Abstract 4915: Identification and validation of novel prognostic genetic markers in HER2-negative advanced gastric cancer (AGC) by artificial intelligence (AI) deep learning and machine learning algorithm

Abstract Introduction: Despite advances in anticancer treatments, there has been urgent need to identify novel prognostic markers for HER2-negative AGC. We propose AI based deep learning and machine learning pipeline to explore genetic markers that predict patient response to chemotherapy in HER2-negative AGC. Methods: We retrospectively assessed 179 stage IV HER2-negative AGC patients who have been treated with first-line chemotherapy in Yonsei Cancer Center, Korea between 2015 and 2021. In-house targeted sequencing panel data (CancerSCANTM and CancerMaster) were used to identify candidate prognostic markers. DeepSurv was mainly used to analyze the progression-free survival (PFS), which is a deep learning algorithm that can investigate prognostic roles. The SHapley Additive exPlanations (SHAP) method was applied to open the deep learning models’ black-box and calculate the importance ranking of gene features. Machine learning models-random survival forest, elastic-net, and lasso-were also investigated to identify potentially meaningful gene variants. To rank the gene features, we calculated variable importance (VIMP) for random survival forest, and penalized regression coefficients for elastic-net and lasso. All deep learning and machine learning models were trained using 5-folds cross-validation in 1,000 iterations of re-sampling bootstrapping with hyperparameter tuning by grid search. To classify responder or non-responder related genetic markers to chemotherapy, we used the signs of averaged penalize coefficients obtained from elastic-net and lasso. Based on the median linear predictor with candidate gene features, patients were classified into high-risk and low-risk group. Results: A total of 7,824 common variants were analyzed and 20 prognostic genetic markers were identified based on the top average values of SHAP, VIMP, and penalized regression coefficients. The top 10 non-responder genetic markers are included as follows: PARP4(p.S873N), CHUK(p.V268I), BARD1(359_365del), CREBBP(p.Y1125F), BARD1(p.P24S), PHLPP2(p.R1312Q), FAT3(p.Q3375R), CASP5(p.T106A), PHLPP2(p.I544V), and PTCH2(p.T988M). Otherwise, the top 10 responder genetic markers are defined as follows: IL7R(p.I66T), NOTCH4(L16delinsLL), FGFR3, BCL2A1(p.G82D), ZNF217(p.T548I), BRCA1(p.K1183R), FANCA(p.A412V), ADGRA2, CDKN2B, and FANCM(p.S175F). The high-risk group had worse PFS compared with low-risk group (median PFS 4.1 vs. 9.1 months; P-value <0.0001). Conclusion: This study showed the potential of AI deep learning and machine learning pipeline that employs an innovate prognostic genetic markers for HER2-negative AGC. Current ongoing analyses of larger cohort with more comprehensive clinical data will be presented. Citation Format: Sejung Park, Seok-Jae Heo, Choong-Kun Lee, Yaeji Lee, Woo Sun Kwon, Jingmin Che, Minseok Kim, Hyun Cheol Chung, Sun Young Rha. Identification and validation of novel prognostic genetic markers in HER2-negative advanced gastric cancer (AGC) by artificial intelligence (AI) deep learning and machine learning algorithm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4915.