Abstract LB-352: Reversal of resistance to endocrine therapy by mTOR pathway targeting in a panel of patient derived breast cancer xenografts
Authors: Cottu Paul H. , Assayag Franck , Chouchane-Mlik Olfa , Reyal Fabien , Cremoux Patricia De , Gentien David , Chateau-Joubert Sophie , Vincent-Salomon Anne , Poupon Marie-France , Decaudin Didier , Marangoni Elisabetta 
Published: August 2012

Introduction: Resistance to endocrine therapy (ET) is a major complication of luminal breast cancers. The aims of this study were: 1) to evaluate the response to endocrine and targeted therapies in a large series of luminal breast cancer xenografts, 2) to generate hormone-resistant xenograft models and 3) to use these models as a support to study ET resistance reversal by mTOR targeting Methods: More than 400 tumor fragments obtained directly from patients with ER+ve breast cancer have been grafted in Swiss nude mice. After stable engraftment, xenografted tumors have been validated by pathology and immunohistochemistry (IHC) examination (ER, PR, HER2 and Ki67). In vivo response to different endocrine treatments (tamoxifen, fulvestrant, ovariectomy and letrozole) was evaluated. ET-resistant variants were generated from tumors growing under continuous therapeutic pressure. Models with intrinsic or acquired resistance to ET were tested with the mTOR inhibitor RAD001, alone and in combination with ET. Molecular analyses will be performed. Results: 12 luminal breast cancer xenografts have been characterized and consistently showed maintenance of the luminal phenotype The genetic profile measured by aCGH for both the patient and xenograft tumors showed a similar profile, stable through the in vivo mice generations. Different patterns of response to ET were observed, thus exhibiting heterogeneity similar to what is observed in the clinic. Five xenograft models with acquired resistance to ET were generated after several months of continuous endocrine therapy and were maintained as independent hormono-resistant variants. Two of them were derived from tumors resistant to tamoxifen and 3 from tumors resistant to ovariectomy, used as a surrogate to estrogen deprivation. IHC analysis showed that expression of ER and PR receptors was conserved in the variant models, while proliferation status assessed by Ki67 expression was generally higher. For all 5 models, resistance to ET was confirmed in further engraftment and ET experiments. RAD001 treatment resulted in a strong anti-tumor effect in the tamoxifen resistant xenograft models and an additive effect was observed when RAD001 was given in combination with tamoxifen or fulvestrant.The PI3K/mTOR pathway status and gene expression profiles will be analyzed in all experiments. Detailed results will be presented at the meeting. Conclusion: We have established a large panel of primary luminal breast cancer xenografts, recapitulating the biological and clinical features of patient tumors. ET resistant variants have been generated, which serve as a preclinical platform to test reversal of resistance to ET, e.g; by mTOR pathway targeting. Molecular studies at the gene and protein expression levels will give an insight of the mechanisms associated with acquired resistance to endocrine treatments.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-352. doi:1538-7445.AM2012-LB-352