Early-Onset Colorectal Cancer — Are Sugary Drinks to Blame?

Kate Johnson

May 07, 2021

High consumption of sugar-sweetened beverages (SSB) in adolescence and young adulthood could partially explain the recent rapid rise in early-onset colorectal cancer (EO-CRC) — at least in women, according to the authors of a new analysis.

The study found that women who recalled drinking two or more SSB per day in young adulthoodhad a twofold increase in the risk of colorectal cancer before the age of 50, compared to those who had only one such drink per week or less.

However, experts warn the findings are based on small numbers and do not prove a causal effect.

"Despite these limitations, this signal keeps appearing over and over again," notes Marcus DaSilva Goncalves, MD, PhD, at the Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York City, who was approached for comment.

"There is strong evidence in mice and supportive epidemiologic studies that back the link between fructose-containing sugars and obesity, diabetes, and certain cancers like CRC," he said.

The issue is certainly of great interest. CRC has been considered a disease of the elderly, but there has been a dramatic increase in recent years in the incidence of CRC in younger adults the United States as well as other high-income countries.

Details of the Findings

The study, published in Gut, analyzed data from the Nurses' Health Study II (NHSII).

This analysis prospectively investigated the association of SSB intake among 95,464 female registered nurses who were aged between 25 and 42 years at enrollment and followed them for the development of EO-CRC, defined as onset before the age of 50 years.

A subset of 41,272 participants was also asked about SSB intake when they were 13 to 15 years old.

The nurses filled out food frequency questionnaires every 4 years, which asked about SSBs, defined as soft drinks, fruit drinks, sports drinks, and sweetened tea beverages.

Information on potential CRC risk factors was also collected, including family history of bowel cancer, lifestyle, regular use of aspirin or non-steroidal anti-inflammatory drugs and vitamin supplements, and colonoscopy/sigmoidoscopy.

Participants were also asked about their teenage health, including weight and lifestyle.

Over a maximum follow-up of 24 years (average, about 14 years), the study documented 109 cases of incident EO-CRC, and suggested a 2.2-fold higher risk (RR, 2.18; P trend = 0.02) among women who reported drinking two or more SSB per day, compared to those who reported drinking less than one 12-ounce SSB per week.

Each additional serving of SSB was associated with further risk: 16% in young adults and 32% in adolescents.

The researchers also investigated the impact of substituting SSBs with artificially sweetened beverages (ASBs), as well as coffee, reduced fat milk, or total milk and found a 17% - 36% lower risk of EO-CRC.

The findings "reinforce the public health importance of limiting SSB intake for better health outcomes," noted senior author Yin Cao, MD, from Washington University School of Medicine in St. Louis, Missouri.

"While our sample size was limited and this finding requires further validation, it is important to note that 30% of US children and adolescents consume > 1.5 servings of SSBs daily," he commented in a statement. "Reducing SSB intake and/or replacing SSBs with other healthier beverages among adolescents and young adults may serve as a potential actionable strategy to alleviate the growing burden of EO-CRC."

However, experts reacting to this study on the UK Science Media Centre were less convinced by the research. "Overall, these findings should be considered as preliminary and exploratory until larger studies are done in other populations," said Carmen Piernas, MSC, PhD, university research lecturer and nutrition scientist at Nuffield Department of Primary Care Health Sciences, University of Oxford, England.

Piernas said an important limitation of the analysis is lack of power. "This conclusion is based on just 16 cases of colorectal cancer in 138,469 person-years among the group drinking two or more sugary drinks. The absolute risk is very low. A related analysis reporting the increase in risk with each additional sugary drink serving per day is only borderline significant," she noted.

Nevertheless, she noted that "there is already strong evidence that consuming sugary drinks increases risk of weight gain and diabetes. Everyone should aim to minimize their consumption — this analysis does not change that advice."

"We just can't be sure whether the observed association between sugary drinks and bowel cancer under the age of 50 is one of cause and effect," added Kevin McConway, PhD, emeritus professor of applied statistics at The Open University in Milton Keynes, England. "There were plenty of differences between women who drank few sugary drinks and women who drank a lot.... Maybe the researchers did not adjust for some important factor."

And while the authors "made good attempts" to adjust for confounders "many of the confounders are lifestyle factors, such as red meat consumption, which are difficult to measure accurately," said Adam Jacobs, PhD, director of biostatistics at Premier Research. "Any inaccuracies in measurement of confounding variables could easily bias the results, especially when the associations are so marginal in the first place."

Strong Evidence in Mice

Despite the limitations of this particular study, Goncalves pointed out that other epidemiological studies have also seen this signal and that there is strong evidence in mice.

"We found that ingestion of moderate amounts of dietary fructose promotes the growth of intestinal cancer even in the absence of obesity in mouse tumor models," he told Medscape Medical News. He explained that this process required ketohexokinase, an enzyme that converts fructose to fructose-1-phosphate, which alters tumor cell metabolism and leads to enhanced cell growth. (Science. 2019;363:1345–9.)

"Further, we have new data under review at Nature that will further support these conclusions," DaSilva Goncalves said.

This new analysis of NHSII data "contributes important information to the medical literature," he commented.

"There are several, large, prospective cohort studies that have linked fructose consumption to CRC risk and CRC-specific mortality," he commented. "While it is true that the linkage between fructose and CRC has not been uniformly observed in nutritional epidemiology studies and the significance is typically small, there are intrinsic challenges that limit the rigor of these approaches. For instance, host metabolism and tumor molecular heterogeneity are thought to influence fructose presentation to the colon and uptake by the tumor, but these factors have not been assessed in epidemiologic studies, potentially confounding the interpretation of the results. Similarly, the questionnaires used to track sugar consumption lack the precision and breadth required to estimate intake over the years and decades during which patients develop or die from cancer."

The study was funded by the National Institutes of Health. Cao has disclosed no relevant financial relationships. Disclosures for the remaining study authors can be found in the paper. DaSilva Goncalves is a co-founder of Faeth Therapeutics, whose mission is to pair anti-cancer therapies with nutritional strategies; however, the company is not directly targeting fructose metabolism. Piernas has disclosed no relevant financial relationships. McConway reported no conflicts, but is an adviser to the SMC. Jacobs reported no conflicts, but noted that he wrote a blog post about sugar tax a few years ago.

Gut. Published online May 6, 2021. Full text

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