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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast Cancer
Affiliations of authors: Medical Oncology Program, Medical Oncology Department (MS, AO, JA, MG, JC, SDC, JA, JB) and Pathology Department (FR, SRC), Vall d'Hebron University Hospital and Research Institute, Barcelona, Spain; Pathology Department, Hospital Universitari Arnau de Villanova, Lleida, Spain (XMG); Universitat Autónoma de Barcelona, Barcelona, Spain (JB)
Correspondence to: José Baselga, MD, PhD, Medical Oncology Program, Medical Oncology Department, Psg Vall d'Hebron 119-129, Barcelona 08035, Spain (e-mail: jbaselga{at}vhebron.net).
Background: Women with HER2–overexpressing breast cancers have poor prognosis, and many are resistant to the HER2 monoclonal antibody trastuzumab. A subgroup of HER2–overexpressing tumors also express p95HER2, an amino terminally truncated receptor that has kinase activity. Because p95HER2 cannot bind to trastuzumab but should be responsive to the HER2 tyrosine kinase inhibitor lapatinib, we compared the sensitivity of tumors expressing p95HER2 and tumors expressing the full-length HER2 receptor to these agents.
Methods: MCF-7 and T47D breast cancer cells were stably transfected with either full-length HER2 or p95HER2. We studied the effects of trastuzumab and lapatinib on receptor signaling, cell proliferation, and the growth of xenograft tumors. A paraffin-based immunofluorescence assay was developed to study the association between p95HER2 expression and sensitivity to trastuzumab in patients with advanced breast cancer. All statistical tests were two-sided.
Results: Treatment of p95HER2–expressing cells with lapatinib inhibited p95HER2 phosphorylation, reduced downstream phosphorylation of Akt and mitogen-activated protein kinases, inhibited cell growth (MCF-7p95HER2 clones, lapatinib versus control, mean growth inhibition = 57.6% versus 22.6%, difference = 35%, 95% confidence interval [CI] = 22.5% to 47.3%; P<.001; T47Dp95HER2 clones, lapatinib versus control, mean growth inhibition = 36.8% versus 20%, difference = 16.8%, 95% CI = 11.3% to 22.3%, P<.001), and inhibited growth of MCF-7p95HER2 xenograft tumors (lapatinib versus control, mean = 288.8 versus 435 mm3, difference = 146.2 mm3, CI = 73.8 to 218.5 mm3, P = .002). By contrast, treatment with trastuzumab had no effect on any of these parameters. Of 46 patients with metastatic breast cancer who were treated with trastuzumab, only one of nine patients (11.1%) expressing p95HER2 responded to trastuzumab (with a partial response), whereas 19 of the 37 patients (51.4%) with tumors expressing full-length HER2 achieved either a complete (five patients) or a partial (14 patients) response (P = .029).
Conclusions: Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2–targeting strategies.
| CONTEXT AND CAVEATS Prior knowledge HER overexpression is associated with poor outcome in patients with breast cancer, and many of these tumors are resistant to the HER2 monoclonal antibody trastuzumab. A subgroup of HER2–overexpressing tumors also expresses p95HER2, a truncated form of the receptor that does not bind to trastuzumab but retains tyrosine kinase activity. Study design Response to trastuzumab and the tyrosine kinase inhibitor lapatinib in in vitro and in vivo models of breast cancer expressing full-length HER2 or truncated p95HER2. Response of advanced breast cancer to trastuzumab and p95HER2 expression was measured in patient samples using a new immunofluorescence technique. Contributions p95HER kinase activity and cell proliferation in cell lines and growth of xenograft tumors expressing p95HER2 was inhibited by lapatinib, whereas these cells and tumors were resistant to trastuzumab. p95HER2 expression was directly associated with trastuzumab resistance in human breast tumors. Implications p95HER2–overepxressing breast cancers may be resistant to trastuzumab and therefore may require secondary anti-HER2–targeting therapies. Limitations Because the studies were performed using cell lines, mouse models, and a limited number of human tumor samples, it is unknown how applicable the results are to human breast cancer.
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Manuscript received October 10, 2006; revised January 30, 2007; accepted March 2, 2007.
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J Natl Cancer Inst 2007 99: 577.
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