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

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

1. Josep Lluís Parra-Palau*, 
2. Beatriz Morancho*, 
3. Vicente Peg, 
4. Marta Escorihuela,
5. Maurizio Scaltriti, 
6. Rocio Vicario, 
7. Mariano Zacarias-Fluck, 
8. Kim Pedersen, 
9. Atanasio Pandiella,
10. Paolo Nuciforo, 
11. Violeta Serra, 
12. Javier Cortés, 
13. José Baselga, 
14. Charles M. Perou, 
15. Aleix Prat,
16. Isabel T. Rubio and 
17. 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 mm³; P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.

• © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.