Pulmonary Embolism–Attributable mortality among patients with breast cancer in the United States, 1999-2021

Abstract Introduction: Pulmonary embolism (PE) remains a leading preventable cause of morbidity and mortality in cancer patients. Over the last two decades, the management of breast cancer has undergone major changes. In addition to chemotherapy and tamoxifen, the introduction of new therapeutic agents, including cyclin-dependent kinase 4/6 inhibitors, antibody-drug conjugates, poly(ADP-ribose) polymerase inhibitors, and immune checkpoint inhibitors, has been associated with venous thromboembolism risk. We analyzed trends in PE-related mortality from 1999 to 2021 among U.S. patients with breast cancer, stratified by age, sex, race and ethnicity, and U.S. Census region. Methods: Mortality data were obtained from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause of Death database. We identified deaths from 1999 to 2021 in which both breast cancer (ICD-10: C50) and pulmonary embolism (ICD-10: I26, I82.8, I82.9) were listed on the death certificate, and all breast cancer deaths to estimate PE-attributable proportion. Age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated annually. Corresponding trends in age-adjusted cancer incidence over the same period were obtained from the United States Cancer Statistics database. Joinpoint regression modeling was utilized to assess time trends, with annual percent changes (APCs) for each trend segment, and average annual percent changes (AAPCs) summarizing the overall period. An exploratory evaluation of 2022-2023 mortality data was performed to assess post-COVID-19 pandemic trends. Results: From 1999 to 2021, the age adjusted incidence of breast cancer remained stable, from 94.2 to 89.7 per 100,000 persons (AAPC, –0.13%; 95% CI, –0.35 to 0.09; p = 0.23). CDC WONDER analysis identified a total of 16,518 PE–attributable deaths among individuals aged 15 years or older with breast cancer in the United States, accounting for 1.4% of all breast cancer-related deaths (n = 1,181.067). Of these PE-attributable deaths, 98.8% (16,314) occurred in female adults. Over this period, the AAMR for PE-attributable mortality in breast cancer increased significantly (AAPC, 1.35%; 95% CI, 0.68 to 2.03; p < 0.001), with a stable trend until 2017 (APC, 0.34%; 95% CI, −0.66 to 1.02; p = 0.42) and followed by a significant rise through 2021 (APC, 8.71%; 95% CI, 3.92 to 19.18; p < 0.001). An exploratory analysis of 2022-2023 showed the upward trend persisted beyond 2021 (APC, 1.54%; p < 0.0001). Across 1999-2021, the AAMR for PE in breast cancer patients increased significantly in females, both age group (<65 and ≥65 years), race (White, Black, and non-Hispanic individuals), and was observed in Midwest, South, and West Census regions, but not in the Northeast. Conclusions: Age-adjusted PE–attributable mortality among individuals with breast cancer was stable until 2017, then rose significantly through 2021. The increase was observed overall, in females, across age groups, racial/ethnic subgroups, and regions (except the Northeast), despite stable breast cancer incidence. Continued elevation in 2022-2023 suggests factors beyond COVID-19. Potential contributing factors, such as treatment-related thrombotic risk, increased awareness, and evolving diagnostic practices, warrant further investigation.