In this pooled analysis of two large clinical trials of adenoma recurrence, we found that a high BMI is a risk factor for recurrent adenomas after polypectomy. Similar to what has been observed for the association between BMI and colon cancer24, 27, 34
, when we stratified by gender, we found that a high BMI was associated with adenoma recurrence in men, but not women. A separate analysis for waist circumference did not appreciably alter the direction or magnitude of the association between BMI category and odds of recurrence. Our results do not support similar studies of colon cancers that suggest that the measurement of waist size may be a better predictor of risk in women than BMI27, 41
, as we detected no significant results with either measure.
The magnitude of the association between body size and colorectal adenomas remains equivocal. Our results are in agreement with epidemiological studies showing a relationship between body mass index and risk for colorectal adenomas9–18
. Further support for this association was provided in a small study by Almendingen et al.42
, who reported a direct relationship between obesity and the growth rate of adenomas. In that study, a strongly positive association between obesity and growth of unresected adenomas in patients followed for three years was observed42
. However, other studies have failed to demonstrate an association between body size and colorectal adenoma recurrence43–48
, including secondary analyses conducted in randomized trials of chemopreventive agents for adenoma recurrence similar to our own47, 48
. One possible explanation for the failure of these studies to detect an effect of obesity on recurrence under similar study conditions could be the use of combined analyses of men and women and/or smaller sample sizes.
Our study supports a gender-specific effect of obesity on adenoma recurrence following polypectomy. The consistently weaker association between obesity and colon cancer risk in women has been explained in part by the protective action of female sex hormones, particularly estrogen elevated in overweight/obese women33
. Among premenopausal women, the direct relationship between increasing body size and odds of colorectal neoplasia has been observed consistently, while for older women, the effect is attenuated49
. Whether sex hormones act differentially in the colonic epithelium as growth regulators50
or if they differentially influence risk through action on body fat disposition and adverse biochemical changes51–54
is currently unclear. Efforts are ongoing to abstract information on the use of hormone replacement therapy in our two trials along with collecting data on serum biochemical markers (hormone, insulin, IGF levels) to explore these issues in subsequent analyses to address potential explanations for our findings.
For advanced adenoma recurrence in the current study, BMI was strongly associated with risk in men, but not women. In several studies of colorectal adenomas reported to date, high BMI has been shown to be associated with the development of advanced, larger adenomas of the colon 9, 11, 15, 16
. Unlike the results for any adenoma recurrence, an association between body size and large or advanced adenoma recurrence has been demonstrated in both women and men in the literature, generally in mixed populations9, 15, 16
. The current results do not show such an association, possibly because heavier women in our population showed a modest, non-significant trend for protection from advanced recurrence with increasing body size. As mentioned above, there may be effect-modification of body size by estrogen in these women.
Our results also demonstrated that BMI was positively associated with adenoma recurrence in subjects with a family history of colorectal cancer in at least one first degree relative, but not for those without a family history. This is consistent with previous studies suggesting a stronger effect of lifestyle factors and risk for colon cancer in patients with a family history36, 37
. BMI again appeared to be a better estimator of the association between body size and adenoma recurrence than waist circumference, which may help in deciding which estimate of body size is optimal for large epidemiological studies of colorectal neoplasia.
A further advantage to the use of BMI to measure body size is that it accounts for the height of the individual. Though it did not achieve statistical significance, exploratory analyses revealed a modest positive association between tall height and risk (data not shown), which may explain part of the independent effects of BMI on odds of recurrence. This is consistent with previous positive associations between tall height and colon cancer risk12, 45, 55
Our data support recent findings from MacInnis et al.55
that suggest, at least for males, there may be two independently acting effects of body composition on colon cancer risk; one acting through central adiposity and the other acting through higher fat free mass, perhaps mediated by the insulin-like growth factor/growth hormone axis, which in the MacInnis study included height as a component trait of the variable55
. Given that BMI captures aspects of both height and girth for the majority of men, it can be easily integrated into clinical care in discussing the odds for subsequent adenomas, particularly advanced adenomas, in male patients. Overall, our data further strengthen the hypothesis that adverse biochemical changes such as hyperinsulinemia associated with adiposity may be mechanistically coupled with risk for development and growth of premalignant lesions in the colon56
. These data strongly support the consideration of BMI as a simple measure for assessing elevated odds for adenoma recurrence, particularly for men or for those with a family history of colorectal cancer
Strengths of our study include the large sample size and the prospective nature of the data collected for adenoma recurrence using colonoscopy. Additional strengths include the use of measured height and weight in all subjects for BMI calculation and the completeness of the variable data set. A limitation of our study lies in the design that includes only individuals with a recent history of at least one adenoma and for whom the average follow up time was three years. These adenoma patients are a distinct group, and therefore the generalizability of the results is somewhat limited. Our findings apply only to the association of body size with recurrent adenomas, not the formation of a first-time adenoma. The short interval between endoscopy procedures limits our ability to demonstrate associations between obesity and adenoma over longer periods of time in study participants that may not have increased susceptibility to the effects of obesity, such as those without a family history of colorectal cancer. Finally, because of the design of the original clinical trials, it is likely that polyps missed at baseline colonoscopy may be included as recurrences in some cases. The rate for missed polyps at colonoscopy have been estimated to be approximately 13% for adenomas 5–10mm in size and 26% for those 1–5 mm57
. However, our results support a stronger association between body size and advanced adenomas than smaller, non advanced lesions. This increases the validity of the observed association given that the proportion of missed large/advanced adenomas is far lower (2.1%) than for smaller lesions57
. In the unlikely event that a significant difference in miss rates by BMI explains more lesions at follow up in our studies in the obese, our finding of an association between obesity and risk for advanced adenoma at polypectomy remain relevant as the association yields a higher risk population regardless of the underlying cause.
In summary, our results support previous studies that suggest that obesity is associated with the growth of adenomas in the colon among men, and is particularly related to the development of advanced lesions. Though these data may not directly impact current screening paradigms in a broad sense, they do lend support to the growing body of evidence that body weight, by whatever causal mechanism, is an important determinant in risk of colonic neoplasia and therefore a valid and important clinical factor to consider in patient and high risk family counseling. Simple measures of obesity offer an additional factor in patient education when emphasizing vigilance to follow up particularly among high-risk family members for which the gastroenterologist can advocate. This aspect of our findings may be most relevant in persons with lower- risk lesions where screening recommendations are extending to longer and longer intervals in attempts to reduce health care costs. Finally, it may be particularly important to take steps to achieve high compliance with colorectal cancer screening and surveillance recommendations in subjects with high BMI.