Assessing adjuvant chemotherapy benefit in younger and older molecular residual disease–positive patients with stage II/III colorectal cancer.

216 Background: Identifying patients with colorectal cancer (CRC) who derive benefit from adjuvant chemotherapy (ACT) presents a significant challenge. This is especially true given the aging patient population, which accounts for over half of all new CRC diagnoses and represents a diverse group susceptible to chemotherapy toxicities. The survival benefit of oxaliplatin-based regimens (doublet ACT) for younger patients with stage III CRC is well-established; however, this has not been conclusively demonstrated for patients aged 70 or older, and clinical uncertainty remains. This retrospective study assessed disease-free survival (DFS) in younger and older patients with molecular residual disease post-surgery when treated or not treated with ACT. Methods: Among 6,061 patients from the GALAXY cohort, patients (N= 260) with stage II or III CRC and with ctDNA-positivity during the molecular residual disease (MRD) window (2-10 weeks post surgery) were included in the analysis. A tumor-informed, 16-plex PCR-NGS assay (Signatera Natera, Inc.) was used for ctDNA analysis. This study evaluated DFS among MRD-positive patients when stratified by age (≥70 years vs. <70 years) and ACT status. The survival analysis was adjusted for age, sex, stage, ECOG performance status, MSI status, and BRAF and RAS mutations, where applicable. Results: Among the 260 MRD-positive patients included in this study, 49.2% (128/260) were <70 years old and 50.3% (132/260) were ≥70 years old at the time of diagnosis; 21% (55/260) had stage II and 79% (205/260) had stage III disease. Overall, 72% (187/260) received ACT, and 28% (73/260) did not receive ACT. MRD-positive patients showed a clear benefit of ACT in improving DFS in both age groups compared to patients who did not receive ACT (<70 years, adj. HR: 0.19, 95% CI: 0.1-0.35; p<0.0001; ≥70 years, adj. HR: 0.2, 95% CI: 0.11-0.37, p<0.0001). Notably, the use of oxaliplatin resulted in similar DFS (p=0.87) regardless of age. The multivariate analysis demonstrated ACT and BRAF mutation status to be the only significant predictors of DFS (ACT: HR = 0.22, 95% CI: 0.14-0.33; p<0.001; BRAF mutation: HR = 4.32, 95% CI: 1.86-10.01, p<0.001), whereas age was not an independent prognostic factor (p=0.28). Conclusions: This study demonstrated that MRD-positive stage II-III colon cancer patients derive a clear DFS benefit from ACT, irrespective of their age. Oxaliplatin-based regimens were similarly effective in younger and older patients. Future studies evaluating whether the benefit of ACT outweighs the risk of toxicity in older patients are warranted to further validate the findings of this study. Clinical trial information: UMIN000039205 .