, 6-12 was 45%, 12-18 was 42%, 18-24 was 36%, >24 was 28%. ADT was associated with improved 7 year CSS (68% vs. 46%, p=0.015). Of the 314 men with PSADT >6 months, 124 received ADT and 190 were observed. With a median follow-up of 38 months from BF, there was no demonstrable benefit to ADT in the 7 year CSS (87% vs. 79%, respectively; p=0.758). Independent predictors of FDM were PSADT (p<0.0001), GS (p=0.011), and the use of initial ADT (p=0.005). CONCLUSION: PSADT remains a significant predictor of clinical failure and CSS for men treated with 3DCRT or IMRT who fail according to the Phoenix definition. Immediate use of ADT in patients with PSADT <6 months is significantly associated with improved CSS, although the benefit is less apparent in patients with longer PSADT. These results further refine the role of PSADT in predicting which patients may benefit from salvage ADT and those who may be observed expectantly.