Presence of Concurrent TP53 Mutations Is Necessary to Predict Poor Outcomes within the SMAD4 Mutated Subgroup of Metastatic Colorectal Cancer

SIMPLE SUMMARY: Prior studies have resulted in conflicting conclusions on the value of SMAD4 mutations as a prognostic biomarker in metastatic colorectal cancer. In a cohort study of 433 patients with metastatic colorectal cancer, we showed that the presence of a coexisting mutation in TP53 is necessary to culminate in a negative overall survival impact in patients with SMAD4 mutations (multivariate HR = 2.5, 95% CI 1.44–4.36, p = 0.001). Our findings indicate that patients with concurrent SMAD4 and TP53 mutations represent a distinct poor-prognosis subgroup that may benefit from further translational studies. ABSTRACT: Prior studies have resulted in conflicting conclusions on the value of SMAD4 mutations as a prognostic biomarker in metastatic colorectal cancer. In this study, the impact of coexisting mutations with SMAD4 on overall survival was evaluated retrospectively in 433 patients with metastatic colorectal cancer. SMAD4 mutation was found in 16.2% (70/433) of tumors. A systemic univariate and multivariate survival analysis model including age, gender, sidedness of primary tumor, RAS, BRAF(V600E), APC, TP53 and SMAD4 status showed that SMAD4 mutations were not associated with worse prognosis (multivariate HR = 1.25, 95% CI 0.90–1.73, p = 0.18). However, coexisting mutations in SMAD4 and TP53 were significantly associated with worse overall survival (multivariate HR = 2.5, 95% CI 1.44–4.36, p = 0.001). The median overall survival of patients with coexisting SMAD4 and TP53 mutation was 24.2 months, compared to 42.2 months for the rest of the population (p = 0.002). Concurrent SMAD4 and TP53 defines a new subgroup of patients of metastatic colorectal cancer with poor clinical outcomes.