Differential effects of <i>RAS</i> mutations on chemoradiotherapy and total neoadjuvant therapy in locally advanced rectal cancer

Limited data are available on the impact of RAS mutations in patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT). This retrospective study aimed to evaluate the effect of RAS mutations on treatment efficacy in 290 patients with locally advanced rectal cancer without distant metastasis, treated between 2015 and 2021 with neoadjuvant long-course chemoradiotherapy (CRT) with or without neoadjuvant systemic chemotherapy. RAS mutations were analyzed using pretreatment biopsy specimens. Associations between mutations and clinical outcomes were assessed separately in 146 patients who underwent conventional CRT and 144 patients who underwent TNT. RAS mutations were identified in 42.5% and 51.4% of the CRT and TNT groups, respectively. No significant association was observed in either group between RAS mutation and complete response (CR, defined as pathological CR or sustained clinical CR after non-operative management). However, in the multivariable analysis, RAS mutations were significantly associated with a high neoadjuvant rectal score and worse recurrence-free survival in the CRT group. Yet, no such associations were observed in the TNT group, suggesting that TNT may mitigate the adverse effects of RAS mutations. Although further prospective, multicenter studies are required, our data suggest that RAS mutations may predict poor responses and higher recurrence risk among patients with locally advanced rectal cancer, and that TNT may be the better treatment option for these patients.