We previously reported CHFR methylation in a subset of
colorectal cancer (CRC; ∼30%) with high concordance with
microsatellite instability (MSI). We also showed that CHFR methylation predicted for sensitivity to
docetaxel, whereas the MSI-high phenotypes were sensitive to
gemcitabine. We hypothesized that this subset of patients with CRC would be selectively sensitive to
gemcitabine and
docetaxel. We enrolled a Phase 2 trial of
gemcitabine and
docetaxel in patients with MSI-high and/or CHFR methylated CRC. The primary objective was Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate. Enrolled patients were treated with
gemcitabine 800 mg/m2 on days 1 and 8 and
docetaxel 70 mg/m2 on day 8 of each 21-day cycle. A total of 6 patients with CHFR-methylated, MSI-high CRC were enrolled from September 2012 to August 2016. The study was closed in September of 2017 due to poor accrual prior to reaching the first interim assessment of response rate, which would have occurred
at 10 patients. No RECIST criteria
tumor responses were observed, with 3 patients (50%) having stable disease as best response, 1 lasting more than 9 months. Median progression-free survival (PFS) was 1.79 months (95% confidence interval [CI] = 1.28, not available [NA]) and median overall survival (OS) was 15.67 months (95% CI = 4.24, NA). Common grade 3 toxicities were
lymphopenia (67%),
leukopenia (33%), and
anemia (33%). Although negative, this study establishes a proof-of-concept for the implementation of epigenetic
biomarkers (CHFR methylation/MSI) as inclusion criteria in a prospective clinical trial to optimize combinatorial strategies in the era of
personalized medicine. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CHFR silencing via DNA methylation has been suggested to be predictive of
taxane sensitivity in diverse
tumors. The frequent association of CHFR methylation with
microsatellite instability (MSI) suggested a possible combination
therapy with
gemcitabine, because the MSI phenotype may result in sensitivity to
nucleoside analogues. WHAT QUESTION DID THIS STUDY ADDRESS? We hypothesized that metastatic
colorectal cancer (mCRC), which have CHFR methylation and MSI phenotype were sensitive to
gemcitabine and
docetaxel, and have designed this Phase 2 trial in
biomarker-selected mCRC to test this prediction. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study enrolled a molecularly defined subgroup of patients with
colorectal cancer (CRC) and showed that the combination is safe in this population. Nevertheless, due to poor enrollment and early termination, no conclusions on the primary and secondary end points could be made. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study supports the feasibility of implementing DNA methylation markers in a prospective clinical trial and further efforts toward their application as predictive
biomarkers for therapeutic agents in defined subsets of patients are warranted.