Association between metabolic syndrome and risk of second primary malignancy among patients with a history of cancer

Background: Prior studies have reported associations between modifiable comorbid conditions such as obesity, insulin resistance, hypertension, and hyperlipidemia (collectively known as Metabolic Syndrome [MetS]) and the risk of first primary cancer (FPC). However, the role of MetS on the risk of a second primary malignancy (SPM), a histologically and clonally distinct tumor that develops in a cancer survivor, is a heavily understudied area. Given that ~1 in 5 cancer survivors get diagnosed with a SPM in their lifetime, the purpose of this investigation was to understand the complex interplay between MetS, its individual components, other patient-related risk factors and risk of SPM. Methods: The study cohort included 11,617 cancer patients who survived at least 12 months after their FPC diagnosis without a disease event (death, SPM or recurrence) and seen at the Roswell Park Comprehensive Cancer Center's dedicated survivorship clinic. Data on specific biomarkers to capture individual components of MetS was abstracted from electronic medical records. Patients were identified as having MetS if they had at least three of four MetS conditions (obesity, insulin resistance, hypertension, and hyperlipidemia). The association between MetS and risk of SPM was evaluated using Fine-Gray sub distribution hazard models adjusting for age, sex, smoking status, and TNM stage at FPC diagnosis. Results: A total of 10,462 patients (90%) had data on ≥3 MetS conditions. Of those, 8,910 had fewer than three MetS conditions, while 1,552 had three or more. Overall, 4,963 patients developed SPMs ≥12 months after FPC diagnosis. In our multivariable analyses, we found that presence of MetS was independently associated with a significantly increased risk of SPM (Hazard Ratio [HR]=1.20; 95% Confidence Interval=1.01-1.40; P=0.043). Additionally, the risk of SPM increased significantly with number of MetS conditions (P<0.001). A majority of patients were obese (Body Mass Index ≥30 kg/m) (70%), and obesity was one of the primary conditions driving the increased SPM risk associated with MetS (HR=1.54; P=0.013). Among the other patient-related risk factors adjusted for, older age was associated with increased SPM risk (HR=1.02, P<0.001), whereas being a non-/former-smoker was associated with a decreased SPM risk compared to current smokers (HR=0.72, P<0.001, HR=0.83, P=0.019, respectively) as was having a higher stage of FPC (TNM III-IV vs. I-II) (HR=0.33, P<0.001). Conclusion: MetS is significantly associated with the risk of developing SPMs among cancer survivors, with the risk of SPM increasing with number of MetS conditions, of which obesity was the strongest predictor. SPMs have emerged as an important concern for cancer survivors as treatment options for FPC have improved. Further research into the interrelationship between MetS conditions in cancer survivors and risk of SPM is therefore warranted.