Role of depth of response and MTHFR genotype as predictors of fluorouracil rechallenge therapy for refractory metastatic colorectal cancer.

ABSTRACT

There is limited data on the clinical and biological parameters that enable the prediction of the benefits derived from additional chemotherapy after disease progression compared with standard chemotherapy in patients with metastatic colorectal cancer (mCRC). The present study evaluated the role of tumor response as a clinical parameter and single nucleotide polymorphisms (SNPs) as a biomarker to predict the benefit of additional 5-fluorouracil (5-FU) rechallenge chemotherapy in patients with refractory mCRC. Tumor responses were retrospectively reviewed based on the Response Evaluation Criteria in Solid Tumors, early tumor shrinkage (ETS) and depth of response (DoR) following first-line chemotherapy in patients with stage IV CRC. Together with these parameters, SNPs known to be associated with the response to chemotherapy were analyzed with survival outcomes. In total, the tumor responses of 242 patients with mCRC were evaluated. Overall response and ETS were identified in 110 (45.4%) and 103 patients (42.6%), respectively, and the median DoR was 38.5±30.08%. ETS and DoR were significantly associated with survival outcomes, including progression-free survival, post-progression survival and overall survival. Among these patients, SNPs were analyzed in 171 patients. X-ray repair cross complementing 1 (XRCC1) (AG/AA) with a DoR >60%, good performance status and the absence of bone lesions were associated with improved overall survival. In patients receiving third-line chemotherapy with 5-FU rechallenge therapy, the methylenetretrahydrofolate reductase (MTHFR) (C677T) CC genotype and a DoR >60% were significantly associated with a good prognosis in multivariate analysis. XRCC1 (AG/AA) was also associated with a good prognosis in patients with mCRC. Patients with a DoR >60% following first-line chemotherapy and a MTHFR (C677T) CC genotype exhibited a survival benefit from 5-FU retreatment. Therefore, the DoR and MTHFR genotype are potential markers for selecting patients with refractory mCRC that would benefit from 5-FU rechallenge therapy.