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Annals of Oncology Advance Access published online on November 4, 2009
Annals of Oncology, doi:10.1093/annonc/mdp496
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts

C. Larbouret1,2,3,4, B. Robert1,2,3,4, C. Bascoul-Mollevi4, F. Penault-Llorca5, A. Ho-Pun-Cheung4, S. Morisseau1,2,3,4, I. Navarro-Teulon1,2,3,4, J.-P. Mach6, A. Pèlegrin1,2,3,4,* and D. Azria1,2,3,4,7

1 Institut de Recherche en Cancérologie de Montpellier, Montpellier
2 Institut National de la Santé et de la Recherche Médicale, U896, Montpellier
3 Université Montpellier1, Montpellier
4 CRLC Val d'Aurelle Paul Lamarque, Montpellier
5 Department of Pathology Centre Jean Perrin, Clermont-Ferrand
6 Institut de Biochimie, Université de Lausanne, Epalinges, Switzerland
7 Department of Radiotherapy CRLC Val d'Aurelle Paul Lamarque, Montpellier, France

* Correspondence to: Dr A. Pèlegrin, Institut de Recherche en Cancérologie de Montpellier, CRLC Val d'Aurelle Paul Lamarque, 34298 Montpellier Cedex 5, France. Tel: +33-0-467613032; Fax: +33-0-467613787; E-mail: Andre.Pelegrin{at}valdorel.fnclcc.fr

Background: Pancreatic carcinoma remains a treatment-refractory cancer with a poor prognosis. Here, we compared anti-epidermal growth factor receptor (EGFR) and anti-HER2 monoclonal antibodies (2mAbs) injections with standard gemcitabine treatment on human pancreatic carcinoma xenografts.

Materials and methods: Nude mice, bearing human pancreatic carcinoma xenografts, were treated with either combined anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) or gemcitabine, and tumor growth was observed.

Results and conclusion: In first-line therapy, mice survival was significantly longer in the 2mAbs group compared with gemcitabine (P < 0.0001 for BxPC-3, P = 0.0679 for MiaPaCa-2 and P = 0.0019 for Capan-1) and with controls (P < 0.0001). In second-line therapy, tumor regressions were observed after replacing gemcitabine by 2mAbs treatment, resulting in significantly longer animal survival compared with mice receiving continuous gemcitabine injections (P = 0.008 for BxPC-3, P = 0.05 for MiaPaCa-2 and P < 0.001 for Capan-1). Therapeutic benefit of 2mAbs was observed despite K-Ras mutation. Interestingly, concerning the mechanism of action, coinjection of F(ab')2 fragments from 2mAbs induced significant tumor growth inhibition, compared with controls (P = 0.001), indicating that the 2mAbs had an Fc fragment-independent direct action on tumor cells. This preclinical study demonstrated a significant improvement of survival and tumor regression in mice treated with anti-EGFR/anti-HER2 2mAbs in first- and second-line treatments, compared with gemcitabine, independently of the K-Ras status.

EGFR, gemcitabine, HER2, monoclonal antibodies, pancreatic carcinoma

Received for publication August 17, 2009. Accepted for publication September 8, 2009.


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