Molecular prognostic factors of irinotecan efficacy.

3621 Background: The most commonly used chemotherapeutic drugs in the treatment of metastatic colorectal cancer (CRC) are 5-fluorouracil (5-FU), oxaliplatin and irinotecan (CPT-11). There are no reliable prognostic factors to predict clinical outcome of CPT-11 treatment. We investigated whether mRNA levels of factors involved in the 5-FU metabolism (TS, DPD), in the CPT-11 metabolism (MDR1, Topoisomerase I), in angiogenesis (Cox-2, EGFR, IL-8, VEGF) and in DNA-repair/drug detoxification (ERCC1, GSTP1) are associated with the clinical outcome of patients with CRC treated with first-line 5-FU/Leucovorin/CPT-11.,Thirty-three patients with metastatic CRC treated with first-line CPT-11 at USC between 2000 and 2003 were included in the study. Intratumoral gene expression levels were assessed from paraffin-embedded tissue samples using laser capture microdissection and quantitative Real-time PCR.,There were 16 women and 17 men (median age 53; range 40-75) with a median survival time of 27.9 months, median time to tumor progression of 9.9 months and median follow-up of 24.8 months. Complete response was observed in 1 (3%) patient, partial response in 12 (36%), stable disease in 13 (40%) and progressive disease in 6 (18%) patients (response was inevaluable for 1 patient). High intratumoral mRNA levels of EGFR, ERCC1, GSPTP1 and MDR1 were each significantly associated with response to CPT-11 based chemotherapy (p≤0.05). No significant association was found between mRNA levels and time to tumor progression. The mRNA levels of EGFR had a statistically significant correlation with ERCC1, GSTP1, MDR1 and VEGF (Spearman correlation coefficients ≥0.4; p<0.05).,This retrospective study, with a small number of patients, suggests that gene expression levels of EGFR, ERCC1, GSPTP1 and MDR1 may be useful to predict the clinical outcome of patients with metastatic CRC with first-line CPT-11 based chemotherapy. It is consistent with recent studies suggesting an increased CPT-11 sensitivity mediated by higher EGFR expression and supports the previously reported relationship between EGFR and ERCC1/GSTP1. The role of MDR1 remains unknown. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text].