Abstract 3449: Impact of BRCA2 mutation in primary human triple negative breast cancer xenografts on the responses to ionizing radiation and in vivo tumor growth after treatment

Abstract

Abstract Introduction: Triple negative breast cancer (TNBC) is an aggressive disease associated with a high risk of distant recurrence and poor overall survival and, as for other BC subtypes, loco-regional treatment relies on surgery and radiotherapy. To prevent relapses, there is a need for both better systemic therapies and improvements in local treatments. Primary human TNBC xenografts are a useful tool for such preclinical studies. Using two TNBC models, one of which carrying a BRCA2 mutation (De Plater et al, BJC 2010;103:1192-200), we have investigated ionizing radiation sensitivity and the impact of the treatment on the growth of irradiated tumors. Experimental design: Two TNBC models, the BRCA2 HBCx-17 and the wild-type HBCx-12A xenografts were subcutaneously transplanted into the flanks of nude mice. After immobilization of the animals, the tumors were locally irradiated with low energy photons generated by an X-Ray tube (voltage: 200 kV, filter: 1 mm Al + 0.3 mm Cu, mean energy: 100 keV). Irradiation fields adapted to the targeted tissue were obtained using Cerrobend shields. With a daily fraction of 3.25 Gy, the cumulative dose ranged between 0 Gy to 32.25 Gy. In addition for both models, three tumor fragments from non irradiated tumors, 9.25 Gy-irradiated tumors with initial partial local control and subsequent progressive disease, and 19.5 Gy-irradiated tumors with initial complete remission and subsequent relapse were regrafted 3 months after treatment into nude mice. In all experiments, tumor take and growth were assessed by measuring tumor volume with a caliper twice a week for 5 months. Results: In both TNBC models, a strong sensitivity to ionizing radiation was observed with the occurrence of complete remission seen at higher doses. However, after 32.25 Gy, this was 100% in the BRCA2-mutated xenograft and only 50% in the HBCx-12A model (p < 0.05). Similarly, relapses occurred more frequently in the wild-type xenograft (57.1% vs 14.9%; p < 0.001). With respect to the treated or untreated tumors that were regrafted into mice, no differences of tumor take, in vivo tumor growth nor kinetics were observed for the BRCA2-mutated model for the 3 tumor types, in contrast to the HBCx-12A xenograft where 9.25 Gy-irradiated tumors grew faster than the 2 other groups. Conclusion: Our preclinical results confirm the sensitivity of TNBC to ionizing radiation and the impact of BRCA2 mutations on this sensitivity. In addition the presence of BRCA2 mutations would appear to modulate the post-radiotherapy growth of the tumors making them less aggressive. Such a characterization of highly relevant preclinical models supports their use for pharmacological assessments that will combine both radiotherapy and new therapeutic approaches to improve the outcome of TNBC patients. 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 3449. doi:1538-7445.AM2012-3449