High serum TGF-alpha predicts poor response to lapatinib and capecitabine in HER2-positive breast cancer

Abstract

Lapatinib and capecitabine combination therapy is effective in trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We investigated the biomarkers from serum of patients receiving lapatinib and capecitabine Patients received lapatinib 1,250 mg once daily and capecitabine 2,000 mg/m(2)/day, day 1-14, every 3 weeks. Serum samples were obtained before treatment initiation. Levels of transforming growth factor-alpha (TGF-alpha), epidermal growth factor (EGF), extracellular domains of EGFR and HER2 were measured by enzyme-linked immunosorbent assay. The effect of TGF-alpha on in vitro sensitivity of SK-BR-3 cells to lapatinib was investigated. Sixty-four patients were included. Response rate was significantly higher in patients with low serum TGF-alpha (a parts per thousand currency sign3.75 pg/ml) compared to high TGF-alpha (> 3.75 pg/ml) [61.1% (11/18) vs. 17.4% (8/46), respectively; P = 0.001]. Low serum TGF-alpha was independently associated with better response in multivariate analysis [adjusted odds ratio, 8.96; 95% confidence interval (CI) 2.4-34.2]. Time-to-progression tended to be shorter in patients with high serum TGF-alpha compared to low TGF-alpha [median 3.8 months (95% CI 2.3-5.4) vs. 6.5 (95% CI 6.1-6.8), respectively; P = 0.067]. We confirmed that TGF-alpha diminished the sensitivity of SK-BR3-cells to lapatinib in vitro. The in vitro antiproliferative effect of cetuximab in combination with lapatinib was higher than that of lapatinib alone in SK-BR3-cells exposed to TGF-alpha. These data suggest that TGF-alpha plays a role in resistance to lapatinib and capecitabine therapy among HER2-positive breast cancer.