Abstract 2496: Molecular characterization of stage III colon cancer patients with recurrence after adjuvant chemotherapy

Abstract

Abstract Introduction: Patients with stage III colon cancer are routinely treated with resection followed by adjuvant chemotherapy (ACT) with a fluoropyrimidine and oxaliplatin. This one-size-fits-all approach does not account for heterogeneity in tumor biology and fails to cure ~30% of patients, highlighting the urgency for biomarkers to better understand and predict resistance to ACT or to offer alternative targeted treatment. Aim: To identify molecular characteristics predictive of resistance to standard ACT in stage III colon cancer. Methods: Patients with resected stage III colon cancer who received ACT (93% CAPOX, 7% CAP) were selected from the Prospective Dutch Colorectal Cancer cohort (PLCRC). RNA exome capture sequencing was performed on resected FFPE tumor tissue to compare differential gene expression, hallmark pathway enrichment, immune cell deconvolution and consensus molecular subtypes (CMS) between patients with versus without recurrence after surgery and ACT. Postsurgery circulating tumor DNA (ctDNA) detected in PLCRC-PROVENC3 (separate abstract) was used to select a subgroup with minimal residual disease (MRD) postsurgery, as sensitivity analysis of patients with recurrence despite ACT (chemoresistant) versus curation by ACT (chemosensitive). Results: For 264 out of 278 patients (95%), tumor-derived RNA sequencing libraries were of sufficient quality. 67 patients (25%) with recurrence (median after 13 months [IQR 7-23]) were compared to 178 patients with at least 2 year recurrence-free follow-up (median 42 months [IQR 30-53]). A total of 320 genes were differentially expressed between patients with versus without recurrence. Genesets defining epithelial-mesenchymal transition (p = 0.002) and angiogenesis (p < 0.001) were enriched in the primary tumor of patients with recurrence, in part explained by the estimated larger fraction of stroma (Wilcoxon effect size r 0.18, p < 0.001) and cancer-associated fibroblasts (CAFs) (r 0.19, p = 0.003). In contrast, the fraction of CD4+ T cells was lower (r 0.14, p = 0.001). Consistently, CMS4 was found more frequently in tumors from patients with versus without recurrence (57% versus 34%, p < 0.001). Of the subgroup with ctDNA-based MRD postsurgery (26 out of 171 assessed patients), 19 patients (73%) with recurrence (median after 12 months [IQR 7-17]) were compared to 7 patients without recurrence (minimum follow-up 32 months). This sensitivity analysis showed similar trends in pathways, immune cells and CMS as the main analysis, with a more pronounced effect size for CAFs (r 0.27). Conclusion: Stage III colon tumors of patients who experience recurrence after resection and ACT are enriched for stroma and CAFs, while displaying less CD4+ T cells. The observed trends are sustained in the patients with MRD postsurgery. These findings may help to better predict resistance to standard ACT and elucidate targets for alternative personalized treatment. Citation Format: Ingrid Franken, Steven Ketelaars, Carmen Rubio-Alarcón, Sietske van Nassau, Suzanna Schraa, Gerrit Meijer, Mark Sausen, Miriam Koopman, Geraldine Vink, Sanne Abeln, Remond Fijneman, Jeanine Roodhart, on behalf of the PLCRC-MEDOCC group. Molecular characterization of stage III colon cancer patients with recurrence after adjuvant chemotherapy [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 2496.