Risk of Radiation-Associated Secondary Malignancies among Patients with Breast Cancer Harboring TP53 Germline Variants

Abstract

Radiation-associated malignancies are rare and poorly understood. TP53 encodes a multifunctional protein that maintains genome integrity and is the most common somatically mutated gene in cancer. Germline pathogenic variants of TP53 predispose carriers to several cancers comprising the Li-Fraumeni syndrome. It is hypothesized that carriers are also at increased risk of radiotherapy (RT)-associated secondary malignancies; however, reports are mixed. We evaluated the risk of secondary malignancies after breast RT among patients with Li-Fraumeni syndrome. This multi-institutional cohort study included carriers of TP53 germline variants who underwent surgical treatment for breast cancer between 1980 and 2020. Patients were stratified based on germline TP53 classification (pathogenic variants [PV] vs variants of uncertain significance [VUS]). The primary outcome of interest was the cumulative incidence risk of developing an in-field secondary cancer after radiotherapy for primary breast carcinoma. Ninety-one patients (57 PV and 34 VUS) were evaluated with a median age of 36 years (interquartile range [IQR] 31, 42) and a median follow up of 7.9 years (IQR 4.7, 14.4). Among those with PV who received RT (n = 22), 4 secondary non-breast cancers developed in the radiation field (15-year cumulative incidence 19% [95% CI: 4-43%]), whereas, among those with PV who did not receive RT (n = 35), 0 secondary non-breast cancers were observed in the treated breast (15-year cumulative incidence 0%; p = 0.043). We observed 3 radiation-associated sarcomas among patients with PV who received RT (15-year risk 12% [95% CI 2-33%]) compared with 0 among those who did not receive RT (p = 0.08). No RT-associated sarcomas were observed among 18 patients with TP53 VUS who received RT. RT was not associated with overall survival, despite higher T and N breast cancer stage among those receiving RT (p = 0.33). As expected, patients with PV were more likely than those with VUS to develop any secondary cancer following breast cancer treatment (15-year risk: 54% [95% CI: 33-72%] vs. 14% [95% CI: 3-36%]). Carriers of pathogenic variants of TP53 are at elevated risk of developing secondary malignancies after breast cancer treatment. This population is at particular risk of developing in-field secondary cancers following RT. This iatrogenic risk must be weighed against the anticipated therapeutic benefit of tumor control. Shared decision making is crucial in the radiotherapeutic management of breast cancer patients harboring the Li-Fraumeni syndrome.