Rising Risk of Subsequent Primary Cancers Among US Cancer Survivors, 2000–2021

BACKGROUND: As cancer survival improves, the population at risk for subsequent primary cancers (SPCs) is growing rapidly. Yet, contemporary trends in SPC incidence remain undercharacterized, limiting the development of targeted surveillance and survivorship strategies. OBJECTIVE: To evaluate long-term trends in SPC risk among US cancer survivors and identify high-risk subgroups by cancer type and demographic characteristics. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from 17 SEER registries and included over 6 million individuals diagnosed with an index primary cancer between 2000 and 2021. MAIN OUTCOMES AND MEASURES: Standardized incidence ratios (observed-to-expected ratios, OERs) and Cox proportional hazards models were used to assess SPC trends among male and female cancer survivors. Analyses were stratified by cancer site, latency between index and SPC, stage, age, and race/ethnicity. RESULTS: SPC risk increased substantially from 2000 to 2020. Among men, OERs rose from 0.95 (95% CI = 0.94, 0.97) to 1.75 (95% CI = 1.70, 1.80); among women, from 1.23 (95% CI = 1.21, 1.24) to 1.76 (95% CI = 1.70, 1.83). The highest SPC incidence occurred within 6 months of the index diagnosis. Variations were observed across demographic and cancer-related characteristics. CONCLUSIONS AND RELEVANCE: The rising burden of SPCs highlights a critical need in survivorship care. These findings support the need for updated, risk-stratified surveillance protocols and inform national cancer control strategies aimed at reducing long-term morbidity among survivors. STUDY TYPE: Cohort study.