Abstract
IMPORTANCE: Comorbidities in midlife are common but how these conditions are associated with cancer outcomes is poorly understood. OBJECTIVE: To investigate the association between different comorbidities and risk of incident cancer and cancer mortality. DESIGN, SETTING, AND PARTICIPANTS: This cohort study is a secondary analysis of the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial conducted at 10 PLCO screening centers across the US. Participants included adults aged 55 to 74 years without a history of cancer enrolled between 1993 and 2001. Statistical analysis was performed from June 2023 to December 2024. EXPOSURES: Self-reported history of 12 comorbid conditions classified into 5 distinct classifications guided by World Health Organization categorization. MAIN OUTCOME AND MEASURES: Outcomes included risk of all cancers combined, risk of 19 individual cancer types, and cancer mortality. Multivariable Cox proportional hazards models were used to estimate the association between comorbidity classifications and cancer outcomes. RESULTS: Among 128 999 participants included in the analysis, 330 (0.3%) were American Indian, 5414 (4.2%) were Asian or Pacific Islander, 6704 (5.2%) were non-Hispanic Black, and 114 073 (88.4%) were non-Hispanic White; 64 171 (49.7%) were male; and the median (IQR) age was 62 (58-66) years. After a median (IQR) follow-up of 20 (19-22) years, the risk of any incident cancer was significantly higher for individuals with a history of respiratory (hazard ratio [HR], 1.07 [95% CI, 1.02-1.12]) and cardiovascular conditions (HR, 1.02 [95% CI, 1.00-1.05]). History of each comorbid condition evaluated was significantly associated with incidence of at least 1 cancer type. The strongest association was between history of liver conditions and risk of liver cancer (HR, 5.57 [95% CI, 4.03-7.71]), whereas metabolic conditions (obesity or type 2 diabetes) were significantly associated with higher risk of 9 cancer types and lower risk of 4 cancer types. Respiratory (HR, 1.19 [95% CI, 1.11-1.28]), cardiovascular (HR, 1.08 [95% CI, 1.04-1.13]), and metabolic (HR, 1.09 [95% CI, 1.05-1.14]) conditions were positively associated with a higher hazard of cancer death. CONCLUSIONS AND RELEVANCE: In this cohort study of 128 999 adults without a history of cancer, comorbidities in midlife were associated with the overall risk of cancer and more strongly associated with risk of multiple individual cancer types, with the direction of association differing across cancer types. These results may inform clinical management of patients at risk for cancer.