Evolution and Revolution in Pharmacotherapy for Rectal Cancer: The Rise of Personalized Precision Therapy for Rectal Cancer

The treatment of rectal cancer is shifting from the traditional anatomy-driven model to molecular-guided precision medicine. The limitations of traditional methods result in 28 to 43% of low-risk patients suffering from toxicity due to overtreatment and poor survival due to undertreatment in high-risk patients. Based on 37 phase III trials and 23 translational studies, this review proposes three key translational pillars: (1) Molecular stratification (RAS/RAF mutation and MSI status) to optimize subgroup therapy. Patients with wild-type RAS had a pCR rate of 28.6% versus 9.2% (p=0.003). Patients with BRAF v600e mutation had a significantly longer survival after triple-targeted therapy (median OS 9.3 months vs. 5.4 months, HR=0.52). (2) Liquid biopsied dynamic monitoring could detect minimal residual disease at 0.01% sensitivity. Postoperative ctDNA positivity predicted a 7-fold increased risk of recurrence (HR=7.0, p<0.001), improved DFS by 21% (p=0.006), and 48% of low-risk patients were free from chemotherapy toxicity; (3) AI-supported multimodal decision-making integrated genomic, radiomics and ctDNA data, and the machine learning model (AUC=0.89 vs. 0.65) dynamically adjusted the treatment intensity. Clinical validation showed that the decision accuracy was improved by 58% (p<0.001). Despite breakthroughs in targeted therapies and immunotherapy, challenges in accessibility and biomarker validation remain. In the future, we should focus on real-time molecular sensors and cross-omics integration technologies.