Evaluation of predictive and prognostic significance of serum TGF-beta1 levels in breast cancer according to HER-2 codon 655 polymorphism.

The present study was conducted to clarify the predictive and prognostic significance of serum TGF-I(2)1 in breast cancer in relation to Ile655Val single nucleotide polymorphism (SNP) of human epidermal growth factor receptor-2 (HER-2). In a case-control study, 56 consecutive patients with primary breast cancer were prospectively included and evaluated. The control group consisted of 45 healthy women. Serum concentrations of TGF-I(2)1 were measured by quantitative sandwich enzyme immunoassay (ELISA). HER-2 SNP was genotyped using PCR-RFLP method. Serum levels of TGF-I(2)1 were significantly increased in breast cancer patients compared to healthy controls (p<0.001). For the evaluation of the diagnostic significance of serum TGF-I(2)1 the area under the receiver operating characteristic (ROC) curve (AUC) was 0.804, while the optimal cut-off point of 30.86 ng/ml was determined to classify breast cancer patients, which yielded sensitivity of 77%, specificity of 78% and accuracy of 77%. Significantly elevated serum TGF-I(2)1 levels were associated with advanced stages (p=0.023), positive lymph nodes (p=0.019) and postmenopausal status (p=0.031). A marginal trend towards higher TGF-I(2)1 levels was found among patients with Val-containing genotypes compared to homozygous Ile-Ile (p=0.094). In multivariate analysis lymph node metastases (p=0.009) remained the only significant independent determinant of high TGF-I(2)1 levels. With regard to prognostic significance for advanced stages (AUC, 0.704) and lymph node metastasis (AUC, 0.683), when the optimal cut-off value was set at 65.15 pg/ml, the sensitivity was 86% and 67%, the specificity was 60% and 62% and accuracy was 66% and 64%, respectively. Survival was shorter in patients with increased serum TGF-I(2)1 (36 months vs 46 months, p=0.022). Multivariate analysis demonstrated a marginal prognostic significance of serum TGF-I(2)1 for survival (p=0.072). The combination of high TGF-I(2)1 and Val-Val genotype predicts a worse prognosis than high serum TGF-I(2)1 alone. Our findings suggest that serum TGF-I(2)1 is involved in tumor malignancy and lymph node metastasis and could be used clinically as a useful tumor marker for evaluation, the extension and the outcome of the disease. They also provide clinical evidence for a significant association between HER-2 Ile655Val SNP and serum TGF-I(2)1, resulting to more aggressive phenotype of the tumor and poor prognosis.