Cumulative incidence of second primary cancers in a large nationwide cohort of Danish cancer survivors: a population-based retrospective cohort study

Background A new primary cancer is a serious late effect of a pre-existing cancer diagnosis, and can be attributed to hereditary cancer syndromes, immune or hormonal factors, cancer treatment, or modifiable lifestyle or environmental factors. We investigated the absolute and relative incidence of second primary cancers in a large cohort of Danish cancer survivors. Furthermore, we examined the association between alcohol-related, smoking-related, virus-related, and hormone-related first and second primary cancers. Methods In this retrospective cohort study, we identified a cohort of Danish adults (aged >= 40 years) diagnosed with cancer from Jan 1, 1997, to Dec 31, 2014 and alive 1 year after diagnosis. Follow-up was from date of first cancer diagnosis and lasted up to 24 years, ending on Dec 31, 2020. Cohort identification and information on second primary cancers was obtained from the Danish Cancer Registry, and comorbidity and sociodemographic information was obtained from Danish population-based registries. Overall, and for 27 cancer types, cumulative incidence functions and Cox proportional hazard regression models were used to estimate the incidence of second primary cancer and death, and hazard ratios (HRs) and 95% CIs of second primary cancer adjusted for sex, age and year of diagnosis, cohabitation status, income, and comorbidity. Findings 457 334 Danish adults were included in our study (230 150 [50 center dot 3%] male individuals and 227 184 [49 center dot 7%] female individuals; median age at diagnosis 68 center dot 3 years, IQR 59 center dot 7-76 center dot 6; median follow-up 3 center dot 6 years, IQR 0 center dot 6-9 center dot 3). The cumulative incidence of second primary cancer increased over time from 6 center dot 3% (95% CI 6 center dot 2-6 center dot 4) 5 years after diagnosis to 10 center dot 5% (10 center dot 4-10 center dot 6) 10 years after diagnosis and to 13 center dot 5% (13 center dot 4-13 center dot 7) 15 years after diagnosis. The highest cumulative incidence of second primary cancer 10 years after diagnosis was observed in survivors of cancers in the larynx (21 center dot 8%, 20 center dot 5-23 center dot 1), oropharynx and oral cavity (19 center dot 5%, 18 center dot 7-20 center dot 3), and bladder and urinary tract (18 center dot 5%, 18 center dot 0-19 center dot 0). Survivors of cancers related to alcohol (HR 1 center dot 09, 95% CI 1 center dot 06-1 center dot 13), smoking (1 center dot 73, 1 center dot 68-1 center dot 78), diet high in red or processed meat (1 center dot 32, 1 center dot 24-1 center dot 39), or virus (1 center dot 23, 1 center dot 13-1 center dot 35) were at increased risk of developing a second cancer with the same aetiology, whereas having had a hormone-related first cancer was associated with lower risk of a second hormone-related cancer (0 center dot 77, 0 center dot 73-0 center dot 81). Interpretation Our results could help optimise prevention efforts targeting modifiable risk factors to reduce risk of developing a second primary cancer.