Comprehensive genomic profiling to identify gene alterations in DNA repair pathway across solid tumors.

Abstract

3124 Background: Deleterious events in DNA damage response (DDR) are hallmarks of cancer associated with sensitivity to PARP inhibitors (PARPi) and immune checkpoint inhibitors (CPI). This study investigated DDR pathway alterations across solid tumors. Methods: Samples were sequenced with the Oncomap ExTra assay using tumor-normal paired whole-exome DNA sequencing to detect single base substitutions, indels, and copy number alterations that were clinically actionable, defined as associated with FDA approved drugs or clinical trial enrollment. Here, we report the frequency of MSI-high and TMB-high (>10 mutations/Mb), and clinically-actionable alterations for the following 49 DDR genes: ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CDK12, CHEK1/2, EPCAM, ERCC1/2/3/4/5, FANCA/C/D2/E/F/G/I/L/M, MLH1, MRE11A, MSH2/6, MUTYH, NBN, PALB2, PMS2, PPP2R2A, PTEN, RAD21/50/51/51B/51C/51D/52/54L, XRCC1/2/3. Results: Of the 6055 patient samples profiled, 1633 (27.0%) had clinically actionable alterations in DDR genes; DDR alterations varied from 0-64.3% across tumor types. For the 5657 samples with TMB/MSI data, 429 (7.6%) had high TMB and 193 (3.4%) were MSI-high; MSI-high samples were usually TMB-high (n = 180; 93.2%). The percent of cancers that were TMB-high or MSI-high varied from 0-64.8% and 0-20.8% respectively. Actionable BRCA1/2 gene alterations were present in 319 patients (5.3%, range 0-15.3%). Three cancers (biliary, brain and liver) had BRCA1/2 alterations in less than 2% of patients but across the 49 DDR genes alterations were present in more than 20% of patients, representing a greater than 10-fold difference. Across solid tumors, this analysis identifies a group of 1314 patients (21.7%) who harbor a DDR gene alteration other than BRCA1/2. Conclusions: Defective DNA repair as detected by deleterious alterations in DDR genes along with TMB/MSI status has the potential to guide clinicians to FDA-approved therapy or clinical trial enrollment in a large percentage of patients across solid tumor types.[Table: see text]