Clinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in Neoadjuvant Chemotherapy for Urothelial Cancer.

BACKGROUND: Level 1 evidence has demonstrated increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Usage remains low, however, in part because neoadjuvant chemotherapy will not be effective for every patient. To identify the patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in 2 large cohorts of patients with urothelial cancer. PATIENTS AND METHODS: Patients receiving neoadjuvant cisplatin-based chemotherapy for muscle-invasive urothelial cancer were eligible. Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for an association with a complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (

Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival.

PURPOSE: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators. EXPERIMENTAL DESIGN: Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients. RESULTS: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22-0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage. CONCLUSION: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted.

Prospective health-related quality of life analysis for patients undergoing radical cystectomy and urinary diversion.

OBJECTIVE: To better define health-related quality of life (HRQOL) for patients undergoing radical cystectomy (RC) and urinary diversion. MATERIALS AND METHODS: Patients undergoing RC and urinary diversion for urothelial carcinoma by 1 of 2 surgeons (G.D.S. or N.D.S.) had a HRQOL assessment at baseline and at follow-up using the validated, bladder cancer-specific Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index questionnaire. The primary outcome was change in HRQOL between baseline and follow-up. RESULTS: From September 15, 2011, to July 23, 2012, 74 of 103 eligible patients were enrolled, and all but 1 completed the baseline Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index leaving 73 patients in the study. Median age was 68 years (interquartile range, 60-74 years), 58 (78%) were Caucasian, 53 (73%) were ≥ cT2, 45 (62%) underwent incontinent diversion, and the mean age-adjusted Charlson Comorbidity Index score was 2.4 ± 1.8, with no significant differences among the 73 participants and 30 nonparticipants. The median time from surgery to response was 175 days (interquartile range, 102-232 days), and the response rate was 67%, with 9 deaths during follow-up. Baseline HRQOL scores did not significantly differ between respondents and nonrespondents or between those living vs deceased. Overall, RC-specific, physical, social, and functional HRQOL scores did not differ from baseline to follow-up, whereas emotional HRQOL scores were significantly improved (15.7 ± 5.8 vs 18.1 ± 3.9, P = .03). Overall or domain-specific HRQOL measures did not differ significantly between patients undergoing incontinent (n = 27) vs continent (n = 16) diversions. CONCLUSION: Overall, HRQOL scores did not statistically differ from baseline to the median 6-month follow-up for patients undergoing RC and urinary diversion for urothelial carcinoma. Patients undergoing continent vs incontinent urinary diversions had similar overall HRQOL scores at follow-up.