Wild-type APC Is Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

[摘要] Background The prognostic implication of wild-type APC ( APC -WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined. Materials and Methods APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC). Results In comparison with the APC -mutant ( APC -MT) population ( n = 255), APC -WT patients ( n = 86) tended to be younger (59% of age  50), right-sided (41.7% vs. 27%), BRAF V600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1 , were over-represented in the APC -WT versus APC -MT population (7% vs. 0.4% and 4.7% vs. 0.4%, respectively). APC -WT patients had a worse overall survival (OS) than APC -MT patients (22.6 vs. 45.6 months, p < .0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival ( APC -MT vs. APC -WT, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44–0.86, p = .0037). The prognostic implication of APC -WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database ( APC- MT vs. APC -WT, HR, 0.63, 95% CI, 0.49–0.81, p < .0001). Conclusion APC -WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC -MT mCRC tumors, APC -WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1 . Our data suggest alternative therapy needs to be investigated in APC -WT patients. Implications for Practice Patients with microsatellite stable metastatic colorectal cancer with wild-type APC had a worse overall survival than patients with mutated APC regardless of RAS/RAF status. APC status should be considered as a stratification factor in prospective trials, and novel therapeutic strategies need to be developed for this subgroup of patients.

[学科分类] 地质学

[关键词] APC;Metastatic colorectal cancer;Microsatellite stable;prognostic;Wnt signaling