*2.1. Study Population*

Data for this registry-based prospective cohort study were obtained from National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program which covers about 34% of the US population and obtains information from 17 population-based cancer registries located in the following states: Alaska, California, Connecticut, Georgia, Hawaii, Iowa, Kentucky, Louisiana, New Mexico, New Jersey, Utah. and Washington [19]. Men aged ≥ 40 years who were diagnosed with histologically confirmed stage I–III primary breast cancer from 1 January 2000 to 31 December 2019 were eligible for the current study. Of the 5508 eligible samples whose diagnosis was not made only at autopsy or via death certificates, the following exclusions were made: 219 persons that did not undergo surgery, 72 persons with no follow-up information or unknown cause of death, and 1 person with no information on tumor laterality. This resulted in an analytic sample of 5216 MBC patients. Institutional review board approval was not required for this study as the SEER registry is a de-identified publicly available database.

#### *2.2. Definition of Study Variables*

Information obtained from the SEER database included age at diagnosis, year of diagnosis, race and ethnicity, geographic region, location (rural or urban), marital status, annual median household income of the county of patient's residence, disease stage, tumor

grade, tumor size, laterality, number of regional lymph nodes examined, hormone (estrogen and progesterone) receptor status, cancer therapy, cause of death, and survival time.

The main exposure of interest in the current study was first course of cancer therapy. For the current analysis, both radiotherapy and chemotherapy were classified as received or not received. The reported sensitivity, specificity, and positive predictive value of the SEER database correctly identifying individuals with breast cancer who received therapy are 69%, 98%, and 91% for chemotherapy and 80%, 98%, and 98% for radiotherapy [20]. Breast cancer was defined using International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) codes C500-C509. Race and ethnicity were defined as non-Hispanic White, non-Hispanic Black, Hispanic, and other which includes American Indians/Alaska Native, Asian or Pacific Islander, and other race or ethnic groups. Cancer stage at time of diagnosis was defined using the American Joint Committee on Cancer's staging manual that uses information on tumor size, regional lymph node involvement, and the presence of metastasis [21]. Editions of the manual that were applicable during the period of the current study were used.

Cause of death information was classified using the World Health Organization's International Classification of Diseases, Tenth Revision codes. CVD mortality was defined as deaths due to diseases of heart (I00–I09, I11, I13, I20–I51), hypertensive heart disease (I10–115), cerebrovascular diseases (I60–I69), atherosclerosis (I70), aortic aneurysm and dissection (I71), or other diseases of arteries, arterioles, or capillaries (I72–I78).
