Retrospective analysis of colorectal cancer mutations and their associated risk of oxaliplatin-induced peripheral neuropathy.

e24091 Background: Oxaliplatin-induced peripheral neuropathy (OIPN) presents a huge clinical challenge for patients and clinicians as reliable biomarkers to identify patients at risk of developing OIPN are lacking. Previous studies have focused on circulating molecules (e.g., neurofilament light chain) as potential biomarkers associated with OIPN risk in the post-chemotherapy period. Conversely, insufficient investigations have concentrated on the potential effects of the tumor itself (pre-chemotherapy) and OIPN. In order to address this gap, we sought to determine whether there was a relationship between colorectal cancer (CRC) and OIPN. Methods: This is a retrospective cohort study enrolling patients with CRC (any stage) from 2013-2024 with clinically documented OIPN by comprehensive medical record review documenting demographic and other clinical features. OIPN was defined as “cold sensitivity”, “numbness” “tingling” or “neuropathy” and/or dose reduction, delay or discontinuation as a result of OIPN symptoms. Our study leveraged routine primary tumor DNA sequencing of CRC patients treated at AHWFBCCC (n=156) by FoundationOneCDx testing, which analyzes over 360 tumor mutations. Results: We found that patients with OIPN (n=123) received a higher cumulative dose of oxaliplatin and have a higher proportion of non-smokers compared to current smokers than non-OIPN patients (n=33). While we did not find any single mutation associated with OIPN, notably, we observed that patients with a low number of primary tumor mutations (<11) have an increased risk of developing OIPN compared to patients harboring a high number of tumor mutations (≥11) (p = 0.0138) after adjusting for race, age, sex, oxaliplatin cumulative dose, and smoking status. Using ROC Curve analysis, we also found that number of mutations was promising as a predictive marker for OIPN (AUC = 0.668). We next aimed to ascertain how these mutations potentially function together and performed cancer pathway analysis comparing patients by OIPN status. Our analysis revealed that mutations in the Notch and TGFβ pathway were enriched in patients without OIPN. Conclusions: Our findings suggest, for the first time, that the primary tumor mutational profiles of patients with and without OIPN differ in their mutation number and associated pathways associated. We speculate that a low number of tumor mutations and/or inactive pathways may trigger immune cell activation to induce pro-inflammatory cytokine release that damages nerves, resulting in OIPN, although mechanistic studies are warranted. Our studies indicate harboring less tumor mutations may be a factor in altering the risk of developing OIPN and thus routine tumor sequencing has the potential to be utilized as an OIPN predictive biomarker.