ERCC1 and Thymidylate Synthase mRNA Levels Predict Survival for Colorectal Cancer Patients Receiving Combination Oxaliplatin and Fluorouracil Chemotherapy

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Abstract
PURPOSE: To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and the excision cross-complementing (ERCC1) gene are associated with response to and survival of fluorouracil (5-FU)/oxaliplatin chemotherapy in metastatic colorectal cancer. PATIENTS AND METHODS: Patients had progressive stage IV disease after unsuccessful 5-FU and irinotecan chemotherapy. All patients were evaluated for eligibility for a compassionate 5-FU/oxaliplatin protocol. cDNA was derived from paraffin-embedded tumor specimens to determine TS and ERCC1 mRNA expression relative to the internal reference gene beta-actin using fluorescence-based, real-time reverse transcriptase polymerase chain reaction. RESULTS: The median TS gene expression level from 50 metastasized tumors was 3.4 × 10−3 (minimum expression, 0.18 × 10−3;maximum expression, 11.5 × 10−3), and the median ERCC1 gene expression level was 2.53 × 10−3 (minimum, 0.0; maximum, 14.61 × 10−3). The gene expression cutoff values for chemotherapy nonresponse were 7.5 × 10−3 for TS and 4.9 × 10−3 for ERCC1. The median survival time for patients with TS ≤ 7.5 × 10−3 (43 of 50 patients) was 10.2 months, compared with 1.5 months for patients with TS greater than 7.5 × 10−3 (P < .001). Patients with ERCC1 expression ≤ 4.9 × 10−3 (40 of 50 patients) had a median survival time of 10.2 months, compared with 1.9 months for patients with ERCC1 expression greater than 4.9 × 10−3 (P < .001). A TS of 7.5 × 10−3 segregated significantly into response, stable disease, and progression (P = .02), whereas the association between ERCC1 and response did not reach statistical significance (P = .29). CONCLUSION: These data suggest that intratumoral ERCC1 mRNA and TS mRNA expression levels are independent predictive markers of survival for 5-FU and oxaliplatin combination chemotherapy in 5-FU–resistant metastatic colorectal cancer. Precise definition of the best TS cut point will require further analysis in a large, prospective study.