Purpose Due to 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 to non-carriers (median 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% CI 0.22 to 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.

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BACKGROUND Level 1 evidence demonstrates increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Utilization remains low, however, in part because neoadjuvant chemotherapy is not effective for every patient. To identify patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in two large cohorts of urothelial cancer patients. 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 association with complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (

290 Background: Despite level 1 evidence demonstrating survival benefit for cisplatin-based neoadjuvant chemotherapy in urothelial cancer, its utilization remains low, likely due to the modest benefit and potentially significant toxicities. To improve selection of patients (pts) most likely to benefit, we evaluated the association of pharmacogenomic markers of cisplatin sensitivity with neoadjuvant therapy outcome. Methods: Pts receiving standard neoadjuvant cisplatin-based chemotherapy for muscle-invasive disease were recruited to provide a germline DNA sample. Nine single nucleotide polymorphisms (SNPs) selected for their associations with platinum sensitivity in various clinical and pre-clinical studies were tested for association with complete pathologic response (pT0) rate at cystectomy. Results: Sixty-three Caucasian pts were analyzed (median age=64; 67% male; all bladder primary and cN0). The overall pT0 rate was 27%; 52% were <pT2. Using a multivariate, recessive genetic model, rs244898 in RARS (odds ratio [OR] 6.8 [95% CI 1.6-32.6], P=0.01) and rs7937567 in GALNTL4 (OR 5.2 [95% CI 1.1-26.2], P=0.03) were associated with likelihood of achieving pT0. For each SNP, pts carrying the favorable genotype achieved pT0 in >58% of cases. Demonstrating the apparent independent nature of the two SNPs, pts carrying either favorable genotype had pT0 OR=8.5 (95% CI 2.5-31.8, P=0.0008). The combined effect of detecting both SNPs was most informative, as 2/3 pts with both favorable genotypes achieved pT0 (67%), compared to 9/15 pts with one favorable genotype (60%), and only 6/43 lacking both favorable genotypes (14%). The negative predictive value considering both SNPs was 86%. Conclusions: Two germline SNPs having prior evidence of governing platinum sensitivity in pre-clinical and clinical models were demonstrated to confer strong associations with complete response to cisplatin-based neoadjuvant chemotherapy. Validation testing in an independent, multi-institutional cohort of urothelial cancer pts is underway. If reproducible, these SNPs deserve consideration as predictive clinical biomarkers to inform the use of neoadjuvant chemotherapy in this disease.