Alcohol and Cancer: It’s Not That Simple Many people think that alcohol is the best food partner; no one wants to hear that “drinking alcohol causes cancer”. But, you know what, drinking alcohol increases the risk of cancer, and the correlation has been clear for a long time: in 1988, the International Agency for Research on Cancer (IARC) declared alcohol a carcinogen; recent data show that alcohol cancer has increased worldwide. It is believed that this increase is largely due to an increase in the number of drinkers and an increase in alcohol intake, especially among women. Dr. Rehm, Director of the Social and Epidemiological Research Section at the Centre for Addictive and Mental Health Research in Toronto, describes our findings on the carcinogenic effects of alcohol this way, “…… Alcohol causing certain cancers has been proven and this no longer needs to be discussed… In recent years, several large cohort studies have been published on the association between alcohol and cancer, and the results suggest a stronger link. In August 2015, data from two large ongoing prospective studies, the Nurses’ Health Study and the Health Professionals Follow-up Study, were published, showing that alcohol intake was significantly associated with an increased risk of cancer in both women and men, with a linear dose-effect relationship. Cao and colleagues analyzed the risk of so-called “alcohol-related cancers” (colorectal, female breast, oral cavity, throat, liver, and esophagus) and showed that the leading cause of alcohol cancer in women was breast cancer, while the leading cause of cancer in men was liver cancer. The results show that the leading cause of alcohol-related cancer in women is breast cancer, and in men, colorectal cancer. A cohort study conducted by Dr. Klatsky and colleagues at Kaiser Permanente Cardiology and Research Institute, a large Northern California health care system and insurer, found that heavy drinkers (≥3 drinks per day) had an increased risk of five types of cancer compared to lifetime abstinence from alcohol: upper respiratory/digestive tract cancer, lung cancer, female breast cancer, colorectal cancer, and malignant melanoma; light to moderate drinkers had an increased risk of all of these cancers except lung cancer. However, there is believed to be confounding evidence in light to moderate drinkers due to underestimation of the amount of alcohol consumed. The study by Bagnardi and colleagues also showed a clear dose-risk correlation for the increased relative risk of certain cancers in heavy drinkers relative to non-drinkers and occasional drinkers. Heavy drinkers had significantly higher risks of stomach, liver, gallbladder, pancreatic, and lung cancers. There is also a positive association between alcohol intake and the risk of developing melanoma and prostate cancer. Alcohol intake is currently considered to be significantly associated with the risk of breast cancer. One study specifically explored the relationship between breast cancer and alcohol and found a dose-effect relationship between breast cancer and alcohol intake in premenopausal and postmenopausal women, with a dose-dependent increase in risk and no lower limit. How does alcohol cause cancer? Ethanol and its direct metabolite, acetaldehyde, are classified by the International Agency for Research on Cancer as “Group 1 carcinogens”. Ethanol first comes into contact with saliva and is converted to acetaldehyde, making the level of acetaldehyde in saliva 10-100 times higher than in the blood; this is a factor in the development of upper gastrointestinal/respiratory cancers. Ethanol causes hepatocellular carcinogenesis first by causing cirrhosis of the liver, which is primarily a function of the conversion to acetaldehyde. Ethanol also promotes the production of highly reactive oxygen species, which have multiple mutagenic effects on DNA and can affect histone methylation and acetylation. Ethanol also has hormonal effects, such as elevated estradiol levels, which may be a risk factor for breast cancer development. Genetics certainly plays a role in the risk of alcohol-related cancers. The amount of acetaldehyde in tissues following ethanol ingestion may depend not only on the amount of ethanol ingested, but also on the genes encoding the enzymes that metabolize ethanol. Mutations affecting ethanol dehydrogenase or acetaldehyde dehydrogenase activity can elevate and prolong acetaldehyde levels following alcohol accumulation, thereby increasing the risk of cancer development. Cancer is a heterogeneous disease, and the mechanisms of alcohol carcinogenesis vary among cancers. What are the factors that influence the increased risk of cancer from alcohol? A constant question is: What is a safe level of intake? What level of alcohol intake does not increase the risk of developing cancer? Unfortunately, to the best of our knowledge, the “safe zone” is not clear, if it exists at all. Severe alcohol use is definitely associated with cancer, but little is known about the effect of light to moderate alcohol consumption on cancer risk. Heavy drinking has been found to significantly increase the risk of developing certain cancers. Light to moderate drinking has become a gray area. In the case of breast cancer, there is no doubt that the answer is “yes”, says Dr. Rehm! “Most of the published studies so far have come to the clear and consistent conclusion that the more alcohol a woman drinks, the higher her risk of developing breast cancer, and there is no lower limit of safety.” For other cancers, the relative risk due to light to moderate alcohol consumption remains unclear. Dr. Rehm explained that the “official word” from the IARC is that there is no lower limit! Dr. Rehm says that this view is that “individual studies may not have found an increased risk of cancer with small amounts of alcohol, but when meta-analysed, the evidence does not support the existence of a safe lower limit for alcohol intake.” In fact, “the less the better” is becoming a common understanding. With regard to the types of alcohol consumed, in the past we thought that certain alcoholic beverages increased the risk of certain cancers. Recent studies have failed to provide strong evidence of a correlation between the type of alcoholic beverage and cancer, and Cao and colleagues found the same risk for all alcoholic beverages, suggesting that acetaldehyde, rather than other components of alcoholic beverages, is the culprit. History of alcohol consumption (in years) and age at the start of drinking are both important influences on cancer risk, and drinking once a day from age 25 does not have immediate health effects. However, Dr. Rehm explained that most people drink regularly throughout their adult lives. The higher the overall intake of alcohol, the higher the risk. “The risk of developing cancer is a reflection of the overall level of function of all organs that are exposed to alcohol. If cancer is diagnosed today, it is likely to be the result of alcohol consumption that began at least 15-20 years ago.” In terms of drinking patterns, most studies have not evaluated alcohol abuse. Still, the current view is that alcohol causes cancer primarily as a result of chronic heavy drinking rather than occasional alcohol abuse, although there will be isolated exceptions, of course. There is also an interaction between alcohol consumption, smoking and cancer. In fact, evidence suggests that alcohol and tobacco have a more significant synergistic effect on head and neck cancers (oral cavity, pharynx, larynx) than multiplication. This interaction is biologically plausible. When smoking, alcohol can be a solvent for carcinogens, which leads to better permeability of the mucosa to carcinogens. Data extracted from 17 case-control studies in Europe and the United States (11,221 subjects, 16,168 controls) showed that the population-attributable risk of alcohol-caused cancer was 72% for head and neck cancer, but only 4% for alcohol per se, 33% for smoking per se, and 35% for the combination of alcohol and tobacco. Recent studies have confirmed the role of smoking in the carcinogenesis of alcohol. dr. Klatsky explains, “Smoking and drinking are related, but it is difficult to separate the culpability of smoking and drinking because few people smoke much and don’t drink.” However, the fact that a large proportion of GI/respiratory cancers may be the result of alcohol consumption plus smoking does not make alcohol less culpable for causing cancer. Do the cardiovascular benefits of alcohol consumption outweigh the cancer risks? With alcohol consumption associated with cancer on the one hand, and cardiovascular benefits associated with alcohol consumption on the other, we wonder if long-term daily alcohol consumption will be beneficial, or harmful? There are no data from randomized controlled trials on the relationship between alcohol and cardiovascular prognosis. However, the two do not cancel each other out: light to moderate alcohol consumption may have cardiovascular benefits, but the carcinogenic risk cannot be denied. Dr. Klatsky insists that “there is little controversy about light to moderate alcohol consumption reducing the risk of heart attack and coronary heart disease death. The benefits of light to moderate healthy drinking, such as drinking wine with a meal, are well established.” Dr. Klatsky explained that light to moderate alcohol consumption was associated with the lowest overall mortality among people 50 years of age and older who had no significant risk factors for cancer or heart disease. However, young women with a family history or risk factors for breast cancer but no serious risk factors for heart disease should not drink alcohol for cardiovascular benefit, Dr. Klatsky said. “If older adults want to reduce their risk of heart attack, there are many things that make sense-quit smoking, maintain an ideal weight, exercise, and control risk factors such as high blood pressure and high blood cholesterol. Moderate alcohol consumption may have a place, but it’s not the most important.” “Light to moderate drinkers under 50 years of age do not have a pure benefit from this – these people are more likely to have adverse effects from alcohol consumption.” Dr. Rehm’s view is that “overall, the adverse effects of alcohol accumulation exceed the benefits by a factor of 10. Recent international cohort studies in different regions of drinking have not found a net health benefit for alcohol accumulation. Heavy alcohol intake (defined as 14 or more drinks per week for women and 21 or more drinks per week for men) was associated with increased risk of death, cancer, and injury, but no significant reduction in the risk of heart attack was seen. Risk communication Of all the dietary factors associated with cancer risk, the evidence for the carcinogenic effect of alcohol is the strongest and most consistent. Reducing alcohol intake alone could reduce the enormous global burden of cancer incidence and death. However, the public underestimates the importance of alcohol as a carcinogen. Not only is the general public reluctant to accept the idea that alcohol is linked to cancer, it is also reluctant to change its drinking habits. 94% of Americans know that smoking is a cancer risk factor, but only 43% have heard that alcohol may cause cancer. Even serious alcohol-related diseases, such as chronic liver disease, are not always enough to convince the population to quit drinking. Reports of the health benefits of alcohol consumption can affect the dissemination of information about the association between alcohol and cancer and influence the perception of this relationship. In fact, this association is sometimes overlooked, so much so that the Pink Ribbon, a global breast cancer awareness campaign, has suggested that beer and wine can be consumed.