Sugar intake and cancer risk: when epidemiologic uncertainty meets biological plausibility.

Reprogramming metabolism is an emerging hallmark of cancer cells, with glycolysis as the main pathway of energy production, even when sufficient oxygen is present, a phenomenon referred to as the Warburg effect. Owing to this metabolic adaptation, cancer cells consume large quantities of glucose to survive through hypoxic conditions, commonly found in tumors, and support their anabolic requirements for uncontrolled growth and division. Therefore, dietary restriction of carbohydrates and pharmacologic agents that decrease insulin production or inhibit insulin signals have been exploited as potential therapeutic methods for cancer prevention or treatment. On the other hand, how carbohydrate intake may influence the incidence of cancer in the general population remains unclear. Meta-analyses of prospective studies have largely reported a null association between carbohydrate intake and cancer incidence. Similar null associations with cancer risk have also been reported for glycemic index and glycemic load, indicators of carbohydrate quality based on the ability of foods to raise postprandial blood glucose concentrations. Although these results suggest no major influence of total carbohydrate on cancer development, the possibility that specific groups of carbohydrates or carbohydrate-contributing foods may affect cancer risk cannot be ruled out. Among them, sugar has received growing attention due to its known effect on weight gain and the established link of sugar-sweetened beverages with cardiometabolic health. Given the important role of obesity and metabolic disturbances in cancer, it is reasonable to hypothesize that higher sugar intake may increase cancer risk. However, again, epidemiologic evidence thus far has indicated a null association of total sugar, sucrose, and fructose intake with cancer risk, although some reported studies showed positive associations with cancer risk for added sugar and sugary beverages (1). In the current issue of the Journal, Debras and colleagues (2) report the findings of a prospective analysis of total and added sugars, specific sugar types (glucose, fructose, galactose, maltose, lactose, and sucrose), and food sources of sugar in relation to cancer risk in the NutriNet-Santé cohort (2009–2019). Participants reported their dietary intake through web-based 24h dietary records administered at baseline and every 6 mo. Total, but not added, sugar intake, was associated with a modest increase in overall cancer risk (HR for comparison of quartiles Q4 to Q1: 1.17; 95% CI: 1.00, 1.37). Among specific cancer types, only breast cancer showed a positive association with total and added sugar intake. The associations were more pronounced for sucrose, non–fruit-derived sugars, and added and natural sugars present in sugary drinks. Major strengths of the study include the large sample size and rigorous control for potential dietary and lifestyle confounders, the inclusion of a series of sensitivity analyses that indicate the robustness of the findings, and most uniquely, the comprehensive analysis according to sugar types and food sources that have variable nutritional values. However, some limitations of the study need to be considered as well. First, although the webbased 24-h dietary records have been validated against blood and urinary markers and 24-h dietary recall conducted by dietitian interviews, the validity of the instrument for assessing the participants’ usual diets and accounting for the day-today variation remains uncertain. Although repeated dietary assessments were conducted every 6 mo, it is unclear whether the time-varying dietary exposures were modeled throughout the follow-up. Moreover, while the web-based dietary recording has interactive features and facilitates real-time assessment of eating practices and portion sizes, compliance and accuracy have to be considered with great care. In a prior validation study, nearly 20% of participants completed the dietary record within 10 min and another 30% in 11–20 min (3). Compared with a median of 20–30 min needed to complete other web-based dietary assessments, the short completion time raises questions about the completeness and quality of reporting. Nevertheless, given the prospective study design, any measurement error is likely to have biased the associations toward the null. Another limitation is the relatively short duration of follow-up (median 5.9 y) for examination of cancer that can take decades to develop. Because of this shortcomong, the numbers of cases for nonbreast cancers are fairly small, precluding examination of less common cancers