Abstract 1231: Prognostic and predictive drug-induced gene signatures for colorectal cancer patients personalized based on p53 status and treatment with FOLFOX, 5-FU, oxaliplatin, or irinotecan
Authors: Carlsen Lindsey , Elliott Andrew , Capelletti Marzia , Hall Micheal , Philip Philip A. , Lenz Heinz-Josef , Safran Howard , Almhanna Khaldoun , Breakstone Rimini , Raufi Alexander G. , Lou Emil , Marshall John L. , Korn W. Michael , El-Deiry Wafik S. 
Published: June 2022

Abstract
Metastatic colorectal cancer (CRC) is a deadly disease with a 13% survival rate. CRC is often treated with chemotherapeutic agents 5-fluorouracil, irinotecan, and oxaliplatin, but predictive biomarkers are limited. We hypothesized that tumor expression of genes related to extent of drug exposure, stratified by p53 status, is associated with clinical outcomes on these regimens. To this end, we evaluated the prognostic and predictive significance of genes within p53-independent, p53-dependent, pan-drug, and drug-specific gene signatures established in CRC cells treated with 5-FU, irinotecan, or oxaliplatin. CRC patient samples were analyzed by DNA/RNA next-generation sequencing at Caris Life Sciences, and real-world survival outcomes were inferred from insurance claims data and Kaplan-Meier estimates. Samples with benign or no TP53 mutations detected (wt) (n=2983) or TP53 loss-of-function (LOF) mutations (n=6229) were stratified (high/low) by median expression of signature genes for comparison. Overall prognostic and predictive values in response to 5-FU, irinotecan, or oxaliplatin, regardless of line of therapy or concurrent therapies, or first-line FOLFOX were evaluated to estimate the contribution of each drug. From signatures established in CRC cell lines, a prognostic effect was observed for genes in p53 wt (n=19) and LOF (n=22) subgroups, with a similar survival effect observed for several genes (n=16). Both prognostic and non-prognostic gene expression had a significant effect on survival outcomes following specific drug treatments. Predictive genes included BTG2, a p53-dependent gene upregulated by 5-FU, irinotecan, and oxaliplatin in CRC cells that predicted better outcomes when expressed at high levels in p53 wt patients. Several genes in drug-specific signatures were predictive in a drug-specific manner including RABGAP1L and RAD51B (irinotecan), and SAT1 (oxaliplatin), suggesting their particular relevance for patients receiving these drugs. For some genes such as RABGAP1L and RAD51B, drug treatment downregulated gene expression but high expression predicted better survival in patients, suggesting benefit of combination therapy to limit such effects. From a real-world cohort of p53 wt and LOF CRC tumors, we demonstrate the prognostic and predictive potential of candidate gene expression in response to commonly used chemotherapeutics. Accompanying data on drug regulation of predictive genes provides valuable information in evaluating clinical impact of pan-drug or drug-specific mechanisms. Future directions include associations with clinically relevant features (microsatellite instability, tumor sidedness, and age), establishment of multi-gene signatures to improve clinical utility, and evaluation of other regimens including FOLFIRI and FOLFOXIRI.
Citation Format: Lindsey Carlsen, Andrew Elliott, Marzia Capelletti, Micheal Hall, Philip A. Philip, Heinz-Josef Lenz, Howard Safran, Khaldoun Almhanna, Rimini Breakstone, Alexander G. Raufi, Emil Lou, John L. Marshall, W. Michael Korn, Wafik S. El-Deiry. Prognostic and predictive drug-induced gene signatures for colorectal cancer patients personalized based on p53 status and treatment with FOLFOX, 5-FU, oxaliplatin, or irinotecan [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 1231.