DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy.

Background: Loss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown.
Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy.
Results: Del DDR were detected in 43/229 patients (19%). The most frequently altered genes were CHEK2 and ATM . Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14-1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903).
Conclusion: Del DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.
Competing Interests: Competing interests: MIC reports consulting/advisory role for Pfizer. C-HL reports consulting/advisory role for Exelixis and Eisai. DRF reports research support from Novartis and Seattle Genetics. TAC reports research support from Bristol-Myers Squibb, AstraZeneca, Eisai, An2H and Illumina. TAC holds a patent for the use of TMB to predict immunotherapy response. This is licensed to PGDx and MSKCC and TAC are entitled to receive royalties. TAC is a cofounder of Gritstone Oncology and holds equity. RJM reports grants and personal fees from Pfizer, grants and personal fees from Eisai, personal fees from Exelixis, grants and personal fees from Novartis, grants from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, personal fees from Merck, personal fees from Incyte, grants from GlaxoSmithKline, outside the submitted work. MHV reports receiving commercial research grants from Bristol-Myers Squibb and Genentech/Roche. Honoraria from Novartis. Travel/accommodation from Eisai, Novartis and Takeda. Consultant/advisory board member for Alexion Pharmaceuticals, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, GlaxoSmithKline, Natera, Novartis and Pfizer.
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