FBXW7 mutation is associated with poor overall survival in metastatic colorectal carcinoma: A retrospective single-center next-generation sequencing cohort study

BACKGROUNDExpanded next-generation sequencing (NGS) panels are increasingly used for metastatic colorectal carcinoma (CRC).Although primary tumor sidedness and conventional biomarkers influence treatment and prognosis, the clinical relevance of the less frequently altered genes detected by expanded NGS remains unclear.We hypothesized that some of these less frequently detected alterations may be associated with prognosis in metastatic CRC (mCRC). AIMTo evaluate the association between FBXW7 mutation and overall survival (OS) in patients with mCRC, with secondary analyses of primary tumor sidedness and other recurrent NGS-detected molecular alterations. METHODSThis retrospective study included 208 patients with mCRC diagnosed between 2019 and 2021 who had available NGS results from formalin-fixed paraffin-embedded tumor tissues.Clinicopathological characteristics, primary tumor sidedness, mismatch repair status when available, pathogenic or likely pathogenic molecular alterations, and survival data were analyzed.OS was evaluated using Kaplan-Meier analysis and logrank tests.Associations with OS were assessed using multivariable Cox proportional hazards regression analysis. RESULTSThe median OS was 29 months, and the 3-year OS rate was 38.2%.The most frequent mutations were in KRAS, PIK3CA, SMAD4, BRAF, FBXW7, and NRAS, with BRAF mutations being more frequent in right-sided than in left-sided tumors (20.0%vs 2.7%, P < 0.001).Kaplan-Meier analysis revealed that BRAF [16/208 (7.7%)] and FBXW7 [13/208 (6.25%)] mutations were associated with shorter OS.In the multivariable Cox regression model including age, sex, primary tumor sidedness, and KRAS, PIK3CA, SMAD4, BRAF, FBXW7, and NRAS mutation status, increasing age and FBXW7 mutation (hazard ratio = 3.553; 95% confidence interval: 1.738-7.267;P = 0.001) were associated with shorter OS, whereas tumor sidedness and BRAF mutation were not.CONCLUSION FBXW7 mutation was associated with poor OS after adjustment for the available covariates in patients with mCRC, although this finding should be interpreted cautiously given the small number of FBXW7-mutant cases and the unavailability of data on key clinical confounders.