Human epidermal growth factor receptor-2 (HER2) Ile655Val single nucleotide polymorphism (SNP) is associated with gender-specific outcome in patients with metastatic colorectal cancer (mCRC) treated with cetuximab in a phase II study (IMCL-0144).

Abstract

441 Background: HER2 pathway is an important growth-regulatory pathway in many malignancies. In-vitro data from various cell lines suggest that activation of HER family members predicts resistance to cetuximab. HER2 also interacts with hormone receptors and estrogen, promoting tumor proliferation in breast cancer models. We previously demonstrated that polymorphisms in HER1 and ER-β were associated with gender-specific survival in colorectal cancer patients. HER2 Ile655Val (rs1136201) SNP's functionality was shown in breast cell lines with Val-expressing cells exhibiting increase growth capacity. We tested whether this SNP may predict gender-specific clinical outcome in mCRC treated with cetuximab. Methods: Tissue samples of 130 patients, 64 males and 66 females, with mCRC, enrolled in a phase II trial of cetuximab monotherapy were analyzed. Genomic DNA was extracted from FFPE tumor tissue. K-Ras mutation status and HER2 Ile655Val (rs1136201) SNP were analyzed using direct DNA-sequencing and PCR-RFLP. 23 out of 130 patients were still alive at the time of data analysis with a median follow-up of 12.3 months. Results: Females with the low activity HER2 Ile/Ile (n = 41) genotype had better progression-free survival (PFS) when compared to Ile/Val or Val/Val (n = 21) genotypes (median PFS = 2.4 vs. 1.2 months; HR = 2.06 (95% CI: 1.08-3.92), p = 0.0281) based on the multivariable Cox regression model adjusting for KRAS, performance status and severity of skin rash and stratified by race. In KRAS wild-type females, 15 patients out of 20 (75%) with HER2 Ile/Ile genotype responded or had stable disease when compared to 4 out of 12 (33%) Ile/Val or Val/Val genotypes (exact conditional test p = 0.143). In males, HER2 Ile655Val SNP is not associated with outcome. HER2 Ile655Val SNP is not associated with gender-specific overall survival. Conclusions: Our data suggest that HER2 Ile655Val SNP may identify females with mCRC likely to experience better outcome when treated with cetuximab. Prospective biomarker-embedded clinical trials are needed to validate our results. [Table: see text]