1. Froelich, Warren

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Consuming higher levels of folate found in foods and supplements lowered the risk of colorectal cancer in women with no previous history of cancer, according to a study covering 36 years of data from the Nurses' Health Study.

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The findings from a team at the Harvard T. H. Chan School of Public Health in Boston also determined that increased total folate consumption from supplements, natural foods, as well as certain fortified foods, mandated by the FDA, did not increase colorectal cancer risk in otherwise healthy participants, a concern raised by some in the past.


"Our core message for the public: for individuals free of cancer, avoid folate insufficiency to help reduce colorectal cancer," said Fenglei Wang, a doctoral candidate at Harvard who presented the results during the AACR 2020 Virtual Annual Meeting.


"Our findings support lack of harm from increased folate intake due to folic acid fortification policy," he added. "This finding is important because some countries have not fortified food with folate because of this concern."


"This new analysis with decades of follow-up provides substantial evidence that folate fortification has not led to an increase in colorectal cancer, and more likely is contributing to a decrease in risk over the long term," added Walter Willett, MD, DrPH, Professor of Epidemiology and Nutrition at Harvard T.H. Chan School of Public Health, Professor of Medicine at Harvard Medical School, and the study's senior investigator. "Concerns about colorectal cancer rates should not be reason to avoid food fortification, which is proven to reduce rates of serious birth defects."


According to a 2019 study, about 26.1 percent of the U.S. population are now taking folic acid as dietary supplements in addition to consumption through fortified foods and naturally occurring folate sources such as spinach, kale, and other leafy green vegetables.


Folate, or vitamin B9, is considered an essential nutrient that plays a critical role in cell growth, including the synthesis, repair and methylation of DNA. Folic acid is a synthetic form of folate used in supplements and added to fortified foods.


In the early 1990s, folic acid also was confirmed to protect against neural tube defects and has since been recommended to women of childbearing age to prevent birth defects. In 1998, the FDA required manufacturers to fortify flour and cereal grains with 140 micrograms of folic acid per 100 grams of flour.


Shortly after this mandate, however, some studies suggested that the national folate intake might be excessive, contributing to a small rise in colorectal cancer in the U.S. at that time. Of particular concern were signs of increased colorectal cancer among the elderly and those with a prior history of pre-cancerous polyps and benign adenomas.


A debate, stretching across the Atlantic to Europe, ensued over the long-term safety of folate. Of note, multiple analyses soon appeared, suggesting that the temporal increase in colorectal cancer following mandated folic acid fortification could be attributed to several factors, most notably the increase in colonoscopies. In subsequent decades, colorectal cancer in the U.S. saw a dramatic drop in cases and mortality.


To further clarify the impact of folate consumption on colorectal cancer incidence, the Harvard team turned to the Nurses' Health Study, the largest prospective investigation into risk factors for major chronic diseases in women.


Researchers delved into the link between folate intake and colorectal cancer among 83,168 women, aged 34-59 (mean age 46) at baseline, over a time span from 1980 to 2016-including 18 years in the post-fortification period. At that time, the racial composition of nurses was 97 percent white.


Participants were asked to complete food-frequency questionnaires about their dietary information every 2-4 years. Total folate intake was calculated from both unfortified and fortified foods and supplements, including multivitamins containing folic acid; synthetic folic acid was calculated from fortified foods and supplements. Women previously diagnosed with cancer (except for non-melanoma skin cancer) or ulcerative colitis were excluded from the study. Subgroup analyses were conducted by age, alcohol intake, family history of colorectal cancer, and endoscopy screening.


The findings were dramatic. From 1980 to 2016, each 200 microgram per day increase in total folate consumption 12-24 years before diagnosis was linked to an 8 percent to 16 percent lower risk of colorectal cancer. Each 200 microgram per day increase in synthetic folic acid 16-24 years before diagnosis was associated with a 12-17 percent lower risk of colorectal cancer.


These results also confirmed prior epidemiological evidence that showed a substantial time lag of at least 12-16 years between folate intake and colorectal cancer risk.


"One surprising finding was that the pre-fortification intakes of total folate and synthetic folic acid were also inversely associated with colorectal cancer risk in the post-fortification period," Wang said. "This finding of pre-fortification folate was consistent with the long time lag we found over the whole study period."


The team's subgroup analysis by age also found no increased risk of colorectal cancer among elderly women aged 60 and over, a prior concern. No other subgroup in the study experienced an increased risk.


As for the brief increase in colorectal cancer incidence in years immediately following mandated fortification with folic acid, Wang said: "This increase was at a time of large increase in colonoscopy screening, which would tend to increase incidence of cancer, and colorectal cancer death rates were not increased (consistent with an artifact due to screening)."


So, does this study end the debate over folate use and colorectal cancer risk?


"Personally, I think the debate about folate and colon cancer will still remain and there are many other questions that require further analysis," Wang said. "For example, what are the effects of folate among individuals with existing adenomas? Among colorectal cancer patients? What are the effects of folate on other cancers?"


Wang said that his next study will focus on folate intake among individuals with a history of colorectal adenomas. Another researcher at the Harvard T. H. Chan School of Public Health is planning to analyze the impact of folate consumption on prostate cancer.


"Our finding emphasizes the importance of very long-term follow-up to fully understand the effects of folate intake on cancer risk, which appear to be beneficial," he said.


Warren Froelich is a contributing writer.