Patient-Specific, Tiered, Variant-Level Actionability Correlates With Functional Effect In Growth Survival Assay.

Abstract Purpose: There is increasing recognition that variants within an actionable gene may differ in their functional impact and therapeutic implications. The Precision Oncology Decision Support (PODS) team at MD Anderson Cancer Center (MDA) curates a knowledgebase of cancer-associated genomic alterations for their functional impact and therapeutic actionability. However, a substantial number of variants are not characterized within the published literature. In the MDA-PODS classification scheme, these variants are classified as “potentially” actionable, as opposed to “unknown”, if evidence exists that other variants within the same region are oncogenic. To determine the value of this tiered actionability approach, we assessed if a variant with a “potentially” assertion is more likely to have an experimentally validated oncogenic effect within a functional genomics platform (Ng et al., Cancer Cell, 2018). Procedures: Alterations researched within the published literature and found to be of unknown significance were submitted to the functional genomics platform. These variants were tested within two cell line models (Ba/F3 and MCF10A) to assess growth factor-independent survival. Results were returned to PODS indicating whether the variant conferred a change in cell viability compared with the wildtype gene. PODS then compared the functional effect of the variant with the predetermined actionability assertion. Results: During 2015-2019, PODS received functional genomics results for 485 alterations spanning 38 genes. 115 (24%) of the alterations increased survival and were thus actionable, while 364 (75%) had no effect or suppressed cell viability. Six alterations had conflicting effects in the two cell line models and were not further considered. Of the 479 variants (in 38 genes), 208 variants (43%) in 20 genes were classified as “potentially” actionable prior to functional genomics, while 254 variants (53%) in 35 genes were classified as “unknown”. 17 (4%) were classified as Yes/No for actionability based on other criteria, such as drug response. 78 (38%) of the 208 “potentially” actionable variants were found to be oncogenic in the functional genomics platform as opposed to only 29 (11%) of the 254 variants classified as “unknown” for actionability (p<.01). 70% of the 78 “potentially” actionable, experimentally-validated variants were located within two amino acids of another known oncogenic variant, per our current knowledgebase. Conclusions: These data display the value of providing a tiered, variant-level actionability scheme that includes a “potentially” actionable assertion, as it is associated with a greater likelihood of being functionally validated. Although genomically-matched therapy is most compelling for patients with known actionable variants and functional testing adds value, tiered actionability predictions can inform therapeutic decisions. Citation Format: Amber Johnson, Patrick Kwok-Shing Ng, Michael Kahle, Julia Castillo, Bianca Amador, Vijaykumar Holla, Thuy Vu, Le Huang, Fei Su, Sunhee Kim, Jia Zeng, Md Abu Shufean, Tara Conway, Kenna R. Shaw, Timothy A. Yap, Jordi Rodon, Funda Meric-Bernstam. Patient-specific, tiered, variant-level actionability correlates with functional effect in growth survival assay [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 392.