Prediction of pathologic complete response to neoadjuvant chemotherapy in urothelial cancer by genetic determinants of platinum sensitivity.

Abstract

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.

Cytotoxic and DNA‐targeted therapy in urothelial cancer: Have we squeezed the lemon enough?

“…[43][44][45][46][47] These data have yet to be independently validated and a recent analysis demonstrating a significant association between 2 SNPs in the RARS and GALNTL4 genes with pT0 in patients treated with neoadjuvant cisplatin-based chemotherapy failed to be validated in an independent data set. 48,49 Although likely important, the incorporation of inherited genetic variation as a determinant of chemotherapy response is early in development in patients with UC and additional studies are needed.…”