lunes, 13 de octubre de 2014

Effect of p95HER2/611CTF on the Response to Trastuzumab and Chemotherapy

Effect of p95HER2/611CTF on the Response to Trastuzumab and Chemotherapy



Effect of p95HER2/611CTF on the Response to Trastuzumab and Chemotherapy

  1. Joaquín Arribas
+Author Affiliations
  1. *Authors contributed equally to this work.
  2. Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d’Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
  1. Correspondence to: Joaquín Arribas, PhD, Preclinical Research Program, Vall d'Hebron Institute of Oncology. Psg. Vall d'Hebron 119-129, 08035 Barcelona, Spain (e-mail:jarribas@vhio.net).
  • Received February 21, 2014.
  • Revision received April 29, 2014.
  • Accepted August 8, 2014.

Abstract

Human epidermal growth factor receptor 2 (HER2)–positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906mm3, 95% confidence interval = 1274 to 538 mm3; trastuzumab+doxorubicin: 259mm3, 95% confidence interval = 387 to 131 mm3P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.

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