Abstract 1243: Identification of aneuploidy biomarkers associated with response to first-line treatment of metastatic pancreatic cancer
Authors: Chen Kuei-Ting , Sharaf Radwa , Frampton Garrett , Albacker Lee , Ebot Ericka 
Published: June 2022

Background: NCCN guidelines for first-line treatment of patients with metastatic pancreatic cancer includes either FOLFIRINOX or gemcitabine plus paclitaxel; however, these two treatment regimens have not been compared in a randomized clinical trial. In this study, we investigated genomic predictors of treatment response to guide this treatment decision.

Methods: We selected 1,250 patients with metastatic pancreatic cancer who were treated with first-line FOLFIRINOX (FOLF, n = 588) or gemcitabine plus paclitaxel (G+P, n = 662) within the nationwide de-identified Flatiron Health-Foundation Medicine clinico-genomic database (CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care). Comprehensive genomic profiling was performed by Foundation Medicine on tumor samples from each patient as part of the standard of care. Gain/loss status as well as loss of heterozygosity (LOH) status of each chromosome arm was assessed using a custom research-use only algorithm that utilizes copy number model calls for each segment and SNP MAF information from sequencing data. Univariable Cox proportional hazards regression was used to identify chromosome arm-level aneuploidies associated with survival in patients treated with first-line FOLF or G+P. In each treatment cohort, a multivariable Cox model was built using the bidirectional stepwise regression procedure to select aneuploidy features associated with survival. A binary risk score was calculated based on the linear predictor of the multivariable Cox model and categorized as high vs low using a median threshold.

Results: Among the FOLF-treated cohort, we identified six aneuploidy features associated with survival (Bonferroni adjusted p &lt; 0.05). FOLF-treated patients with a low FOLF risk score had better survival compared to those with a high FOLF risk score (HR: 0.46, 95%CI: 0.34-0.61, p = &lt;0.001). This association was not observed among G+P-treated patients (HR: 0.86, 95%CI: 0.66-1.11, p = 0.25). Among the G+P treated cohort; eight aneuploidy features were associated with survival (Bonferroni adjusted p &lt; 0.05). G+P-treated patients with a low G+P risk score had better survival compared to patients with a high G+P risk score (HR: 0.43, 95%CI: 0.33-0.57, p = &lt;0.001). This association was not observed among FOLF-treated patients (HR: 0.86, 95%CI: 0.66-1.12, p = 0.25). These findings remained after adjusting for clinical features including surgery and ECOG performance status (HRG+P: 0.52, p = &lt;0.001; HRFOLF: 0.5, p = &lt;0.001).

Conclusions: In metastatic pancreatic cancer, we found different chromosome arm-level aneuploidies were associated with survival for FOLF and G+P regimens which suggests an aneuploidy-based risk score may have utility in choosing first-line treatment.

Citation Format: Kuei-Ting Chen, Radwa Sharaf, Garrett Frampton, Lee Albacker, Ericka Ebot. Identification of aneuploidy biomarkers associated with response to first-line treatment of metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1243.