Colorectal cancer (CRC) is a significant public health concern and is the third most commonly diagnosed cancer among men and women in the United States. While advancements in screening and detection have resulted in earlier diagnoses, the number of annual incident CRC cases remains high, possibly due to increased risk factors such as obesity. Obesity has been linked to various adverse outcomes, including cancer, and it is estimated that about 20% of cancers may be attributed to excess weight gain.
Gastrointestinal cancers, in particular, have been strongly associated with obesity due to the chronic inflammation caused by obesity. However, the impact of heightened baseline inflammation attributed to obesity on cancer risk, such as obesity or weight gain in early life on later cancer risk or how changing BMI over time alters cancer risk, is still not well understood.
This study aims to evaluate the association between GI cancer, CRC, and Non colorectal GI cancer risk and BMI at different stages of adulthood and the association between changing BMI and cancer risk.
The findings of a recent cohort study published in the JAMA Network suggest that being overweight or obese at different ages and changes in BMI over time could increase the risk of gastrointestinal (GI) cancers. However, the study also found that regular use of aspirin (3 or more times per week) did not modify this association.
Decades of epidemiological evidence supports aspirin use for cancer prevention, with previous analyses demonstrating its efficacy in reducing the risk of colorectal (CRC) and bladder cancer mortality. However, the impact of BMI on this association has yet to be adequately studied.
Obesity results from accumulating and storing white adipose tissue, or fat. Adipose cells can induce an inflammatory response and promote immune cell dysfunction through the secretion of adipokines and proinflammatory cytokines. This can lead to further downstream mechanistic dysregulation, which puts individuals with obesity at higher risk of several conditions, including cancer.
Interestingly, not all cancers are significantly associated with obesity; instead, it is more limited to those where cancer cells grow near adipose cells. This may be due to the impact of adipose cells on tumorigenesis. Research has shown significant crosstalk between cancer cells and adipocytes. For example, in vitro studies have demonstrated that colorectal cancer cell lines co-cultured with adipocytes had increased cancer cell proliferation, migration, and nutrient transfer (such as ketones and fatty acids) from adipocytes to cancer cells.
Transcriptomic analysis of the ColoCare Study, a prospective cohort of newly diagnosed CRCs, found enrichment of pathways associated with adipose-tumor tissue crosstalk, such as fibrosis and glycolytic metabolism. Similar findings have been observed for non-colorectal GI cancers. Although excess adipocytes are not the initiator of tumorigenesis, but they promote it by supplying cancer cells with much-needed nutrients and stimulating oncogenic pathways. Therefore, cancer prevention mechanisms that target the harmful physiologic effects of obesity may work to counteract tumorigenesis.
The current study found that obesity may alter the cancer-preventive effect of aspirin. Individuals with overweight and obese BMIs had an increased risk of CRC and non colorectal GI cancer with aspirin use three or more times per week, suggesting that aspirin may not be efficacious for prevention in overweight or obese states. This may be due to inadequate dosing, as the ability of aspirin to protect against GI cancers may be blunted in people with obesity. However, increased aspirin use has risks, such as gastrointestinal bleeding.
The study did not account for participant dosing, a noted limitation. Additional studies are needed to evaluate the impact of aspirin dose on cancer prevention, accounting for participant BMI or weight gain, to delineate aspirin’s role better. The Cancer Prevention Project 3 (CaPP3) is underway to discern the effect of differential aspirin dosing (100, 300, or 600 mg) in a cohort of individuals with Lynch syndrome. The eventual results of this study may be translatable to the general, average-risk population.
While the current study provides significant findings, it is essential to note its limitations. One of the limitations is that the study was a secondary analysis of a completed cancer screening trial, which means that the collection of exposure and outcome information was not originally intended. Furthermore, the participants collected all self-reported data, including BMI and aspirin use, which could result in inaccurate data.
Additionally, the study could not capture changes in BMI over time, and aspirin dosing information was not collected, which limited the ability to correlate changes in BMI with aspirin use. Despite using multivariable logistic regression models, it is possible that some confounders needed to be taken into account. It is important to note that the study only evaluated the association between these factors, not causation.
