Prognostic Value of Reduced SMAD4 Expression in Patients With Metastatic Colorectal Cancer Under Oxaliplatin-Containing Chemotherapy: A Translational Study of the AIO Colorectal Study Group

Background: SMAD4 is a polypeptide with tumor suppressor function being investigated as a prognostic biomarker in Union Internationale Contre le Cancer stages II and III in previous studies, but its role as a prognostic marker in stage IV colorectal cancer (CRC) is still undefined. We investigated the prognostic value of reduced SMAD4 expression in patients with metastatic (mCRC) under first-line oxaliplatin-containing combination chemotherapy. Patients and Methods: Tumor samples were obtained from patients who took part in a prospective randomized phase III chemotherapy trial of the Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society colorectal study group, comparing the use of capecitabine plus oxaliplatin with infusional 5-fluorouracil (5-FU) plus oxaliplatin as first-line therapy in mCRC. SMAD4 expression was determined by immunohistochemistry. Results: Tumor tissues from 230 patients were obtained. Reduced SMAD4 expression was identified in 34% of samples. Patients with reduced nuclear SMAD4 expression in tumor tissue showed a shorter progression-free survival (PFS; 7.0 months vs. 8.9 months; P = .024) and overall survival (OS; 13.9 months vs. 17.8 months; P = .044) compared with patients retaining SMAD4 expression. The effect of SMAD4 expression on PFS and OS could be demonstrated in univariate and multivariate analyses. Conclusion: Our data demonstrate the importance of reduced SMAD4 expression in patients with mCRC receiving chemotherapy with oxaliplatin and 5-FU.