Impact of TP53, KRAS, and APC Mutations on Neoadjuvant Chemotherapy Outcomes in Locally Advanced Rectal Cancer

Abstract

Despite recent advances in neoadjuvant strategies for locally advanced rectal cancer (LARC), optimal chemotherapy regimens and the role of genetic biomarkers in guiding treatment remain unclear. Moreover, predictive markers are urgently needed for radiation-sparing strategies. Therefore, we aimed to assess the predictive and prognostic value of TP53, KRAS, and APC mutations in patients with LARC undergoing neoadjuvant chemotherapy (NACT) by retrospectively analyzing 43 patients with LARC who underwent NACT without radiation. Treatment response was assessed using RECIST criteria, revealing that 55.8% of patients exhibited a complete or partial response, which was significantly correlated with improved recurrence-free survival (p = 0.015). Conversely, tumor regression grade (TRG) did not predict survival outcomes. Targeted amplicon sequencing of pre-treatment biopsy and surgical specimens revealed high mutation frequencies in TP53 (74.4%), KRAS (44.1%), and APC (32.5%). TP53 mutations included diverse alterations, particularly gain-of-function missense variants, reflected in distinct immunohistochemical patterns. KRAS mutations mainly affected codon 12, and APC mutations were predominantly truncating. Notably, KRAS + APC co-mutations, observed in 11.6% of patients, were significantly associated with poor overall survival (p = 0.046), suggesting a synergistic role in poor prognosis. Conversely, patients with TP53 mutations exhibited improved survival (p = 0.007), underscoring their potential as favorable prognostic markers. Therefore, specific genetic alterations influence both prognosis and response to chemotherapy, offering critical insights into personalized treatment planning. Incorporating comprehensive molecular profiling-particularly TP53, KRAS, and APC mutation status-for preoperative evaluation may refine risk stratification, inform surgical decision-making, and support tailored therapeutic approaches in LARC.

Keywords: APC; KRAS; TP53; locally advanced rectal cancer; neoadjuvant chemotherapy.