Purpose: DNA damage response (DDR) deficiency is a hallmark of cancer and can be exploited with therapeutic interventions such as the use of PARP inhibitors and PD-1/PD-L1 immune checkpoint inhibitors. To understand the relationship between clinically actionable DDR genomic alterations (GA) and DDR deficiency biomarkers, we investigated the distribution of the GA in the most common DDR genes and explored the association with DDR deficiency biomarkers by utilizing the Foundation Medicine comprehensive genomic database across different cancer types. These data may provide essential information to refine and define the clinical translational strategies for innovative cancer therapies in clinical development. Methods: Molecular profiles from a total of 269,371 clinically advanced and diverse malignancies were analyzed using FoundationInsightsTM. Genomic alterations including short variants, copy number alterations and rearrangements in 35 DDR genes, more complex biomarkers (tumor mutation burden [TMB], genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status) and PD-L1 expression were studied. Only functional alterations (known or likely oncogenic) were analyzed. Results: DDR gene alterations are frequent and non-uniformly distributed by type and frequency across cancer types including breast, ovarian, colorectal, esophagus, biliary track, gastric, head and neck, pancreas, melanoma, lung, bladder, and prostate. TP53 is the most frequently altered DDR gene across all cancers as expected (59%), followed by ARID1A (9%), ATM (4%), SMARCA4 (3%), MDM2 (3%), BRCA2 (3%), BRCA1 (2%), CHK2 (2%), MUTYH (2%), whereas many other DDR genes are rarely altered (≤1%). Excluding TP53 from the analysis, bladder cancer has the highest cumulative rate of cases with mutations in DDR genes (46.59%), while other cancers have rates ranging between 20-40%. Further analyses including the relative distribution of TMB, MSI, gLOH and PD-L1 expression by tumor type and their association with DDR GA are ongoing. Conclusion: Identifying associations of DDR alterations and immuno-oncology associated predictive biomarkers (TMB, PD-L1) as well as assessment of signatures of genomic instability (MSI, gLOH) are critical for enabling biomarker-driven precision oncology. We systematically analyzed somatic alterations using the Foundation Medicine comprehensive genomic database and provide a comprehensive molecular profiling of DDR deficiencies in advanced solid tumors. It is anticipated that this data will collectively contribute to identify molecularly defined tumor subsets, where single and/or combination therapies such as DDR inhibitors, immunotherapies, targeted therapies etc. may result in increased clinical benefit for patients with cancer.

Citation Format: Danyi Wang, Brian Elenbaas, Karthikeyan Murugesan, Lee A. Albacker, Julien Doudement, Juergen Scheuenpflug, Giuseppe Locatelli, Zheng Feng. Comprehensive molecular profiling of DNA damage response (DDR) deficiencies in advanced solid tumors using a real-world genomic database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2062.