Abstract C115: Response to trastuzumab of HER2-overexpressing breast cancer patient-derived xenografts depends on the host mouse strain.
Authors: Judde Jean-Gabriel , Deas Olivier , Lassalle Myriam , Boissay Victorine , Delaitre Anais , Nicolle Delphine , Cairo Stefano , Ginestier Christophe , Poupon Marie-France , Charafe-Jauffret Emmanuelle 
Published: August 2014

Breast cancer is one of the most commonly diagnosed form of cancer and the second leading cause of cancer-related death in women. Human epidermal growth factor receptor 2 (HER2) is overexpressed in around 20-30% of breast cancer tumors. It is associated with a more aggressive disease, higher recurrence rate, and increased mortality. The availability of trastuzumab for HER2-targeted therapy has substantially improved outcomes of patients with breast cancer that overexpresses HER2. Although trastuzumab has become a standard of care for both early-stage and metastatic HER2 positive breast cancer, not all patients respond to trastuzumab, and many will progress after an initial response. Lack of response in some patients and relapse during the course of therapy continue to challenge researchers towards the development of novel treatment strategies.

XenTech has developped a large number of patient-derived breast cancer xenografts (PDX) recapitulating the molecular diversity as well as the heterogeneity of responses to standard of care treatments observed in patients. Here, we characterized three HER2 overexpressing models: HBCx-5; HBCx-13B and T226 and performed efficacy studies to evaluate their sensitivity to trastuzumab and lapatinib, two HER2 targeting agents.

Briefly, two different immunodeficient mouse strains, athymic nude and SCID Hairless Outbred mice, were engrafted subcutaneously with HER2+ breast tumor models. Mice bearing growing tumors were treated with trastuzumab or lapatinib for 6 weeks.

Although the three tumor models were all sensitive to lapatinib, a dual tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways, none of them were sensitive to trastuzumab if implanted in athymic nude mice. On the other hand, in SHO mice, HBCx-13B and T226 PDX presented a very high response to trastuzumab with 80-90% of tumor growth inhibition, while only HBCx-5 remained insensitive.

This study shows that the host immune background can be of critical importance for the preclinical evaluation of therapeutic antibodies. These HER2+ PDX models are powerful tools to study resistance to trastuzumab occurring prior to drug treatment (primary or innate resistance) in different immunological backgrounds. In addition, they offer the possibility to test other HER2 targeted therapies, such as antibody drug conjugates like trastuzumab emtansine (T-DM1), in a trastuzumab-resistant or -sensitive context.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C115.

Citation Format: Jean-Gabriel Judde, Olivier Deas, Myriam Lassalle, Victorine Boissay, Anais Delaitre, Delphine Nicolle, Stefano Cairo, Christophe Ginestier, Marie-France Poupon, Emmanuelle Charafe-Jauffret. Response to trastuzumab of HER2-overexpressing breast cancer patient-derived xenografts depends on the host mouse strain. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C115.