Alterations in DNA Damage Repair Genes Before and After Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer.

BACKGROUND AND OBJECTIVE

The role of genetic variants in response to systemic therapy in muscle-invasive bladder cancer (MIBC) is still elusive. We assessed variations in genes involved in DNA damage repair (DDR) before and after cisplatin-based neoadjuvant chemotherapy (NAC) and correlation of alteration patterns with DNA damage and response to therapy.

METHODS

Matched tissue from 46 patients with MIBC was investigated via Ion Torrent-based next-generation sequencing using a self-designed panel of 30 DDR genes. Phosphorylation of γ-histone 2A.X (H2AX) was analyzed via immunohistochemistry to evaluate DNA damage. Genetic variants were analyzed along with clinical data and quantitative phospho-H2AX data using the Kaplan-Meier method, Cox regression analysis, and factor analysis of mixed data.

KEY FINDINGS AND LIMITATIONS

Twenty-five patients (54%) had a response (<pT2 pN0 cM0) to NAC. Responders had more somatic DDR gene variants in preNAC (53 vs 11;  < 0.001) and postNAC (51 vs 9;  = 0.038) tumor tissue in comparison to nonresponders, as well as significantly greater phosphorylation of H2AX after NAC. was significantly co-mutated with among responders. Owing to the small cohort, no specific mutation was significantly positively associated with therapy response. However, accumulation of , , , , , , , , and variants was observed for responders.

CONCLUSIONS AND CLINICAL IMPLICATIONS

Patients with MIBC who responded to cisplatin-based NAC had more somatic DDR gene variants than nonresponders. Moreover, responders exhibited significantly greater DNA damage after NAC.

PATIENT SUMMARY

Patients with muscle-invasive bladder cancer who have mutations in genes that are involved in repair of DNA damage are more likely to respond to cisplatin-based chemotherapy. Testing to identify these gene mutations could help in selecting the patients who are most likely to benefit from this treatment.