Analysis of DNA damage response (DDR) genes and tumor mutational burden (TMB) across 17,486 carcinomas of the tubular GI tract: Implications for therapy.

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43 Background: The DDR pathway is important in tumor biology, allowing cancer cells a mechanism to resist damage by chemotherapy and radiotherapy. BRCA1/2 are the most well described genes in the pathway, but several others ( ATM, ATR, PALB2, etc.) are involved with DDR and are mutated in many cancers. Tumors with a DDR defect are susceptible to PARP inhibition (PARPi) in some cases, but also potentially to immune checkpoint inhibitors (ICPIs), given immunomodulatory effects of PARPi and the hypermutated phenotype commonly associated with these genomic alterations (GA). We looked at the prevalence of select DDR defects in tubular GI cancers and the correlation between DDR and TMB. Methods: We prospectively analyzed samples from 17,486 unique patients with advanced colorectal (CRC), esophageal, gastric, or small bowel carcinomas using hybrid-capture based comprehensive genomic profiling. TMB (mutations/Mb) was calculated from 1.11 Mb of sequenced DNA. We looked at GA in 8 genes- ARID1A, ATM, ATR, BRCA1, BRCA2, CDK12, PALB2, RAD51 across these tumors types. Results: DDR GA were found in 16% of cases: gastric 464/1,750 (27%), small bowel 141/666 (21%), esophageal 441/2,501 (18%), and CRC 1,824/12,569 (15%). ARID1A (9.0%) and ATM (5%) were the most commonly altered DDR genes in this series, followed by BRCA2 (2.3%), BRCA1 (1.1%), ATR (0.8%), CDK12 (0.7%), PALB2 (0.6%), and RAD51 (0.1%), with 24% (675/2,870) of DDR-altered cases having GA in more than one DDR gene. Among DDR-altered cases, 21% had high TMB (≥20 mut/Mb) compared to just 1.4% high TMB in DDR-wild-type cases (p < 0.001). Microsatellite instability (MSI) status was available for a subset of cases and 19% (419/2,154) of those with a DDR GA were MSI high. CDK12 and ATR altered cases had the highest proportion of high TMB: CDK12 (55%, median TMB 31.5 mut/Mb) and ATR (55%, median TMB 35.1 mut/Mb), followed by cases with GA in BRCA2 (40%), BRCA1 (28%), ARID1A (27%), ATM (22%), and RAD51 (20%). Conclusions: DDR defects are relatively common across tubular GI tumor types and are associated with a hypermutated phenotype in over 20% of cases. This may be important to identify likely responders to both PARPi and ICPIs.