Molecular predictors of response to trastuzumab and lapatinib in breast cancer (original) (raw)

• King, C. R., Kraus, M. H. & Aaronson, S. A. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229, 974–976 (1985).
  Article CAS PubMed Google Scholar
• Di Fiore, P. P. et al. Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell 51, 1063–1070 (1987).
  Article CAS PubMed Google Scholar
• Finkle, D. et al. HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin. Cancer Res. 10, 2499–2511 (2004).
  Article CAS PubMed Google Scholar
• Drebin, J. A., Link, V. C., Stern, D. F., Weinberg, R. A. & Greene, M. I. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 41, 697–706 (1985).
  Article CAS PubMed Google Scholar
• Hudziak, R. M. et al. P185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell Biol. 9, 1165–1172 (1989).
  Article CAS PubMed PubMed Central Google Scholar
• Sarup, J. C. et al. Characterization of an anti-p185her2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth. Growth Regul. 1, 72–82 (1991).
  CAS PubMed Google Scholar
• Shepard, H. M. et al. Monoclonal antibody therapy of human cancer: taking the her2 protooncogene to the clinic. J. Clin. Immunol. 11, 117–127 (1991).
  Article CAS PubMed Google Scholar
• Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).
  Article CAS PubMed Google Scholar
• Naruse, I., Fukumoto, H., Saijo, N. & Nishio, K. Enhanced anti-tumor effect of trastuzumab in combination with cisplatin. Jpn. J. Cancer Res. 93, 574–581 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Carter, P. et al. Humanization of an anti-p185her2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA 89, 4285–4289 (1992).
  Article CAS PubMed PubMed Central Google Scholar
• Baselga, J. Phase I and II clinical trials of trastuzumab. Ann. Oncol. 12, 49–55 (2001).
  Article Google Scholar
• Baselga, J. et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J. Clin. Oncol. 14, 737–744 (1996).
  Article CAS PubMed Google Scholar
• Esteva, F. J. et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J. Clin. Oncol. 20, 1800–1808 (2002).
  Article CAS PubMed Google Scholar
• Pegram, M. D. et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 16, 2659–2671 (1998).
  Article CAS PubMed Google Scholar
• Pegram, M. D. et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J. Natl Cancer Inst. 96, 759–769 (2004).
  Article CAS PubMed Google Scholar
• Pegram, M. D. et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J. Natl Cancer Inst. 96, 739–749 (2004).
  Article CAS PubMed Google Scholar
• Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).
  Article CAS PubMed Google Scholar
• Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).
  Article CAS PubMed Google Scholar
• Smith, I. et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369, 29–36 (2007).
  Article CAS PubMed Google Scholar
• Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).
  Article CAS PubMed Google Scholar
• Xia, W. et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21, 6255–6263 (2002).
  Article CAS PubMed Google Scholar
• Fabian, M. A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23, 329–336 (2005).
  Article CAS PubMed Google Scholar
• Gomez, H. L. et al. Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J. Clin. Oncol. 26, 2999–3005 (2008).
  Article CAS PubMed Google Scholar
• Geyer, C. E. et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733–2743 (2006).
  Article CAS PubMed Google Scholar
• Esteva, F. J. & Hortobagyi, G. N. Gaining ground on breast cancer. Sci. Am. 298, 58–65 (2008).
  Article CAS PubMed Google Scholar
• Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst. 92, 205–216 (2000).
  Article CAS PubMed Google Scholar
• Dybdal, N. et al. Determination of HER2 gene amplification by fluorescence in situ hybridization and concordance with the clinical trials immunohistochemical assay in women with metastatic breast cancer evaluated for treatment with trastuzumab. Breast Cancer Res. Treat. 93, 3–11 (2005).
  Article CAS PubMed Google Scholar
• Gong, Y. et al. Chromogenic in situ hybridization is a reliable method for detecting HER2 gene status in breast cancer: a multicenter study using conventional scoring criteria and the new ASCO/CAP recommendations. Am. J. Clin. Pathol. 131, 490–497 (2009).
  Article CAS PubMed Google Scholar
• Paik, S. et al. Real-world performance of HER2 testing--National Surgical Adjuvant Breast and Bowel Project experience. J. Natl Cancer Inst. 94, 852–854 (2002).
  Article PubMed Google Scholar
• Wolff, A. C. et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J. Clin. Oncol. 25, 118–145 (2007).
  Article CAS PubMed Google Scholar
• Esteva, F. J. et al. CD40 signaling predicts response to preoperative trastuzumab and concomitant paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide in HER-2-overexpressing breast cancer. Breast Cancer Res. 9, R87 (2007).
  Article PubMed PubMed Central Google Scholar
• Untch, M. et al. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann. Oncol. 19, 1090–1096 (2008).
  Article CAS PubMed Google Scholar
• Seidman, A. D. et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J. Clin. Oncol. 26, 1642–1649 (2008).
  Article CAS PubMed Google Scholar
• Kaufman, P. A. et al. CALGB 150002: Correlation of HER2 and chromosome 17 copy number with trastuzumab (T) efficacy in CALGB 9840, paclitaxel with or without T in HER2+ and HER2- metastatic breast cancer [abstract]. J. Clin. Oncol. 25, a1009 (2007).
  Article Google Scholar
• Paik, S., Kim, C. & Wolmark, N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N. Engl. J. Med. 358, 1409–1411 (2008).
  Article CAS PubMed Google Scholar
• Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signaling network. Nat. Rev. Mol. Cell Biol. 2, 127–137 (2001).
  Article CAS PubMed Google Scholar
• Spivak-Kroizman, T. et al. Heterodimerization of c-erbB2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. J. Biol. Chem. 267, 8056–8063 (1992).
  CAS PubMed Google Scholar
• Ferguson, K. M. et al. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol. Cell 11, 507–517 (2003).
  Article CAS PubMed Google Scholar
• Garrett, T. P. et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell 11, 495–505 (2003).
  Article CAS PubMed Google Scholar
• Cai, Z. et al. Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes. Oncogene 27, 3870–3874 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Scott, G. K. et al. p185HER2 signal transduction in breast cancer cells. J. Biol. Chem. 266, 14300–14305 (1991).
  CAS PubMed Google Scholar
• Nagata, Y. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117–127 (2004).
  Article CAS PubMed Google Scholar
• Nahta, R., Yuan, L. X., Du, Y. & Esteva, F. J. Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling. Mol. Cancer Ther. 6, 667–674 (2007).
  Article CAS PubMed Google Scholar
• Shi, Y. et al. A novel proximity assay for the detection of proteins and protein complexes: quantitation of HER1 and HER2 total protein expression and homodimerization in formalin-fixed, paraffin-embedded cell lines and breast cancer tissue. Diagn. Mol. Pathol. 18, 11–21 (2009).
  Article CAS PubMed Google Scholar
• Molina, M. A. et al. NH2-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin. Cancer Res. 8, 347–353 (2002).
  CAS PubMed Google Scholar
• Esteva, F. J. et al. Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies. Breast Cancer Res. 7, 436–443 (2005).
  Article CAS Google Scholar
• Saez, R. et al. p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin. Cancer Res. 12, 424–431 (2006).
  Article CAS PubMed Google Scholar
• Scaltriti, M. et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J. Natl Cancer Inst. 99, 628–638 (2007).
  Article CAS PubMed Google Scholar
• Xia, W., Liu, L. H., Ho, P. & Spector, N. L. Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 23, 646–653 (2004).
  Article CAS PubMed Google Scholar
• Xia, W. et al. Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene 24, 6213–6221 (2005).
  Article CAS PubMed Google Scholar
• Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518–527 (2008).
  Article CAS PubMed Google Scholar
• Gong, Y. et al. Determination of estrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling study. Lancet Oncol. 8, 203–211 (2007).
  Article CAS PubMed Google Scholar
• Symmans, W. F. et al. Total RNA yield and microarray gene expression profiles from fine-needle aspiration biopsy and core-needle biopsy samples of breast carcinoma. Cancer 97, 2960–2971 (2003).
  Article CAS PubMed Google Scholar
• Paik, S. et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med. 351, 2817–2826 (2004).
  Article CAS PubMed Google Scholar
• Thor, A. D. et al. Activation (tyrosine phosphorylation) of ErbB-2 (HER-2/neu): a study of incidence and correlation with outcome in breast cancer. J. Clin. Oncol. 18, 3230–3239 (2000).
  Article CAS PubMed Google Scholar
• DiGiovanna, M. P. et al. Influence of activation state of ErbB-2 (HER-2) on response to adjuvant cyclophosphamide, doxorubicin, and fluorouracil for stage II, node-positive breast cancer: study 8541 from the Cancer and Leukemia Group B. J. Clin. Oncol. 26, 2364–2372 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Frogne, T., Laenkholm, A. V., Lyng, M. B., Henriksen, K. L. & Lykkesfeldt, A. E. Determination of HER2 phosphorylation at tyrosine 1221/1222 improves prediction of poor survival for breast cancer patients with hormone receptor-positive tumors. Breast Cancer Res. 11, R11 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Johnston, S. et al. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J. Clin. Oncol. 26, 1066–1072 (2008).
  Article CAS PubMed Google Scholar
• Meric-Bernstam, F. & Gonzalez-Angulo, A. M. Targeting the mTOR signaling network for cancer therapy. J. Clin. Oncol. 27, 2278–2287 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395–402 (2007).
  Article CAS PubMed Google Scholar
• Yakes, F. M. et al. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res. 62, 4132–4141 (2002).
  CAS PubMed Google Scholar
• Eichhorn, P. J. et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 68, 9221–9230 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Stemke-Hale, K. et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 68, 6084–6091 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Steck, P. A. et al. Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet. 15, 356–362 (1997).
  Article CAS PubMed Google Scholar
• Scaltriti, M. et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene 28, 803–814 (2009).
  Article CAS PubMed Google Scholar
• Lu, C. H. et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin. Cancer Res. 13, 5883–5888 (2007).
  Article CAS PubMed Google Scholar
• Xia, W. et al. Lapatinib antitumor activity is not dependent upon phosphatase and tensin homolog deleted on chromosome 10 in ErbB2-overexpressing breast cancers. Cancer Res. 67, 1170–1175 (2007).
  Article CAS PubMed Google Scholar
• Kim, C. et al. Trastuzumab sensitivity of breast cancer with coamplification of HER2 and C-MYC suggests proapoptotic function of dysregulated c-MYC in-vivo. Breast Cancer Res. Treat. 88 (Suppl. 1), S6a (2005).
  Google Scholar
• Perez, E. A. et al. c-MYC amplification and correlation with patient outcome in early stage HER2+ breast cancer from the NCCTG adjuvant intergroup trial N9831 [abstract]. Breast Cancer Res. Treat. (Suppl.), a56 (2008).
• Harris, L. N. et al. Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin. Cancer Res. 13, 1198–1207 (2007).
  Article CAS PubMed Google Scholar
• Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68, 9280–9290 (2008).
  Article CAS PubMed Google Scholar
• Nahta, R. & Esteva, F. J. In vitro effects of trastuzumab and vinorelbine in trastuzumab-resistant breast cancer cells. Cancer Chemother. Pharmacol. 53, 186–190 (2004).
  Article CAS PubMed Google Scholar
• Burstein, H. J. et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J. Clin. Oncol. 21, 2889–2895 (2003).
  Article CAS PubMed Google Scholar
• Pirker, R. et al. Characterization of immunotoxins active against ovarian cancer cell lines. J. Clin. Invest. 76, 1261–1267 (1985).
  Article CAS PubMed PubMed Central Google Scholar
• Vogel, C. L. et al. A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (MBC): Final results [abstract]. J. Clin. Oncol. 27 (Suppl.), a1017 (2009).
  Google Scholar
• Adams, C. W. et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol. Immunother. 55, 717–727 (2006).
  Article CAS PubMed Google Scholar
• Agus, D. B. et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2, 127–137 (2002).
  Article CAS PubMed Google Scholar
• Nahta, R., Hung, M. C. & Esteva, F. J. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 64, 2343–2346 (2004).
  Article CAS PubMed Google Scholar
• Lee-Hoeflich, S. T. et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 68, 5878–5887 (2008).
  Article CAS PubMed Google Scholar
• Scheuer, W. et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. (in press).
• Baselga, J. et al. Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T [abstract]. J. Clin. Oncol. 25 (Suppl. 18), a1004 (2007).
  Google Scholar
• Oda, K. et al. PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation. Cancer Res. 68, 8127–8136 (2008).
  Article CAS PubMed Google Scholar
• Junttila, T. T. et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15, 429–440 (2009).
  Article CAS PubMed Google Scholar
• Folkes, A. J. et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3, 2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem. 51, 5522–5532 (2008).
  Article CAS PubMed Google Scholar
• O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500–1508 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, Y., Zi, X., Zhao, Y., Mascarenhas, D. & Pollak, M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (herceptin). J. Natl Cancer Inst. 93, 1852–1857 (2001).
  Article CAS PubMed Google Scholar
• Munster, P. N., Basso, A., Solit, D., Norton, L. & Rosen, N. Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule- dependent manner. Clin. Cancer Res. 7, 2228–2236 (2001).
  CAS PubMed Google Scholar
• Modi, S. et al. Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. J. Clin. Oncol. 25, 5410–5417 (2007).
  Article CAS PubMed Google Scholar
• Swaby, R. et al. Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study [abstract]. J. Clin. Oncol. 27 (Suppl.), a1004 (2009).
  Google Scholar
• Tripathy, D. et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J. Clin. Oncol. 22, 1063–1070 (2004).
  Article CAS PubMed Google Scholar
• von Minckwitz, G. et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03–05 study. J. Clin. Oncol. 27, 1999–2006 (2009).
  Article CAS PubMed Google Scholar
• O'Shaughnessy, J. A. et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy [abstract]. J. Clin. Oncol. 26, a101 (2008).
  Article Google Scholar
• Mittendorf, E. A. et al. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin. Cancer Res. 15, 7381–7388 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Xia, W. et al. Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res. 66, 1640–1647 (2006).
  Article CAS PubMed Google Scholar
• Xia, W. et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc. Natl Acad. Sci. USA 103, 7795–7800 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Le, X. F. et al. The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. J. Biol. Chem. 278, 23441–23450 (2003).
  Article CAS PubMed Google Scholar
• Chu, I., Blackwell, K., Chen, S. & Slingerland, J. The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res. 65, 18–25 (2005).
  CAS PubMed Google Scholar
• Mohsin, S. K. et al. Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J. Clin. Oncol. 23, 2460–2468 (2005).
  Article CAS PubMed Google Scholar
• Molina, M. A. et al. Trastuzumab (Herceptin), a humanized anti-HER2 receptor monoclonal antibody, inhibits basal and activated HER2 ectodomain cleavage in breast cancer cells. Cancer Res. 61, 4744–4749 (2001).
  CAS PubMed Google Scholar
• Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumor biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).
  Article CAS PubMed Google Scholar
• Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).
  Article CAS PubMed Google Scholar
• Lin, N. U. et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 26, 1993–1999 (2008).
  Article CAS PubMed Google Scholar
• Kaufman, B. et al. Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study. Lancet Oncol. 10, 581–588 (2009).
  Article CAS PubMed Google Scholar
• Burstein, H. J. et al. A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann. Oncol. 19, 1068–1074 (2008).
  Article CAS PubMed Google Scholar
• Cameron, D. et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res. Treat. 112, 533–543 (2008).
  Article CAS PubMed Google Scholar