DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma

Abstract

Purpose Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. Experimental Design Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with MSK-IMPACT assay were identified. Patients were dichotomized based on presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. Results One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log rank p=0.007) and overall survival (23.7 vs. 13.0 months, log rank p=0.006). DDR alterations were also associated with higher number mutations and copy number alterations. A trend towards positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable impact on clinical outcomes. Conclusion Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.

Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer

“…Indeed, the PI3K/AKT/mTOR pathway was aberrant in a large proportion of patients, suggesting opportunities for testing of AKT inhibitors such as MK2206 that has previously demonstrated activity in bladder cancer cell lines (14). We detected several mutations in DNA repair genes, including a missense mutation in ERCC2 and two truncating ATM mutations, raising the possibility that ctDNA profiling may also help guide implementation of cisplatin-based chemotherapy (48,49).…”

Predictive biomarkers for drug response in bladder cancer

“…Importantly, all but one alteration in the discovery cohort and 12 out of 14 alterations in the validation cohort were predicted to be deleterious in silico analyses, underscoring the functional impact of alterations in the DDR‐related genes in sensitivity to chemotherapy. The Memorial Sloan Kettering‐Integrated Molecular Profiling of Actionable Cancer Targets assay, which sequences exons of 341 cancer‐associated genes including 34 DDR‐related genes, was carried out on tumors from 100 patients with locally advanced or metastatic bladder urothelial cancer treated with CDDP‐ or carboplatin‐based chemotherapy . A total of 47 out of 100 patients harbored alterations in the 34 DDR‐related genes, and had improved progression‐free survival (9.3 vs 6.0 months) and overall survival (23.7 vs 13.0 months).…”

“…The Memorial Sloan Kettering-Integrated Molecular Profiling of Actionable Cancer Targets assay, which sequences exons of 341 cancer-associated genes including 34 DDR-related genes, was carried out on tumors from 100 patients with locally advanced or metastatic bladder urothelial cancer treated with CDDP-or carboplatin-based chemotherapy. 47 A total of 47 out of 100 patients harbored alterations in the 34 DDR-related genes, and had improved progression-free survival (9.3 vs 6.0 months) and overall survival (23.7 vs 13.0 months). The Memorial Sloan Kettering-Integrated Molecular Profiling of Actionable Cancer Targets was also implemented in the aforementioned multicenter prospective trial of NAC with dose-dense gemcitabine plus CDDP for MIBC.…”

DNA Repair Pathway Alterations in Bladder Cancer

“…Similarly, alterations in one or more of a panel of 34 DNA repair genes were associated with improved survival among patients with locally advanced or metastatic bladder cancer receiving first-line platinum-based chemotherapy [54]. Finally, DNA repair gene mutations were also associated with a trend towards decreased disease recurrence among MIBC patients treated with primary chemoradiotherapy [45].…”