Abstract 3269: Recapitulating the BETH adjuvant breast cancer trial (NCT00625898) using clinically accurate orthotopic surgical resection models

Abstract

Abstract Background: An overwhelming majority of phase III clinical trials in the oncology setting fail as promising results observed in the ‘pre-clinic’ are not successfully translated to patients. As such, improved models which more accurately predict outcomes are now required. Herein, we have established orthotopic surgical resection models of Her2+ breast cancer, which replicate the phenotype of clinical post-resection metastasis [1,2]. Using these models we have recapitulated the BETH adjuvant breast cancer trial (NCT00625898) where the addition of bevacizumab (BVZ) to chemotherapy plus trastuzumab (TRAST) failed to provide additional benefit in the adjuvant setting. Methods: SCID mice were orthotopically implanted with bioluminescent Her2+ MDA-MB-231or HCC1954 cells and palpable tumors resected approximately 5 weeks later. 3 weeks after resection, mice were treated with 10 mg/kg TRAST + 5mg/kg paclitaxel IP once weekly for 6 cycles with or without weekly BVZ (5mg/kg IP). Metastasis was monitored by weekly bioluminescence imaging. Results: Tumor growth and imaging data confirmed that the addition of BVZ to adjuvant TRAST + chemotherapy provided no additional benefit compared with TRAST + chemotherapy alone. Previous pre-clinical studies using inappropriate non-resection models failed to predict this response. Furthermore, Reverse Phase Protein Array analysis of treated tumors implicated HER2, VEGF, mTOR and the intrinsic mitochondrial cell death apoptotic pathways in treatment resistance. Conclusion: In summary, our data provides evidence for pre-clinical models which better predict clinical outcome in the breast cancer adjuvant setting, and which represent an important resource for interrogating resistance pathways and identifying novel biomarker signatures. [1]. Breast. 2013 Aug;22 Suppl 2:S57-65; [2]. Cancer Res. 2013 May 1;73(9):2743-8.This work was performed under Irish HPRA Authorization AE18982 and was supported by the Clinical Cancer Research Trust. ATB receives funding from the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT Grant (CCRC13GAL). Citation Format: Liam S. Shiels, Ian S. Miller, Clare Morgan, Mattia Cremona, Robert Kerbel, Bryan Hennessey, Norma O’Donovan, John Crown, Annette T. Byrne. Recapitulating the BETH adjuvant breast cancer trial (NCT00625898) using clinically accurate orthotopic surgical resection models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3269.