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Treatment of Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy
Affiliations of authors: Breast Center and the Dan L. Duncan Cancer Center (GA, HW, MR, CKO, RS) and Department of Pathology (CG), Baylor College of Medicine, Houston, TX; Department of Medicine and Markey Cancer Center, University of Kentucky, Lexington, KY (SM); Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita di Napoli Federico II, Naples, Italy (GA, SDP); Johns Hopkins Singapore International Medical Centre Pte Ltd, Singapore (LB)
Correspondence to: C. Kent Osborne, MD, Breast Center, Baylor College of Medicine, One Baylor Plaza, MS:600, Houston, TX 77030 (e-mail: kosborne{at}bcm.edu).
Background: Human epidermal growth factor receptor 2 (HER2) is a member of the HER signaling pathway. HER inhibitors partially block HER signaling and tumor growth in preclinical breast cancer models. We investigated whether blockade of all HER homo- and heterodimer pairs by combined treatment with several inhibitors could more effectively inhibit tumor growth in such models.
Methods: Mice carrying xenograft tumors of HER2-overexpressing MCF7/HER2-18 (HER2-transfected) or BT474 (HER2-amplified) cells were treated with estrogen supplementation or estrogen withdrawal, alone or combined with tamoxifen. One to three HER inhibitors (pertuzumab, trastuzumab, or gefitinib) could also be added (n 
8 mice per group). Tumor volumes, HER signaling, and tumor cell proliferation and apoptosis were assessed. Results were analyzed with the t test or Wilcoxon rank sum test and survival analysis methods. All statistical tests were two-sided.
Results: Median time to tumor progression was 21 days for mice receiving estrogen and 28 days for mice receiving estrogen and pertuzumab (difference = 7 days; P = .001; hazard ratio [HR] of progression in mice receiving estrogen and pertuzumab versus mice receiving estrogen = 0.27, 95% confidence interval [CI] = 0.09 to 0.77). Addition of gefitinib and trastuzumab to estrogen and pertuzumab increased this time to 49 days (difference = 21 days; P = .004; HR of progression = 0.28, 95% CI = 0.10 to 0.76). MCF7/HER2-18 tumors disappeared completely and did not progress (for 189 days) after combination treatment with pertuzumab, trastuzumab, and gefitinib plus tamoxifen (19 of 20 mice) or plus estrogen withdrawal (14 of 15 mice). Both combination treatments induced apoptosis and blocked HER signaling and proliferation in tumor cells better than any single agent or dual combination. All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days.
Conclusion: Combined treatment with gefitinib, trastuzumab, and pertuzumab to block signals from all HER homo- and heterodimers inhibited growth of HER2-overexpressing xenografts statistically significantly better than single agents and dual combinations.
| CONTEXT AND CAVEATS Prior knowledge Human epidermal growth factor receptor (HER) inhibitors partially block HER signaling in breast cancer model systems. Study design Human xenograft HER2-overexpressing tumors in mouse model systems. Contribution The combination of three HER inhibitors (gefitinib, trastuzumab, and pertuzumab) inhibited the growth of HER2-overexpressing xenograft tumors better than single-agent or dual-agent combinations. Implications Further investigation into the mechanisms of action and the mechanisms of resistance to the three-drug combination therapy is warranted. Limitations The superiority of the three-inhibitor combination (gefitinib, trastuzumab, and pertuzumab) was tested in only two cell lines in an experimental mouse model system and cannot necessarily be extrapolated to other HER2-positive cell lines or to patients with HER2-amplified breast cancer.
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Manuscript received July 3, 2006; revised February 6, 2007; accepted March 20, 2007.
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J Natl Cancer Inst 2007 99: 1644.
J Natl Cancer Inst 2007 99: 657.
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