217 - Pelvic Radiation-Induced Tumors in Mice Recapitulate the Histologic and Anatomic Spectrum of Human Secondary Malignancies

03:20pm - 03:30pm ET

Room 153

Presenter(s)

John Kincaid, MS, MPhil - Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Boston, MA

J. W. R. Kincaid^1,2, S. Yaffe¹, A. Ward¹, M. Vander Heiden^1,3, and D. R. Schmidt^1,4; ¹Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, ²Harvard Medical School, Boston, MA, ³Dana-Farber Cancer Institute, Boston, MA, ⁴Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA

Purpose/Objective(s):

Radiation-induced secondary malignancies, associated with high mutational burden and poor prognosis, remain an unmet challenge of cancer care. Preclinical models present an opportunity to study the pathogenesis of these tumors and test new therapeutic approaches. Here, we developed a large-scale cohort of pelvic radiation-induced tumors in outbred mice to systematically characterize the anatomic and histopathologic spectrum of secondary malignancies following radiotherapy. Our secondary objective was to quantify the effects of sex, genotype, and age at radiation exposure on tumor type and latency.

Materials/Methods:

Male and female wild-type (WT; n=93) and p53-haploinsufficient (p53+/-; n=122) mice received either single-fraction pelvic radiation (9 Gy) at 4 weeks or 4-5 months of age, or no radiation (controls). Animals were followed until 20 months of age or humane endpoints, then underwent necropsy. Overall survival was evaluated via Kaplan–Meier analysis. Tumors were classified by H&E and IHC on FFPE tissue.

Results:

Radiation increased the incidence of pelvic malignancy in both wild-type and p53+/- animals. Irradiated p53+/- animals developed secondary malignancies closely resembling the anatomic distribution and histopathologic subtypes seen in humans, including soft tissue sarcomas, osteosarcomas, and carcinoma of the breast and gynecologic organs. p53+/- controls primarily developed lymphoid malignancies. While sarcomas predominated in irradiated p53+/- mice, WT counterparts mainly developed carcinomas. Radiation significantly reduced overall survival in p53+/- mice of both sexes compared with non-irradiated controls. Median survival declined from 628 days in male controls to 343 and 426 days in males irradiated at 1 month and 4–5 months, respectively, and from 434 days in female controls to 273 and 344 days in similarly treated females. In radiation-exposed groups, post-radiation latency did not differ by age at exposure. Median survival after radiation exposure was 315 versus 314 days in males and 245 versus 232 days in females treated at 1 month versus 4–5 months, respectively.

Conclusion:

We hereby establish a large-scale cohort of radiation-induced secondary malignancies recapitulating human tumor histology and distribution. We demonstrate sex- and genotype-dependent differences in survival and tumor types. We also find that in outbred mice the incidence and kinetics of tumorigenesis are similar for juveniles and adults, supporting a characteristic latency in which time from exposure, not age, determines risk.