Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment

BACKGROUND: Stage II colorectal cancer(CRC) patients after surgery alone have a five-year survival rate of ~60-80%; the incremental benefit of adjuvant chemotherapy is <5%. Predicting risk of recurrence and selecting effective personalized adjuvant drugs for stage II CRC using formalin-fixed, paraffin-embedded(FFPE) samples is a major challenge. METHODS: 1319 stage II CRC patients who enrolled in 2011-2019 at Sun Yat-sen University Cancer Center were screened. RNAseq data of FFPE tumor samples of 222 stage II microsatellite stable(MSS) CRC patients(recurrence (n=47), norecurrence (n=175), median follow-up=41 months) were used to develop a method TFunctionalProg for dissecting heterogeneous subgroups of recurrence and predicting risk of recurrence. RESULTS: TFunctionalProg showed significant predictive values in 222 stage II MSS CRCs. The TFunctionalProg low-risk group had significantly better recurrence free survival (validation set: HR=4.78, p-value=1e-4, low-risk group three-year recurrence free survival=92.6%, high-risk group three-year recurrence free survival=59.7%). TFunctionalProg dissected two subgroups of transition states of stage II MSS CRCs at a high risk of recurrence; each state displays distinct levels of hybrid epithelial-mesenchymal traits, CD8+ T cell suppression mechanisms and FOLFOX resistance. Based on mechanisms in two subgroups, TFunctionalProg proposed personalized rational adjuvant drug combinations of immunotherapy, chemotherapy and repurposed CNS drugs. TFunctionalProg provides different utilities from ctDNA-based prognostic biomarkers. CONCLUSION: TFunctionalProg was validated using FFPE samples to predict the risk of recurrence and propose rational adjuvant drug combinations for stage II CRC.