Assessment of multiple markers for association with response rate (RR) and failure-free survival (FFS) in patients with advanced colorectal cancer (CRC) treated with chemotherapy in the MRC CR08 (FOCUS) randomized trial

Abstract

9506 Background: We have assessed potential prognostic and predictive markers of response to fluorouracil (FU) in advanced CRC patients randomized 4:1:1 to FU alone, FU+oxaliplatin, or FU+irinotecan. Methods: Pathology specimens were retrieved from 846 patients in the FOCUS trial. 85% were from the primary site. Normal and tumor DNA and RNA were extracted and tissue microarrays were made for immunohistochemistry (IHC). The following factors were assessed for effect on FFS and RR to first-line therapy: age; performance status; primary site; liver metastases; serum ALP; grade; mucoid status; IHC for hMLH1, hMSH2, P53, SMAD4, dUTPase, DPD, thymidine phosphorylase (TP), thymidylate synthase (TS); TS mRNA expression; DNA polymorphisms in TS (TSER, TS1494), hMLH1 (–93 G→A), MTHFR (677 C→T). Results: Overall RR and median FFS to first-line therapy were 42% and 8 months respectively. The table shows markers with significant relationships to RR and FFS. Together markers explained 6% of the variability in outcome, with the IHC/histology markers contributing most. DNA polymorphisms showed no clear association with outcomes. Similar associations of marker status were found for patients treated with FU alone or FU+oxaliplatin/irinotecan. Using logistic regression, a predictive algorithm could separate tumors into groups with RR from 15% to 50% for treatment with FU alone and 25% to 70% for treatment with FU+oxaliplatin/irinotecan. Conclusions: Significant differences in RR have been identified for mucoid status, TS IHC and dUTPase IHC scores allowing development of a predictive algorithm for response to FU-containing chemotherapy. Associations with modest differences in FFS were also identified. Ongoing work is looking at markers specific for oxaliplatin or irinotecan benefit. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis