DNA Damage Response Alterations Predict for Neoadjuvant Chemotherapy Sensitivity in Muscle-Invasive Bladder Cancer: A Correlative Analysis of the SWOG S1314 Trial

Abstract

Purpose: Alterations in DNA damage response (DDR) genes, including ERCC2, have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response.

Methods: Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in ERCC2, and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to <pT2) using logistic regression, adjusting for clinical stage and performance status.

Results: Deleterious DDR alterations were detected in 41 (23%) of 179 patients. Of the 151 patients evaluable for pathologic response, patients with deleterious DDR alterations (n = 39) demonstrated a higher pathologic response rate than those without (odds ratio [OR], 3.24 [95% CI, 1.51 to 6.94]; P = .003). In 24 ERCC2-mutant patients, the OR for pT0 was 3.33 (95% CI, 1.35 to 8.22; P = .009) and for <pT2 was 2.33 (95% CI, 0.92 to 5.89; P = .073). The association between deleterious DDR alterations and PFS provided an estimate of hazard ratio, 0.54 (95% CI, 0.29 to 1.01; P = .053).

Conclusion: Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of ERCC2 and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.

Figure 1:

Disposition of specimens analyzed from the SWOG 1314 clinical trial. *5 patients with sequencing data included in genomic cohort (n=184) who were not clinically assessable for survival endpoints per protocol *Patients receiving fewer than 3 cycles of chemotherapy or who were not assessable for pathologic response per protocol

Figure 2:

A) Oncoprint depicting all deleterious DDR gene alterations identified within the S1314 genomic cohort. B) Progression-free and overall survival outcomes stratified by presence or absence of deleterious DDR gene alterations. *No: DDR gene wild-type; Yes: DDR gene deleterious alteration

Figure 3:

A) Deleterious DDR gene alteration profiles of responders (left) versus non-responders (right). B) ERCC2 alterations identified within the S1314 cohort mapped across protein domains. C) Tumor mutation burden in ERCC2 mutant versus wild-type tumors within the S1314 cohort.