Abstract PD6-4: Risk of radiation induced secondary malignancies in gBRCA carriers following breast cancer therapy

Background: Mutations in germline BRCA genes (gBRCA) are associated with a high incidence and early onset of breast and ovarian cancer. As gBRCA impairs DNA homologous recombination repair, specifically double-strand break repair, it has been hypothesized that gBRCA carriers may be more susceptible to developing radiation therapy (RT) induced secondary primary malignancies (SPMs). The incidence of RT-induced SPMs is relevant both to the treatment of gBRCA women with breast cancer, as well as the potential use of breast RT as cancer prevention as recently demonstrated in a landmark study. The aim of this study is to determine if there is an elevated risk of SPMs in gBRCA carriers treated with breast RT. Methods: Following IRB approval, hospital records of women with gBRCA and stage 0-III breast cancer treated with adjuvant breast/chest wall RT between 1991-2012 with follow-up >5 years were identified. Breast cancer patients treated with prophylactic contralateral RT on a national study were included. Demographic, cancer, treatment, SPMs, and outcome data were recorded. Records were crossed checked against the National Ministry of Health’s mandatory cancer registry for SPMs. Results: 230 women meeting eligibility were identified (266 treated breasts), with median age 45.8 and median follow up 11.4 years (range 5-27 years, a total of 3,042 woman-years). 194 (84%) were irradiated unilaterally, 15 (7%) bilaterally for bilateral breast cancer, and 21 (9%) bilaterally with prophylactic RT to the contralateral unaffected breast. 210 (79%) were treated with RT to the whole breast and 56 (21%) to the chest wall; 41% were treated to the regional lymph nodes. 92% were treated to a dose of 50-50.4 Gy with 6mV photons. 85% underwent BSO at a median age of 48.4. 101 (68%) were gBRCA1, 85 (28%) were gBRCA2, 1% were both gBRCA 1 and 2 and 3% were gBRCA of unknown classification. 199 (74.8%) received neo/adjuvant chemotherapy at diagnosis. Six upper-body, non-BRCA related malignancies were diagnosed following RT at a mean interval of 138 months and mean age of 48.8 years. Of these, only one was within the RT fields and is strongly RT related - a thyroid carcinoma, 204 months following breast and regional nodal RT (crude incidence of 0.43% of treated women, and 0.37% of treated breasts). Two lymphomas developed within the thorax outside of the treatment volume (at 84 and 132 months); a GE junction adenocarcinoma following treatment for bilateral metachronous breast cancer (360 months from first RT course); gastric adenocarcinoma following treatment for right breast cancer (at 54 months) and left lung cancer following treatment for right breast cancer (at 144 months). 5 of 6 women were gBRCA1 185delAG mutation carriers. Conclusions: This is the largest series analyzing RT-induced SPMs in gBRCA women treated with RT for breast cancer. With over 3000 women-years of follow (median of 11.4 years), there was no signal of an increased risk of RT-induced SPMs compared to the general population. While further follow up in larger datasets is needed, breast RT as therapy and prevention should be considered safe in the gBRCA population. Citation Format: Shir Schlosser, Rachel Rabinovitch, Zina Shatz, Sara Finkel, Ilanit Dromi-Shahadi, Galia Jacobson, Shira Galper, Miri Levi Sklair, Eitan Friedman, Rinat Bernstein-Molho, Merav Akiva Ben David. Risk of radiation induced secondary malignancies in gBRCA carriers following breast cancer therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-4.