Abstract 4931: Not all tumors are created equal: Evaluating the impact of comprehensive genomic profiling (CGP) on clinical outcomes in esophageal/gastroesophageal cancer (GEJ CA)

Introduction: Systemic chemotherapy plays a pivotal role in the treatment of localized and metastatic GEJ CA patients (pts), however, there are no reliable predictive biomarkers. CGP is increasingly used to guide selection of targeted therapies, but its role in personalizing cytotoxic chemotherapy is not clear. We investigated the correlation between somatic alterations (SAs) and clinical outcome in pts with GEJ CA treated with cytotoxic chemotherapy. Methods: Medical records of all patients with GEJ CA who had CGP data available were retrospectively reviewed under an IRB approved protocol. DNA was extracted from formalin fixed paraffin embedded clinical specimens and CGP was performed on hybrid-capture, adaptor ligation-based libraries to a mean coverage depth of >600 unique reads utilizing the Foundation Medicine platform (315 gene panel). The effect of the SAs and clinical covariates on response and survival outcomes were modeled using logistic and Cox regression analyses, respectively. Lasso was used for model selection, with the penalty parameter chosen as providing the lowest error-rate via 5-fold cross-validation. Results: Fifty-six patients were identified; median age was 62.5, 51(91%) were male, 39 (70%) had metastatic disease, histology was adenocarcinoma in 41 (73%) and ERBB2 amplification was detected in 11 pts (22%). Median tumor mutational burden (TMB) was 6.1 (0.9-75.7) and one patient had a microsatellite unstable tumor. 46 (82%) pts received a platinum-based combination as first line therapy, mfolfox6 was the most commonly utilized regimen (30%). Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD) were noted in 3 (5.6%), 34 (63.0%), 5 (9.3%) and 12 (22.2%) pts, respectively. Median progression free survival (PFS) and OS was 31.3 and 72.8 months, respectively for patients with localized GEJ CA, while median PFS and OS were 6.3 and 18.7 months, respectively for patients with metastatic GEJ CA. On multivariate analysis, in addition to stage, SA in SPTA1 correlated with improved response (p=0.0026, OR=0.052, 95% CI 0.002-0.378), while SAs in PIK3CG (p = 0.016; HR=-6.7, 95% CI 1.26-30.46) and EGFR (p = 0.041; HR=3.6; 95% CI 0.9-11.8) correlated with worse overall survival (OS). Conclusion: We were able to identify SAs that correlated with objective response and survival, however, confirmatory analyses in larger datasets and prospective validation is necessary. The negative prognostic effect of SAs in PIK3CG and EGFR merit further exploration, considering their viability as therapeutic targets. Robust, quantitative and systematic somatic analysis of pre-treatment biopsies, pathway-network analysis and correlation with clinical outcome are essential to gaining mechanistic insights and maximizing therapeutic impact. Citation Format: Vidya Kollu, Arun Singhavi, Paul S. Ritch, James P. Thomas, Aniko Szabo, Ben George. Not all tumors are created equal: Evaluating the impact of comprehensive genomic profiling (CGP) on clinical outcomes in esophageal/gastroesophageal cancer (GEJ CA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4931.