Abstract 4165: Novel genetic rat models to identify factors that modulate cardiac and tumor radiation sensitivity

Abstract

Abstract Purpose/Objectives: Over 50% of breast cancer patients receive radiation therapy, but radiation doses can be limited by normal tissue toxicity. Radiation therapy can improve breast cancer-specific survival, but cardiac morbidity can be increased in patients with left-sided tumors. We used rat genetic models to identify targets to improve the therapeutic ratio of radiation. We assessed the radiation responsiveness of mammary tumors and the heart in genetically similar consomic rats conducive to genetic mapping. Materials/Methods: Female SS rats and SS.BN3 consomic rats, which are genetically identical to SS rats except that chromosome 3 is inherited from the BN strain, have previously been shown to exhibit different vascular dynamics and breast tumor growth. Human MDA-MD-231 cells or syngeneic mammary tumor cells developed from DMBA-induced mammary tumors were implanted orthotopically into immunodeficient or immunocompetent SS and SS.BN3 rats, respectively, and tumors were treated locally with mock or 5x4 Gy. To examine cardiac toxicity, adult female SS and SS.BN3 rats received image-guided localized whole-heart radiation to a dose of 24 Gy or 9 Gy x 5 (AP and 2 lateral fields, weighted 1:1:1). Echocardiograms with strain analysis were performed at baseline, 3 months and 5 months. The Student's t-test was used to compare values. Results: The BN strain-derived genetic variant(s) on rat chromosome 3 is important for tumor radiation sensitivity. Tumors in SS.BN3 rats were significantly more radiosensitive than tumors in the parental SS strain. A supra-additive effect was seen with both tumor cell lines, with recurrence-free survival of 30% vs. 67% at 137 days in SS vs SS.BN3 rats (p=0.02) in xenografts, and recurrence-free survival of 9% vs. 100% at 141 days in SS vs. SS.BN3 rats (p<0.0001) in syngeneic tumors. The SS female rats that received 24 Gy exhibited enhanced cardiac toxicity compared to SS.BN3 rats, with larger pericardial effusions in SS vs SS.BN3 rats (p<0.05), significantly elevated end diastolic volume (EDV) and end systolic volume (ESV) at 5 months (EDV: 0.62 vs. 0.49 mL, p<0.01; ESV: 0.12 vs. 0.03 mL, p<0.01), and increased cardiac mortality (5/11 SS vs. 0/7 SS.BN3 rats). Fractionated heart radiation yielded similar results. Taken together, the SS.BN3 tumors are more sensitive to radiation, while the hearts of SS.BN3 rats are protected against radiation toxicity, when compared to the SS strain. Conclusions: These results demonstrate that genetic variants on rat chromosome 3 alter the sensitivity to radiation therapy, enhancing tumor responses to radiation and protecting the heart, thus improving the therapeutic ratio. Gene expression analysis and genetic mapping will be performed to identify the causative target(s). This project has the potential to enhance the effectiveness and toxicity profile of radiation therapy in breast cancer. Citation Format: Rachel A. Schlaak, Anne Frei, Aronne M. Schottstaedt, Brian L. Fish, Leanne Harmann, Tracy Gasperetti, Michael J. Flister, Meetha Medhora, Jennifer L. Strande, Carmen R. Bergom. Novel genetic rat models to identify factors that modulate cardiac and tumor radiation sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4165.