Correlation of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) expression in primary and metastatic sites with response to capecitabine plus irinotecan in patients with colorectal cancer

Abstract

3520 Background: In preclinical models, expression of three enzymes involved in the metabolism and antitumor activity of capecitabine, an orally administered prodrug of 5-fluorouracil (5-FU), impact cytotoxicity: TP (final step in conversion of capecitabine to 5-FU), DPD (5-FU degradation), and TS (5-FU target). This study was undertaken to determine whether expression of these enzymes in primary tumors and/or metastatic sites predicts response to capecitabine in patients (pts) with colorectal cancer (CRC). Methods: 67 chemotherapy-naïve (except adjuvant therapy) pts with measurable metastatic CRC were treated with irinotecan 125 (15 pts, cohort 1) or 100 (52 pts, cohort 2) mg/m2 intravenously on days (d) 1 and 8, plus capecitabine orally 1000 (cohort 1) or 900 (cohort 2) mg/m2 twice daily on d2–15, every 21 d. Starting doses were reduced after the first 15 pts because of toxicity (Gold et al. ASCO 2003). Paraffin-embedded tumor samples from primary and metastatic sites (49 pts) were assessed for expression of TP, TS, and DPD by immunohistochemistry (IHC) (Roche Diagnostics antibodies) and mRNA quantification (Roche Diagnostics kits). Results: Mean age was 61.8 years (range 40–81), 37M/30F. Objective response rate (confirmed at >4 weeks, RECIST criteria) was 42% (7 pts cohort 1, 21 pts cohort 2). Grade 3–4 adverse events in >5% of pts in cohort 2 were (#pts): diarrhea (18), dehydration (7), hand-foot syndrome (4), deep vein thrombosis (3), nausea (4), vomiting (4). Response rate was 62% vs. 20% in pts with TP+ vs. TP- primary tumors (p=0.01), and 61% vs. 14% in pts with TP+ vs. TP- metastatic tumors (p=0.04). Similarly, response was more likely in primary tumors with ≥mean levels of TP mRNA (75% vs. 37%, p=0.03). There was no relationship between TS or DPD expression (IHC or mRNA) in primary or metastatic sites and likelihood of response. Conclusions: These data support the hypothesis that TP expression may be useful as a predictive marker for response in CRC pts treated with an active combination of capecitabine plus irinotecan. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MDR Global Systems, LLC; Roche Labs Hoffman LaRoche; MDR Global Systems, LLC; Pfizer; Roche Hoffman LaRoche Roche; Roche Integrated Cancer Care Unit Roche