ERCC1 and thymidylate synthase mRNA levels predict survival for colorectalcancer patients receiving combination oxaliplatin and fluorouracil chemotherapy

Purpose: To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and the excision cross-complementing (ER CC1) gene are associated with response to and survival of fluorouracil (5-F U)/oxaliplatin chemotherapy in metastatic colorectal cancer. Patients and Methods: Patients had progressive stage IV disease after unsuc cessful 5-FU and irinotecan chemotherapy. All patients were evaluated for e ligibility for a compassionate 5-FU/oxaliplatin protocol. cDNA was derived from paraffin-embedded tumor specimens to determine TS and ERCC1 mRNA expre ssion 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 wa s 3.4 x 10(-3) (minimum expression, 0.18 x 10(-3); maximum expression, 11.5 x 10(-3)), and the median ERCC1 gene expression level was 2.53 x 10(-3) (m inimum, 0.0; maximum, 14.61 x 10(-3)). The gene expression cutoff values fo r chemotherapy nonresponse were 7.5 x 10(-3) for TS and 4.9 x 10(-3) for ER CC1. The median survival time for patients with TS less than or equal to 7. 5 x 10(-3) (43 of 50 patients) was 10.2 months, compared with 1.5 months fo r patients with TS greater than 7.5 x 10(-3) (p <.001). Patients with ERCC1 expression <less than or equal to> 4.9 x 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 x 10(-3) (P <.001). A TS of 7.5 x 10 (-3) segregated significantly into response, stable disease, and progressio n (P =.02), whereas the association between ERCC1 and response did not reac h statistical significance (P =.29). Conclusion: These data suggest that intratumoral ERCC1 mRNA and TS mRNA exp ression levels are independent predictive markers of survival for 5-FU and oxaliplatin combination chemotherapy in 5-FU-resistant metastatic colorecta l cancer. Precise definition of the best TS cut point will require further analysis in a large, prospective study. J Clin Oncol 19:4298-4304. (C) 2001 by American Society of Clinical Oncology.