Reclassification of allele mutations predicts the survival benefit of triplet chemotherapy in metastatic colorectal cancer.

Background: Different allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various allele mutations in colorectal cancer (CRC) but the results remain controversial.

Methods: Between March 2017 and September 2022, the patients diagnosed as stages I-IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan-Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models.

Results: A total of 1029 CRC patients were included, and the incidence of mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk /BRAF mutation (group 2, RAS/BRAF mutations other than G13D/G12V/G12C or BRAF V600E), high-risk mutation (group 3, G13D/G12V/G12C), and V600E mutation (group 4). mCRC patients with high-risk mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36-5.12;  = 0.0091).

Conclusion: In the non-hypermutated CRC cohort, the prognostic risk of various allele mutations varied between local and metastatic CRC. G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.