The influence of serum HER-2 levels and HER-2 codon 655 polymorphism on breast cancer outcome

HER-2 (human epidermal growth factor receptor-2) proto-oncogene is a member of the EGFR family and plays an important role in the regulation of cell growth, differentiation and survival and is involved in the regulation of normal breast growth and development. Alterations of HER-2 have been associated with carcinogenesis and poor prognosis of breast cancer. The present case-control study was conducted to clarify the predictive and prognostic significance of serum HER-2 protein in breast cancer patients in relation to Ile655Val single nucleotide polymorphism (SNP) of this gene. Fifty-six consecutive patients with primary breast cancer and 45 healthy women were prospectively included and evaluated. Serum levels of HER-2 were significantly increased in breast cancer patients compared to healthy controls (p=0.035). The optimal cut-off point of 1.98 ng/ml, which was determined to classify breast cancer patients, yielded sensitivity of 54%, specificity of 73% and accuracy of 62%. Significantly elevated serum HER-2 levels were associated with lymphovascular invasion (p=0.022), poor differentiation (p=0.011), advanced clinical stages (p=0.001), lymph node metastasis (p=0.011), higher number of positive lymph nodes (p=0.007) and the immunohistochemical overexpression of HER-2 protein (p=0.016). Regarding to HER-2 Ile655Val SNP, Ile-Val and Val-Val genotypes exhibited highly significant serum HER-2 elevation compared to homozygous Ile-Ile (both p<0.001). In multivariate analysis advanced stages (p=0.003) and Val-containing genotypes (p=0.009) remained the two significant independent determinants of high HER-2 levels. Survival analysis demonstrated an independent prognostic significance of homozygous Val-Val genotype for reduced survival (p=0.045), but not of serum HER-2 (p=0.181). Our findings confirm that serum HER-2 could be used clinically as a useful tumor marker for the diagnosis and the progression of breast cancer. Furthermore, they provide clinical evidence that HER-2 Ile655Val SNP does affect serum HER-2 levels and it can be regarded as a predictive biomarker for breast cancer patients with poor prognosis.