Ataxia-telangiectasia mutated loss of function displays variant and tissue specific differences across tumor types

Abstract Introduction: ATM loss of function (LOF) in cancer may serve as a predictive biomarker of response for antitumor therapies. However, clinical studies of targeted treatments in ATM-aberrant patients have yielded mixed results; thus, identifying the optimal strategy for selecting patients with ATM LOF tumors remains a critical area of unmet need. Methods: In order to investigate the heterogeneity observed in ATM aberrant tumors, we conducted a pan-cancer genomic and proteomic profiling of ATM LOF, and also performed retrospective review of clinical outcomes for a subset of patients with ATM LOF treated with platinum or ATR inhibition. Results: We identified 10,609 ATM variants in 8,587 patients with cancer. The prevalence of deleterious (Tier 1) versus variants of unknown significance (VUS)/benign (Tier 2) variants differed by cancer tissue type, as did selective pressure for loss of heterozygosity (LOH). Analysis of ATM protein staining in 471 patient tumors showed tumors with null, inactivating variants were significantly (p<0.005) more likely to display ATM loss of protein (LOP) than tumors with missense or wildtype, but 19% (N=27/140) and 9% (N=13/149) of tumors with ATM-VUS and wildtype showed loss of protein. In addition, concordance between inactivating mutations and loss of protein also differed based on tumor tissue context, with ovarian and breast cancer showing stronger concordance (greater than 80%) than melanoma and lung cancer ( less than 20%). Patients treated with platinum chemotherapy with select tumor types with deleterious variants in ATM and ATM LOP display improved progression free survival (PFS) (HR 0.50, P=0.03). Lastly, patients with tumor types that have stronger ATM variant-to-protein loss concordance display increased benefit from ATR inhibition (HR 0.40, P=0.04). Conclusions: Our data highlight that there is heterogeneity in ATM LOF in patients due to multiple variables, including notable tissue-specific differences in the type of variants seen and the relationship between ATM variant status and ATM protein. This genomic heterogeneity and tissue-specificity has implications for predictive biomarker development and clinical trial designs. Citation Format: Patrick G. Pilie, Daniel Mcgrail, Wei-Lien Wang, Natalie Ngoi, Keith Kyewalabye, Khalida Wani, Hung Le, Erick Campbell, Vijaykumar Holla, Kenna R. Shaw, Funda Meric-Bernstam, Alexander J. Lazar, Virginia Giuliani, Timothy Heffernan, Timothy A. Yap. Ataxia-telangiectasia mutated loss of function displays variant and tissue specific differences across tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3432.