ERCC1 and Thymidylate Synthase Expression Identified as Promising Biomarkers in Metastatic Colon Cancer
Lower levels of ERCC1 (excision repair cross-complementation group 1) and thymidylate synthase expression may be predictive of longer survival in patients with metastatic colon cancer, according to a study by Choueiri et al in PLOS One. It was shown that patients with low levels of ERCC1 and thymidylate synthase expression responded better to FOLFOX (leucovorin, fluorouracil [5-FU], and oxaliplatin) than FOLFIRI (leucovorin, 5-FU, and irinotecan).
Response to first-line chemotherapy is known to be a predictor of overall survival in patients with metastatic colon cancer. The advent of new cytotoxic and targeted agents has improved overall survival rates; indeed, median survival rates now exceed 20 months. However, there are a dearth of diagnostic tests to determine which first-line chemotherapy regimens offer the greatest chance of response.
In patients with colon cancer, ERCC1 and thymidylate synthase expression levels have been described as potentially promising biomarkers. Patients treated with FOLFOX for gastrointestinal tumors who had low levels of ERCC1 expression have been reported to have an improved response and a longer overall survival. In addition, thymidylate synthase gene expression has been shown to be predictive of response to 5-FU–based therapy in patients with metastatic colon cancer.
Study Details
The clinical records of 41 patients who had metastatic tumors tested by ResponseDX: Colon were included in the study. The median age was 57.6 years, with a range from 31 to 86 years. The majority of patients were treated with first-line FOLFOX (66%), receiving an average of 9.5 doses. The remaining patients were treated with first-line FOLFIRI (34%), receiving an average of 8.5 doses. In a second cohort of patient records, obtained from the Cancer Genome Atlas, samples from 62 metastatic cancer tumors were analyzed.
Longer Overall Survival
Patients with low levels of ERCC1 expression had a significantly longer median overall survival rate compared with those who had higher levels (36.0 months vs 10.1 months). Patients with low levels of thymidylate synthase expression had a significantly longer median overall survival rate than those with higher levels (36.0 vs 14.8 months). Those treated with FOLFOX showed a trend toward longer median overall survival compared with those treated with FOLFIRI (36.0 vs 22.6 months).
When combining data on ERCC1 expression levels and thymidylate synthase expression levels, patients with elevated levels of both ERCC1 and thymidylate synthase expression had a trend toward lower overall response compared with patients with low ERCC1/high thymidylate synthase expression rates (50% vs 63%). The overall response rate was 86% in patients with low levels of both markers.
In addition, the researchers discovered that, compared with high expression of either or both markers, low expression of ERCC1/thymidylate synthase was predictive of response in patients treated with FOLFOX (40% vs 91%) but not in those treated with FOLFIRI (71% vs 71%). Regarding the time to treatment failure, patients with high ERCC1 and thymidylate synthase expression levels had the shortest time to treatment failure of 2.4 months, compared with 14.1 months in patients with low ERCC1 and high thymidylate synthase expression levels.
Closing Thoughts
The results of this study suggest that measurement of ERCC1 and thymidylate synthase expression levels has potential clinical utility in managing patients with metastatic colon cancer. For patients with metastatic colon cancer, the majority of cytotoxic chemotherapy is given without any biomarker to predict response.
The investigators concluded, “Our study identifies a population of metastatic colon cancer patients with poor prognosis (high ERCC1/thymidylate synthase expression) as well as a population with a remarkably high response rate to FOLFOX chemotherapy (low ERCC1/thymidylate synthase expression).”
Paul Fanta, MD, of Moores Cancer Center, University of California San Diego, is the corresponding author of this article in PLOS One.
This study was supported by grants from the Marsha Rivkin Center for Ovarian Cancer Research and a Conquer Cancer Foundation of ASCO Young Investigator Award. The authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
