Association of HER2 and IGF1 germline polymorphisms with outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line irinotecan (IR) with or without cetuximab (CB): The EPIC experience.

BACKGROUND: EPIC, a multinational phase III clinical trial with IR + CB vs IR alone in mCRC pts in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR). We evaluated 6 functional germline polymorphisms involved in the IGF1 and HER2 for their potential role as molecular predictors of clinical outcome in pts treated in the EPIC study. METHODS: DNA was extracted from all available formalin-fixed paraffin-embedded tumor samples from the EPIC trial. Genotyping was performed using PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. Univariate analysis (Fisher's exact test for RR; log-rank test for PFS and OS) was performed to examine associations between polymorphisms and clinical outcome. Multivariate analysis (Logistic regression or Cox regression model) was conducted to control baseline patient characteristics and treatment. RESULTS: 186 pts with available samples were treated either with IR/CB (arm A, 84 pts) or IR alone (arm B, 102 pts). Median age was 59 yrs (range 34-85yrs) for arm A and 61 yrs (range 25-90 yrs) for arm B. In arm A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts (94%) had SD or PD. Median PFS for arm A was 3.0 months (95%CI 2.4- 4.1 months) vs 2.7 months (95%CI 2.2-2.9 months) for arm B; median OS was 9.3 months (95%CI 7.1-21.1 months) for arm A vs 12.3 months (95%CI 10.4- 17.9 months) for arm B. KRAS mutation status was not significantly associated with outcome in our patient cohort. We found that HER2 rs 1136201 was significantly associated with response (RR: AA 6.5%, AG 12.5%, and GG 27.3%, Fisher’s exact test p=0.045). IGF1 rs 2946834 was significantly associated with PFS in both univariate and multivariate analyses (median PFS was 2.8 months in patients with CC or CT vs 1.8 months in patients with TT; log-rank p=0.009; Wald test p=0.008). CONCLUSIONS: Our study suggests the prognostic value of polymorphisms in the IGF1 and HER2-pathway in mCRC pts treated with IR± CB. Prospective validation of these findings in clinical trials is warranted.