With advances in the early detection and treatment of cancer, the incidence of multiple primary cancers (MPC) or second primary cancers has increased over time. Characterization of etiologic risk factors, including family history of cancer, within the general population is critical for assessing MPC risk in patients. We examined the association between family history of cancer among first-degree relatives and MPC risk in a prospective study of 139,958 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox proportional hazard models were used to calculate HRs and 95% confidence intervals (95% CI), adjusting for potential confounders. Over a median follow-up of 16 years (IQR: 11–19 years), 6,170 participants were diagnosed with MPC. Having a family history of cancer increased the risk of MPC by 18% (HR, 1.18; 95% CI, 1.12–1.24). A positive linear trend was observed between the reported number of cancers in the family history and MPC risk with HRs (95% CI) of 1.13 (1.07–1.20), 1.23 (1.14–1.33), 1.29 (1.15–1.45), and 1.42 (1.20–1.70) for one, two, three, and four or more cancers among first-degree relatives, respectively (Ptrend = 2.36 × 10−13). No significant differences were observed by cancer histology or specific cancer types reported in the family history. Our study demonstrates that the family history of cancer is an important risk factor for the development of MPCs and that a comprehensive assessment of the number of cancers reported among first-degree relatives may identify those at higher risk who may benefit from targeted cancer prevention and screening strategies.

Prevention Relevance: Our study makes a substantial contribution to the understanding of risk factors for MPCs in the general population. It demonstrates that individuals with a strong family history of cancer are at higher risk for MPCs and may benefit from more targeted cancer prevention and screening interventions.

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