Risk of second cancer in survivors of early-onset colorectal cancer: racial and ethnic differences in a population-based study

Introduction: Early-onset colorectal cancer (EOCRC) incidence is rising sharply in the US, yet the long-term survivorship experience of this population remains poorly defined particularly among groups experiencing unequal cancer burden. Because racial and ethnic disparities persist in cancer-related exposures, treatment experiences, and survivorship care, the long-term probability of developing a second primary cancer (SPC) after EOCRC may also vary across population groups. We estimated risk of SPC by race and ethnicity to improve understanding of long-term survivorship following EOCRC. Methods: We used SEER 12 registry data to identify adults aged 18-49 years with stage 0-III EOCRC between 1992-2021. SPC was defined as any new primary cancer diagnosed ≥6 months after EOCRC. Accounting for competing risk of death, we estimated cumulative incidence of 1) any SPC and 2) second CRC by calendar time and attained age. Standardized incidence ratios (SIRs) compared risk to the general population. Analyses were stratified by sex and racial/ethnic groups. Results: Among 29,115 EOCRC survivors, 53.5% were male, and the racial/ethnic distribution was non-Hispanic White (NHW: 54%), non-Hispanic Black (NHB: 10.9%), Hispanic White (HW: 16.7%), Asian/Pacific Islander (API: 15%), and other (3.4%). Overall, 8.4% developed any SPC and 2.8% developed a second CRC. Cumulative incidence of any SPC did not differ significantly by race/ethnicity for men and women. Among men, SIRs for any SPC were 1.4 (95% CI: 1.3-1.5) for NHW, 1.4 (1.2-1.6) for NHB, 1.8 (1.5-2.1) for HW, and 2.4 (2.0-2.8) for API. Among women, SIRs were 1.3 (1.2-1.4) for NHW, 1.6 (1.3-1.9) for NHB, 1.6 (1.4-1.9) for HW, and 1.8 (1.6-2.1) for API. Cumulative incidence of second CRC differed significantly by race/ethnicity for men and women. At 25 years after diagnosis, cumulative incidence of second CRC was 2.8% (95% CI: 2.3-3.5) for NHW women; 4.6% (3.9-5.4) for NHW men; 5.5% (4.0-7.4) for NHB women; 4.0% (2.8-5.5) for NHB men; 5.9% (4.2-8.0) for HW women; 7.0% (5.3-9.1) for HW men; 4.0% (2.9-5.5) for API women; and 6.6% (4.8-8.9) for API men. By age 70, estimates were 2.9% (2.3-3.6) for NHW women, 4.7% (4.0-5.5) for NHW men, 5.6% (3.9-7.8) for NHB women, 4.6% (3.1-6.4) for NHB men, 4.9% (3.6-6.5) HW women, 6.7% (5.1-8.6) for HW men, 4.5% (3.1-6.3) for API women, and 6.1% (4.5-8.1) for API men. Second CRC SIRs showed similar patterns, with highest risks in HW men (SIR: 8.0; 95% CI: 6.3-10.0) and HW women (SIR: 7.1; 95% CI: 5.2-9.5). Conclusion: Despite no statistical differences in risk of any SPC, second CRC risk differed significantly by racial and ethnicity. HW men and women showed higher cumulative incidence over time, partly reflecting younger age at diagnosis and longer time at risk. Additional genetic, lifestyle, and care-related factors may contribute and warrant study to guide prevention and early detection in EOCRC survivors.