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

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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/m2/day, day 1–14, every 3 weeks. Serum samples were obtained before treatment initiation. Levels of transforming growth factor-α (TGF-α), epidermal growth factor (EGF), extracellular domains of EGFR and HER2 were measured by enzyme-linked immunosorbent assay. The effect of TGF-α 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-α (≤3.75 pg/ml) compared to high TGF-α (>3.75 pg/ml) [61.1% (11/18) vs. 17.4% (8/46), respectively; P = 0.001]. Low serum TGF-α 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-α compared to low TGF-α [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-α 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-α. These data suggest that TGF-α plays a role in resistance to lapatinib and capecitabine therapy among HER2-positive breast cancer.

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Acknowledgments

This study was supported in part by grants from the Korean Healthcare Technology R&D project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A091081).

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The authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul, Korea

    Jiyoung Rhee, Sae-Won Han, Yongjun Cha, Do-Youn Oh, Seock-Ah Im, Yung-Jue Bang & Tae-You Kim

  2. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Sae-Won Han, Hye Seon Ham, Hwang-phill Kim, Do-Youn Oh, Seock-Ah Im, Yung-Jue Bang & Tae-You Kim

  3. Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea

    Jong-Wan Park

  4. Center for Breast Cancer, National Cancer Center, Goyang-Si, Gyeonggi-Do, Korea

    Jungsil Ro, Keun Seok Lee & In Hae Park

  5. Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Young-Hyuck Im

  6. Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea

    Yung-Jue Bang & Tae-You Kim

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  1. Jiyoung Rhee
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Correspondence to Tae-You Kim.

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Rhee, J., Han, SW., Cha, Y. et al. High serum TGF-α predicts poor response to lapatinib and capecitabine in HER2-positive breast cancer. Breast Cancer Res Treat 125, 107–114 (2011). https://doi.org/10.1007/s10549-010-1200-9

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  • DOI: https://doi.org/10.1007/s10549-010-1200-9

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