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A phase I/II prospective, single arm trial of gefitinib, trastuzumab, and docetaxel in patients with stage IV HER-2 positive metastatic breast cancer

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Abstract

Inhibition of the HER-2 pathway via the monoclonal antibody trastuzumab has had a major impact in treatment of HER-2 positive breast cancer, but de novo or acquired resistance may reduce its effectiveness. The known interplay between the epidermal growth factor receptor (EGFR) and HER-2 receptors and pathways creates a rationale for combined anti-EGFR and anti-HER-2 therapy in HER-2 positive metastatic breast cancer (MBC), and toxicities associated with the use of multiple chemotherapeutic agents together with biological therapies may also be reduced. We conducted a prospective, single arm, phase I/II trial to determine the efficacy and toxicity of the combination of trastuzumab with the EGFR inhibitor gefitinib and docetaxel, in patients with HER-2 positive MBC. The maximum tolerated dose (MTD) was determined in the phase I portion. The primary end point of the phase II portion was progression-free survival (PFS). Immunohistochemical analysis of biomarker expression of the PKA-related proteins cAMP response element-binding protein (CREB), phospho-CREB and DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) plus t-DARPP (the truncated isoform of DARPP-32); PTEN; p-p70 S6K; and EGFR was conducted on tissue from metastatic sites. Nine patients were treated in the phase I portion of the study and 22 in the phase II portion. The MTD was gefitinib 250 mg on days 2–14, trastuzumab 6 mg/kg, and docetaxel 60 mg/m2 every 21 days. For the 29 patients treated at the MTD, median PFS was 12.7 months, with complete and partial response rates of 18 and 46%, and a stable disease rate of 29%. No statistically significant correlation was found between response and expression of any biomarkers. We conclude that the combination of gefitinib, trastuzumab, and docetaxel is feasible and effective. Expression of the biomarkers examined did not predict outcome in this sample of HER-2 overexpressing metastatic breast cancer.

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Acknowledgments

We wish to thank Kim Robinson for her assistance with data management and Carol Wuenschell, Ph.D., for her editorial assistance. We also thank Sofia Loera and members of the City of Hope Anatomic Pathology Core lab for their help with histology work. This work was supported by the National Cancer Institute at the National Institutes of Health through a National Cancer Institute Comprehensive Cancer Center Grant [CA 33572]; and by AstraZeneca. This study was presented in part at the 2005 San Antonio Breast Cancer Symposium.

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Authors and Affiliations

  1. Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, California, 91010, USA

    G. Somlo, C. L. Martel, A. Hurria, C. Chung, T. Luu, R. Morgan Jr, L. Leong, M. Koczywas & M. McNamara

  2. Anatomic Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    S. K. Lau

  3. Division of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    P. Frankel & C. Ruel

  4. Division of Tumor Cell Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    L. Gu & S. E. Kane

  5. Division of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    C. A. Russell

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  1. G. Somlo
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  2. C. L. Martel
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  3. S. K. Lau
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  4. P. Frankel
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  5. C. Ruel
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  6. L. Gu
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  10. R. Morgan Jr
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  14. C. A. Russell
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Correspondence to G. Somlo.

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Somlo, G., Martel, C.L., Lau, S.K. et al. A phase I/II prospective, single arm trial of gefitinib, trastuzumab, and docetaxel in patients with stage IV HER-2 positive metastatic breast cancer. Breast Cancer Res Treat 131, 899–906 (2012). https://doi.org/10.1007/s10549-011-1850-2

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