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Association of Cardiometabolic Disease With Cancer in the Community

Background Obesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear. Objectives The aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer. Methods FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models. Results Among 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer (P < 0.05 for all). Conclusions Obesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI.

C ardiometabolic risk factors, in particular obesity, are known risk factors for many highly burdensome diseases, including diabetes, cardiovascular disease (CVD), cancer, and death. 1,2 Obesity is increasing globally, with more than 40% of adults and 20% of children in the United States currently categorized as obese (body mass index [BMI] $30 kg/m 2 ) and 6.9% of incident cancers attributed to excess body weight. [3][4][5] Increased adiposity creates a chronic proinflammatory state, which may be a shared mechanism underlying the development of many comorbidities, including cancer. 6-8 Additionally, obesity may alter the tumor microenvironment and promote tumor progression via complex immunologic mechanisms. 9 Other putative mechanisms for obesity and cancer risk include adipose production of excess estrogen, hyperinsulinemia or insulin resistance, increased production of adipokines, and direct or indirect effects on cell growth regulators. 6,10 Epidemiologic studies have long shown an association between obesity and incident cancer, and there is consensus among the National Cancer Institute and World Health Organization that 13 cancer types are associated with excess body weight, including breast, female reproductive, and colon cancers. [11][12][13][14] Retrospective electronic health record-based and registry-based studies, however, may introduce selection and ascertainment bias. Furthermore, there is broad agreement that although BMI is a widely available measurement used to categorize obesity, it may not accurately reflect adiposity across age, sex, race, and muscle composition. 15 For example, abdominal adiposity measured by waist circumference (WC) has been more closely associated with CVD risk factors 16 and may impart additional valuable information compared with BMI alone in understanding the association between obesity and cancer. 17 In this context, we sought to leverage 2 large prospective longitudinal community-based inception cohorts to examine the association of obesity with future development of histologically confirmed cancer.
Moreover, we sought to examine detailed phenotyping of obesity-related traits, including anthropometrics, advanced imaging to quantify adipose tissue depots including visceral adiposity as a known source of inflammatory mediators, and circulating biomarker evidence of putative mechanisms linking obesity to cancer risk.
In multivariable Cox models, BMI as a continuous variable and obesity status were both associated with gastrointestinal, gynecologic, and lung cancers but not overall cancer (Tables 2 and 3, Figure 1). Specifically, a 1-SD higher BMI was associated with 14% increased risk for gastrointestinal and colorectal cancers We found no significant associations with other sitespecific cancers.
We found similar associations of pericardial adipose tissue with overall cancer (HR: 1.14; 95% CI:  For PAI-1 and HOMA-IR, models with and without BMI showed inconsistent associations with specific cancer outcomes (Supplemental Table 4).  Table 5). In exploratory analyses with further adjustment for heavy alcohol use in the multivariable model, results were similar to those of the main analyses (Supplemental Table 6).
In sex-stratified analyses, there was no significant sex Â BMI interaction for overall or site-specific cancer. There was, however, a significant sex Â WC interaction (P interaction ¼ 0.03) for overall cancer (HR:    36,37 We explored this inverse association by stratifying lung cancer analyses by smoking status, as smoking is a known risk factor for lung cancer and is associated with lower average BMI. 38 Our findings support a previous prospective cohort study of about 450,000 individuals, 39 demonstrating reduced risk among current smoking but no association among former and never smoking. Although this might suggest that the "obesity paradox" may be explained by smoking, analyses of never smoking were likely underpowered, with other studies supporting an association across all smoking statuses including never smoking. 28 We performed lag-time analyses starting 1 year after baseline examination to account for potentially undiagnosed cancers and found similar results. In contrast to the inverse association of BMI with lung cancer, both visceral and pericardial adipose tissue depots were associated with greater risk for lung cancer, as was inflammation assessed by CRP. This extends prior findings that abdominal adiposity appears to be associated with higher risk for lung cancer. 36 Our findings highlight the importance of examining obesity-related phenotypes to better appreciate adiposity-associated cancer risk. To provide insight into potential mechanisms linking obesity to increased predisposition to specific cancers, we further investigated the association of regional adipose depots with future cancer after accounting for BMI. We show that both visceral and pericardial adipose depots were associated with greater risk for overall cancer, lung cancer, and melanoma. In contrast, subcutaneous adipose depots were not associated with greater risk for future cancer. These findings are notable, as prior studies of VAT and cancer present conflicting findings. [40][41][42][43] The present study expands upon previous findings by assessing site-specific cancers in addition to overall cancer. In contrast to the "obesity paradox," we show importantly and conversely that higher VAT was associated with increased risk for lung cancer, suggesting that BMI and obesity may not fully capture adiposity-associated risk. We also report that VAT was associated with melanoma, which builds upon previous studies showing an association of obesity with risk for melanoma and its progression. 29,44 Previous retrospective studies have reported inverse associations of SAT with cancer mortality and progression of some cancer subtypes. 45,46 Although we did not observe an association between SAT and The multivariable Cox model was adjusted for age, sex, diabetes, systolic blood pressure, hypertension treatment, smoking status (current, former, or never), and ratio of total cholesterol to high-density lipoprotein. Gynecologic and breast cancer analyses were performed only in women, and prostate cancer analyses were performed only in men. Effect sizes for body mass index (BMI) and waist circumference (WC) were expressed per 1-SD change. *P < 0.05. overall cancer, we found that higher SAT was associated with protection against gynecologic cancer. To our knowledge, SAT has not previously been associated with cancer risk in a prospective inception cohort, though some studies have shown that increased SAT may portend better outcomes in patients with cancer. 45,47 The biological mechanisms underlying greater cancer risk in obesity remain incompletely understood, but research has been focused on inflammation and immune cell dysfunction. 7,48,49 It is known that VAT specifically appears to contribute to proinflammatory states, 50

CONCLUSIONS
We report that obesity and abdominal adiposity (WC) were associated with increased future risk for cancer, including gastrointestinal, colorectal, and gynecologic cancers. Of note, although we found that obesity status and higher BMI were associated with lower risk for lung cancer, we further shed light onto these associations by specifically demonstrating that greater visceral and pericardial adipose tissue depots and circulating CRP were associated with greater risk overall cancer and site-specific cancers, including lung and melanoma. These findings highlight the importance of examining obesity-related phenotypes, including adipose tissue depots, to better understand the association between obesity and cancers.
Although the association of obesity-related traits with CVD has been firmly established, 57,58 our data now further support the notion that obesity is a shared risk factor between CVD and cancer. 59