Survival differences after diagnosis of breast cancer as second primary cancer vs as first primary cancer

Introduction: The incidence of second primary cancer (SPC) is on the rise. In the United States, about 20% of all new cancers diagnosed annually are estimated to be SPC. Prior studies of the SEER registries suggested that survival was inferior in SPC compared with that in the first primary cancer (FPC) of the same type. However, these studies did not account for prognostic factors such as comorbidity, obesity, smoking, and insurance status. We examined survival after breast cancer diagnosis as a SPC vs. as a FPC in a large integrated health care delivery system. Methods: We identified female members of Kaiser Permanente Southern California (KPSC) aged 18-84 years diagnosed with an invasive breast cancer as a FPC (for the FPC cohort) or SPC (for the SPC cohort) between 2000-2022 using KPSC's cancer registry. Women were followed until the earliest occurrence of death, diagnosis of a subsequent primary cancer, KPSC disenrollment, or 12/31/2023. All-cause and breast cancer-specific mortality were ascertained. Fine and Gray subdistribution hazard regression was used to estimate survival differences in the SPC and the FPC cohort accounting for competing risks. Multivariable models adjusted for age at diagnosis, stage, breast cancer subtype (luminal A, luminal B, HER2-enriched, and triple negative), race/ethnicity, year of diagnosis, Charlson's comorbidity index, body mass index, and smoking. Stratified analyses were performed by age at diagnosis (<50 yrs and ≥50 yrs), stage, and subtype. Results : A total of 42,972 and 6,363 women were included in the breast FPC and SPC cohort (the mean age at diagnosis: 59.8 yr vs. 66.0 yr), respectively. About half of participants in both cohorts were racial/ethnic minorities. Sixty-five percent of the FPC cohort and 71% of the SPC cohort were diagnosed at localized stage. During a mean follow-up of 7 years, a total of 7,148 (17%) and 1,647 (26%) deaths were observed, including 4,035 (9%) and 838 (13%) breast cancer-specific deaths in the FPC and SPC cohort, respectively. In multivariable-adjusted models, there was an elevated overall mortality in the SPC cohort compared with the FPC [adjusted hazard ratio (aHR) = 1.35 (1.27-1.43)]. Elevated breast cancer-specific mortality was also noted in the SPC cohort: aHR=1.27 (1.17-1.38). Similar findings were observed when stratified by age, stage, or subtype (aHRs range between 1.33-1.40), with the exception that breast cancer-specific mortality was not elevated in SPC for triple-negative breast cancer [aHR=1.04 (0.85-1.27)]. Conclusion : Overall and breast cancer-specific mortality were higher after a breast SPC diagnosis compared to that after a breast FPC diagnosis among an insured population adjusting for prognostic factors. Further research is needed to shed light on the reasons underly the survival difference to inform management for the breast SPC.