HER2 and IGF1 germline polymorphisms are associated with outcome in metastatic colorectal

1. HER2 and IGF1 germline polymorphisms are associated with outcome in metastatic colorectal cancer patients treated with second-line irinotecan (IR) +/- cetuximab (CB): the EPIC-experience Dongyun Yang2, Wu Zhang1, Pierre O. Bohanes1,Yan Ning1, Anthony El-Khoueiry1, Christopher T Harbison3, Ovidiu C Trifan3, Heinz-Josef Lenz1,2 Department of Medical Oncology1, Preventive Medicine2, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA Bristol-Myers Squibb, Princeton, NJ3 Abstract ID: 3615 Introduction Results Background: Recent evidence suggest HER2 and IGF1 signaling pathway may contribute to the acquired resistance of anti-EGFR monoclonal antibody cetuximab in the treatment of metastatic colorectal cancer. EPIC, a multinational phase III clinical trial with cetuximab and irinotecan(IR+CB) vs irinotecan alone in mCRC patients in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR)1.Here we evaluated 6 functional germline polymorphisms involved in the IGF1 and HER2 signaling pathway for their potential role as molecular predictors of clinical outcome in patients enrolled in the EPIC study.2,3 Baseline characteristics among patients whose specimens available for genotyping in EPIC and whole EPIC trial participations We found that HER2 rs136201 was significantly associated with response (shown in fig 1). The association between HER2 rs1136201 and response remained significant when adjusting for treatment (Wald test p=0.034).IGF1 rs2946834 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; Fig 2). The association between IGF1 rs2946834 and PFS did not differ significantly by treatment. Methods 1298 patients were randomly assigned into IR+CB or IR arms. Genomic DNA was extracted from 186 available formalin-fixed paraffin-embedded tumor samples from the EPIC trial. Genotyping was performed using PCR-RFLP assays or PCR-based direct DNA sequence. Patients 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. 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. Fig 1. Response rate by HER2 rs1136201 Fig 2. PFS byIGF1 rs 2946834 References Conclusions 1. Sobrero AF, Maurel J, Fehrenbacher L, et al (2008). EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J ClinOncol 26:2311-9. 2. Winder, T, Zhang, W, Yang, D.,Ning, Y.,et al. Germline polymorphisms in genes involved in the IGF1pathway predict efficacy of cetuximabinwild‐type KAS mCRC patients. Clin Cancer Res.; 2010. Nov 15;16(22):5591-602. 3. Gerger A,Bohanes P, Yang N, Winder T,etal. Human epidermal growth factor receptor2(HER2) Ile655Val single nucleotide polymorphism(SNP) is associated with gender-specific outcome in patientswith metastatic colorectal cancer (mCRC) treated with cetuximab in a phase II study(IMCL--‐0144). J ClinOncol. Abtr 441; 2011. Our study, a subset analysis from EPIC trial, 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.