Part II: Alcohol and breast cancer – a study in weak associations – Part II_ by Erik Skovenborg MD

While smokers’ risk of lung cancer is 20 times higher (equal to 2000% higher) than that of nonsmokers, cancer epidemiology is, to a large extent, the determination of small effects and weak associations and poses major challenges. In comparison, a dose-response meta-analysis of alcohol and risk of postmenopausal breast cancer found a significant increased risk of 0.09 times (equal to 9%) per 10 grams per day compared to nondrinkers. (World Cancer Research Fund/American Institute for Cancer Research. Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. Available at dietandcancerreport.org)
Sir Bradford Hill has proposed some features of the association we should consider before deciding that the most likely interpretation of the association is causation. (Hill AB. The environment and disease. Association or causation? J R Soc Med 2015;108(1):32-37.) With these nine features as aids to thought we will look at the proposed causal association of light alcohol consumption and breast cancer with a critical eye. Part I of this paper (published in our March edition) looked at the first of the nine viewpoints “from all of which we should study association before we cry causation” – Strength – with the conclusion that the alcohol-breast cancer association is weak and several bias and effect modifiers have been identified. Now we continue with the next eight features on the list.
Consistency. Next on Bradford Hill’s list of features to be specially considered is the consistency of the observed association. Has the association been repeatedly observed by different persons, in different places, circumstances and times?
• The majority of the case-control studies and cohort studies published to date have shown a (modest) positive association between alcohol consumption and breast cancer. However, there is a considerable lack of consistency in results of the association between alcohol intake and breast cancer risk in retrospective as well as prospective observational studies. A large number of case-control studies have shown no association (n=34), non-significant positive associations (n=23) or negative associations (n=6). Regarding cohort studies 15 studies have shown no association, 12 studies a non-significant positive association and 1 study a negative association; e.g. among 2,764 women followed > 40 years in the Original Framingham Cohort and 2,284 followed up to 24 years in the Offspring Cohort, light consumption of alcohol or any type of alcoholic beverage was not associated with increased breast cancer risk. (Zhang et al. Alcohol consumption and risk of breast cancer: The Framingham Study revisited. Am J Epidemiol 1999;149(2):93-101.)
• It is likely that overall breast cancer risk in relation to alcohol intake varies among different ethnic groups and different regions. A meta-analysis of 4 case-control studies conducted in China found a significant inverse association between alcohol consumption and breast cancer risk. (Li Y et al. Association between alcohol consumption and cancers in the Chinese population: a systematic review and meta-analysis. PLoS One 2011;6:e18776.) Among the Japanese population, a qualitative review of the existing evidence has indicated that the association between alcohol consumption and breast cancer risk remains inconclusive. (Nagata C et al. Alcohol drinking and breast cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol 2007;37:568-74.)
• Cohort studies with less than 10 years of follow-up gave estimates 11% higher than cohort studies with longer follow-up periods. (Curtis Ellison et al. Exploring the Relation of Alcohol Consumption to Risk of Breast Cancer. Am J Epidemiol 2001;154:740-47.)
• In the dose-response meta-analysis of 22 studies (n=35,221 cases) for postmenopausal breast cancer, high heterogeneity was observed. (dietandcancerreport.org)
• Two recent Mendelian Randomization studies did not find evidence for a causal relationship between genetically predicted alcohol consumption and risk of breast cancer.
a) Zhu et al. Alcohol consumption and risk of breast and ovarian cancer: A Mendelian Randomization study. Cancer Genetics 2020;245:35-41.
b) Ong et al. Evaluating the role of alcohol consumption in breast and ovarian cancer susceptibility using population-based cohort studies and two-sample Mendelian randomization analyses. Int J Cancer 2021;148(6):1338-1350.
Specificity of the association is a strong argument in favour of causation. Harmful alcohol has been linked to more than 200 diseases and injury conditions including several other types of cancer while up to two drinks a day decreases kidney cancer. In comparison, the death rate of smokers is higher than the death rate of non-smokers from many causes of death, but specificity is demonstrated by the magnitude of the association of smoking and lung cancer. However, importance of the characteristic of specificity should not be over-emphasized.
Temporality. The question of temporal relationship of the association is particularly relevant with diseases of slow development. Regarding the association between alcohol consumption and breast cancer risk temporality is more a consideration of the extent to which alcohol affects breast cancer onset or breast cancer progression. There is no evidence of reverse causation (that early stages of breast cancer lead to change of drinking patterns) in the association of alcohol and breast cancer.
Biological gradient refers to the presence of a unidirectional dose–response curve.
• In the collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer, the relative risk of breast cancer increased with alcohol intake, increasing by 7.1% for each additional 10 g per day intake of alcohol consumed on a daily basis. Compared to women who drank no alcohol the relative risk was 1.03 for women whose alcohol consumption was 5-14 g/d, 1.13 for 15-24 g/d, 1.21 for 25-34 g/d, 1.32 for 35-44 g/d and 1.46 for >45 g/d. (Hamajima et al. Alcohol, tobacco and breast cancer – collaborative reanalysis of individual data from 53 epidemiological studies, including 58 515 women with breast cancer and 95 067 women without the disease. British Journal of Cancer 2002;87:1234-45.)
• Regular intake of wine with meals: A population-based case-control study of alcohol and breast cancer (250 cases and 499 controls) was conducted among women under the age of 75 residing in the Province of Vercelli, in northwestern Italy; an area where wine drinking is widespread and regarded by most as an acceptable habit. Wine is sometimes produced by the family for personal consumption and, in general, is economically affordable. In line with Italian customs, wine is consumed mainly during meals, in place of other drinks. As a consequence, levels of alcohol consumption were quite substantial; about 40% of the total study population, or more than 55% of drinkers, reported consumptions of alcohol in excess of 15 g/day and more than 20% of drinkers reported consumptions of 30 g/day or above. The dietary questionnaire was designed primarily for the purpose of estimating alcohol consumption in European countries, such as France, Spain, and Italy, where wine consumption is widespread and habitually consumed during meals. The questionnaire was therefore structured by meals. In comparison with abstainers (30% of women in the study) and after adjustment for potential confounders, no appreciable association was evident for alcohol consumptions as high as 30-40 g/day. Alcohol intake from wine (g/day) and RR (95% CI) of breast cancer: 0: 1.0, >0-10: 0.9 (0.5-1.5), >10-20: 1.2 (0.8-1.9), >20-30: 1.1 (0.7-3.0), >30-40: 1.4 (0.7-3.0), and >40: 2.1 (1.1-3.7). (Toniolo P et al. Breast cancer and alcohol consumption: a case-control study in northern Italy. Cancer Res 1989;49:5203-06.)
• The alcoholism paradox: Barmaids, who have a raised mortality from cirrhosis, have a low proportional mortality from breast cancer. (Office of Population Censuses and surveys. Women’s occupational mortality 1970-72 (Series DHI no. I). London: HM Stationary Office 1985.) In a number of studies (3 from Sweden, 2 from Denmark, 1 from UK and 1 from the US) alcoholic women with a very high intake of alcohol had only a very modest increase (relative risk around 1.15) in breast cancer incidence compared to the general female population. (Kuper et al. Alcohol and breast cancer risk: the alcoholism paradox. British Journal of Cancer 2000;83:949-51). In a Russian retrospective case-control study of alcohol and cause-specific mortality in 48,557 adult deaths, the only significantly inverse association was with mortality from breast cancer (519 deaths), which was substantially lower in the few women in the highest alcohol category (mean > 5 bottles of vodka or equivalent per week) than in women from the lower alcohol consumption categories. (Zaridse D et al. Alcohol and cause-specific mortality in Russia: a retrospective case–control study of 48 557 adult deaths. Lancet 2009; 373:2201–14.) The alcoholism paradox has not been explained away by confounding factors.
Plausibility. “It will be helpful if the causation we suspect is biologically plausible”, Bradford Hill said in his President’s Address. “But this is a feature I am convinced we cannot demand. What is biologically plausible depends upon the biological knowledge of the day.”
Tumor initiation and growth.
Cancer develops when the normal processes that regulate cell behaviour fail and a cell becomes the ancestor of a group of cells that share its functional abnormalities. More than one mutation is generally required to lead to cancer and most cancers result from the accumulation of genetic damage in cells over time. (Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10:789-99.)
• Oncogenes are mutated in ways that render the gene constitutively active or active under conditions in which the wild-type gene is not. A mutation in an oncogene is analogous to a stuck accelerator in an automobile; the car still moves forward even when the driver removes his foot from it.
• Tumor-suppressor genes mutations reduce the activity of the gene product. A mutation in a tumor-suppressor gene is analogous to a dysfunctional brake in an automobile; the car doesn’t stop even when the driver attempts to engage it.
• Stability genes keep genetic alterations to a minimum, and thus when they are inactivated, mutations in other genes occur at a higher rate.
Mutations in these three classes of genes can occur in the germline, resulting in hereditary predispositions to cancer (e.g. inactivation of stability genes BRCA1 and BRCA2), or in single somatic cells, resulting in sporadic tumors. The cells of solid tumors must accumulate several rate-limiting mutations in cancer genes to achieve malignant status. These mutations occur over time, with each mutation engendering a clonal expansion resulting in a large number of cells that then form a substrate for subsequent mutations. It requires 30–40 years for a typical epithelial cell to accumulate the multiple genetic alterations required to progress to metastatic disease. Data-driven approaches provide a consistent estimate of contribution of extrinsic factors of 70-90% in most common cancer types. (Wu S et al. Substantial contribution of extrinsic risk factors to cancer development. Nature 2016;529(7584):43-47.) While numerous behavioral, reproductive, and medical breast cancer risk factors have been established, questions remain regarding the strength of associations with these, and other risk factors, due in part to the etiological heterogeneity among breast cancer subtypes.
A primary tumor starts from one single cell and monoclonality has been shown for the majority of human tumors. The first tumor cell multiplies exponentially with time: 1-2-4-8-16-32, and so forth. If the tumor cells have a diameter of 10 µm, the clone will have reached a volume of about 1 cm3 after 32 cell generations. The net growth of the tumor volume plotted on a semilogarithmic scale, it is linear and the inclination of the slope may be called the tumor volume doubling time (TVDT). (Friberg S, Mattson S. On the Growth Rates of Human Malignant Tumors: Implications for Medical Decision Making. J Surg Oncol 1997;65:284-97.) It takes 22 cell divisions (doublings) to reach a tumor size of 2 mm = the mammographically threshold size for diagnosis. About 32-33 doublings is needed for a tumor to reach a size of 109 cell and a volume of 1 cm3 = a tumor size that may give rise to symptoms and become detectable on palpation. With a TVDT of 150 days and assuming a constant generation time, the tumor is then about 12 years old.
Serial mammographies of untreated breast cancers during an observation period from 2 to 9 years showed great interindividual variability of the growth rates for different cancers of the breast, with TVDTs ranging from 88 days to 523 days. The average doubling time was 280 days, which means that more than 18 years were required from the first tumor cell (10 µm in diameter) to produce a tumor with a diameter of 2 mm (the lowest detection level). (Fournier D v et al. Growth rate of 147 mammary carcinomas. Cancer 1980;45:2198-2207.) In a study of faster growing interval breast cancers average estimated TVDT was 167 days (95% CI 151-186). High grade, ER negativity and younger age were associated with shorter durations of TVDT. (MacInnes EG et al. Radiological audit of interval breast cancers: Estimation of tumour growth rates. The Breast 2020;51:114-19.)
Tumor induction and latent periods
Induction refers to the period between causal action and tumor initiation, and latent period to the period between disease initiation (when the cancer reaches a certain critical point of being irreversible without treatment) and detection. A causal model should contain a specification of the time required for an effect to become manifest and (with the evidence on breast cancer TVDT in mind) interpretation of some epidemiological data may need be reconsidered. If a tumor reaches the diagnostic level when it is 10 years old, it is not likely to have been initiated by a suspected carcinogen to which the patient was exposed only 5 years earlier. The causative agent must be searched for more than 10 years before the diagnosis. (Rothman KT. Induction and latent periods. Am J Epidemiol 1981;114:253-59.) In an analysis of the Copenhagen City Heart Study, in which alcohol intake was measured four times, 9,318 Danish women with no previous diagnosis of cancer were followed for breast cancer for 27 years, from 1976 to 2002. During follow-up, breast cancer was diagnosed in 476 women. The association between alcohol intake at first measurement (baseline alcohol intake) and breast cancer was positive and approximately linear. When alcohol intake was updated during follow-up, no association was observed between breast cancer and alcohol intake. It is suggested that this difference in results may be attributable to long latency time between alcohol intake and breast cancer occurrence. (Thygesen LC et al. Use of baseline and updated information on alcohol intake on risk for breast cancer: importance of latency. Int J Epidemiol 2008;37:669-77.)
Regarding alcohol as a risk factor for breast cancer, the question is whether alcohol is a weak cumulative breast carcinogen or a breast tumor growth promotor or both. (Brooks PJ, Zakhari S. Moderate Alcohol Consumption and Breast Cancer in Women: From Epidemiology to Mechanisms and Interventions. Alcohol Clin Exp Res 2013;37:23-30.) If alcohol acts as a cumulative carcinogen and alcohol consumption by postmenopausal women is a surrogate measure of lifetime alcohol consumption, then assessing alcohol consumption in postmenopausal women monitors lifetime exposure to a presumably cumulative carcinogen. If we presume that the only effect of alcohol drinking was to increase the growth rate of preexisting tumors, then the relationship between breast cancer risk and alcohol drinking would be limited to more recent drinking.
Some epidemiological studies suggest that drinking alcohol during adolescence and early adulthood has a strong impact on breast cancer risk (Liu Y et al. Alcohol Intake Between Menarche and First Pregnancy: A Prospective Study of Breast Cancer Risk. J Natl Cancer Inst 2013;105:1571-78. Romieu I et al. Alcohol intake and breast cancer in the European prospective investigation into cancer and nutrition. Int J Cancer 2015;137:1921-30.), while Swanson et al. found that only contemporary drinking (average intake during the recent 5-year interval) was associated with risk. (Swanson CA et al. Alcohol Consumption and Breast Cancer Risk among Women under Age 45 Years. Epidemiology 1997;8:231-37.) The results from 21,523 postmenopausal women who participated in the Diet, Cancer, and Health Study in two consecutive examinations in 1993-98 and 1999-2003 showed that women who increased their alcohol intake over the five-year period had a subsequent higher risk of breast cancer than women with stable alcohol intake. For women who reduced their alcohol intake over the five-year period, none of the hazard ratios was significantly associated with breast cancer. (Dam MK et al. Five year change in alcohol intake and risk of breast cancer and coronary heart disease among postmenopausal women: prospective cohort study. BMJ 2016;353:i2314.)
The results from a prospective observational study of 105,986 women enrolled in the Nurses’ Health Study followed up from 1980 until 2008 with an early adult alcohol assessment and 8 updated alcohol assessments supports the lifetime carcinogen hypothesis, however when examined separately, alcohol consumption in early adulthood (18-40 years) and after 40 years were both strongly associated with the risk of breast cancer. These findings are consistent with a tumor-promoter type as well as a cumulative carcinogen type mechanism for alcohol and breast cancer. (Chen WY et al. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA 2011;306:1884-90.)
Potential mechanisms for alcohol and breast cancer carcinogenesis
Ethanol is thought to potentially cause breast cancer through several mechanisms: by its metabolite acetaldehyde − a mutagenic and carcinogenic compound that causes formation of DNA adducts and inhibits DNA repair mechanisms, by cytochrome P450 2E1 mediated generation of ROS (reactive oxygen species), by enhancing levels of estrogen, by interference with one-carbon metabolism and by ethanol-induced dysregulation of epigenetic regulation of gene expression (particularly abnormal DNA methylation). All the above-described mechanisms by which ethanol is involved in breast carcinogenesis are important and support the complexity of the interaction between alcohol and breast cancer risk. (Dumitrescu RG et al. The etiology of alcohol-induced breast cancer. Alcohol 2005;35:213-25.)
• Acetaldehyde rapidly binds to DNA and produces DNA adducts, which results in DNA point mutations, DNA crosslinks and chromosomal aberrations. (Garcia CL et al. Relationship between DNA lesions, DNA repair and chromosomal damage induced by acetaldehyde. Mutat Res 2009;662:3-9.) Aldehydes are omnipresent in nature and are generated during normal metabolism. Most aldehydes are highly reactive and to prevent DNA damage, organisms have evolved aldehyde dehydrogenase enzymes that efficiently convert aldehydes into less noxious products. (Joenje H. Alcohol, DNA and disease. Nature 2011;475(7354):45-6.) Human breast epithelium is equipped with ADH and ALDH enzymes with a ratio of ADH to ALDH activity about 13:1. Class I ADH isoenzyme is the main ethanol-metabolising isoenzyme in breast tissues. (Jelski W et al. The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in breast cancer. Clin Exp Med 2006;6:89-93.) The concentration of ethanol in the mammary parenchyma after ingestion of alcoholic beverages is supposed to equivalent to the BAC ranging from 2 to 10 mM (9 to 46 mg alcohol/100 ml blood) after moderate social drinking. Triano et al. found that ethanol metabolism in breast tissue homogenates is inhibited by ethanol in concentrations above 10 mM, so that after consumption of larger amounts of alcohol, other mechanisms for detoxification of ethanol would need to come into play. Cytochrome P450 2E1 is inducible by ethanol and has been shown to be expressed in human breast tissue. Reactions catalyzed by Cytochrome P450 2E1 enzymes are particularly prone to generate reactive oxygen species. (Triano EA et al. Class I Alcohol Dehydrogenase Is Highly Expressed in Normal Human Mammary Epithelium but not in Invasive Breast Cancer: Implications for Breast Carcinogenesis. Cancer Research 2003;63:3092-3100.)
• ADH and ALDH single nucleotide polymorphisms (SNPs). Alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) are subject to genetic variability by single nucleotide polymorphisms (SNPs). ADH polymorphisms associated with fast metabolism would result in higher systemic acetaldehyde levels that could potentially affect breast tissue. Only large changes in kinetic properties are likely to contribute to a relevant change in breast cancer risk. For example, for ADH1B rs1229984, the increase in velocity of ethanol turnover is almost by a factor of 90 in variant allele homozygotes compared with wild-type homozygotes. (Hurley TD et al. Genes encoding enzymes involved in ethanol metabolism. Alcohol Res 2012;34:339-44.) A meta-analysis of 12 case−control studies showed no direct effect on breast cancer risk of these ADH SNPs. (Wang L et al. Lack of association of ADH1C genotype with breast cancer susceptibility in Caucasian population: a pooled analysis of case-control studies. Breast 2012;21:435-39.) In a large prospective cohort study with a considerably high coverage of 76% of common genetic variability in ADH1B and 96% in ADH1C, alcohol intake was associated with overall postmenopausal breast cancer risk as well as with subtypes defined by ER and PR status, however, no significant effect modification of this association by ADH1B and AHD1C variability was observed. (Hahn M et al. Alcohol drinking, ADH1B and ADH1C genotypes and the risk of postmenopausal breast cancer by hormone receptor status: the Netherlands Cohort Study on diet and cancer. Carcinogenesis 2018;39:1342-51.)
The ALDH2 rs671 polymorphism dramatically reduces ALDH2 enzyme activity: In carriers of the ALDH2*2/*2 homozygous and ALDH2*1/*2 heterozygous genotypes the enzyme activity is nearly 0% and 17–38% of the normal activity, respectively. The ALDH2*2 variant is essentially absent among the Europeans, but is highly prevalent among East Asians: an estimated 560 million East Asians are carriers of ALDH2*2. Only three studies have examined the role of ALDH2*2 in the development of breast cancer and all found no association between ALDH2*2 and risk of breast cancer and observed no significant interaction between ALDH2*2 and alcohol consumption on the risk of breast cancer. (Chang et al. ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective. Journal of Biomedical Science 2017:24:19.)
• Estrogens. Estrogens stimulate the division of breast epithelial cells, which increases the risk of mutation thereby inducing or promoting breast cancer. A positive association between estrogens and breast cancer risk has been found in premenopausal women (Key T et al. Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies related to elevated incidence of breast cancer in humans. Lancet Oncol 2013;14:1009-19.) and postmenopausal women (Key T et al. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002;94:606-16.) In comparison to abstainers, pre-menopausal women who consumed 91,4 g alcohol/week showed an 18% increase in serum estradiol. (Muti P et al. Alcohol consumption and total estradiol in premenopausal women. Cancer Epidemiol Biomarkers Prev 1998;7:189-93.) In postmenopausal women, after ovarian estrogen production has ceased, tissues such as adipose tissue, which express aromatase (an enzyme that converts androgens into estrogens) become the major source of estrogen. A meta-analysis of prospective studies among postmenopausal women showed that alcohol intake is positively associated with sex hormones, with the strongest association for dehydroepiandrosterone sulfate (DHEAS) – an androgen that can be metabolized to estrogen in the breast by aromatase. (Key TJ et al. Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. Br J Cancer 2011;105:709-22). Ethanol stimulates proliferation of both normal breast tissue and ER+ breast cancer cells directly, causing a 10- to 15-fold increase in transcriptional activity of ER. Most studies observe an overall stronger association with ER+ and/or PR+ tumors compared with ER– and/or PR– tumors, for the highest versus the lowest alcohol consumption group. (Jung S et al. Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies. Int J Epidemiol 2016;45:916-28.) The analysis of 2160 serum estradiol measurements in 275 postmenopausal women from the ELITE trial found higher BMI and alcohol use associated with higher estradiol levels, whereas current and past smoking were associated with lower estradiol levels. (Sriprasert I et al. Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy. Obstet Gynecol 2020;136:675-84.) While results of some studies indicate that postmenopausal women who are drinkers and use hormone replacement therapy (HRT) have an increased risk of breast cancer (Hvidtfeldt UA et al. Risk of Breast Cancer in Relation to Combined Effects of Hormone Therapy, Body Mass Index, and Alcohol Use, by Hormone-receptor Status. Epidemiology 2015;26:353-61.), findings from other studies do not support the effect of alcohol on HRT-related breast cancer risk. (Allen NE et al. Moderate Alcohol Intake and Cancer Incidence in Women. J Natl Cancer Inst 2009;101:296-305.) Estrogen and alcohol independently have been observed to contribute to angiogenesis − a regulated process used by breast cancer tumors to ensure a constant supply of oxygen and nutrients. (Maniyar R et al. Ethanol enhances estrogen mediated angiogenesis in breast cancer. Journal of Cancer 2018;9:3874-85.)
• Folate deficiency. Folate is a B vitamin that donates its methyl group for homocysteine remethylation to methionine as part of one-carbon metabolism. In turn, methionine is the methyl donor for DNA methylation via S-adenosyl methionine. Results from the Shanghai Breast Cancer Study (whose participants are not regular alcohol drinkers) support a protective role for folate: Dietary folate intake was inversely associated with breast cancer risk with an adjusted OR of 0.71 (95% C, 0.56–0.92) observed among women who were in the highest quintile of intake. (Shrubsole MJ et al. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 2001;61:7136-41.) Alcohol can adversely affect folate metabolism by inhibiting the intestinal absorption, reducing the hepatic storage and increasing the renal excretion. (Halsted CH et al. Metabolic interactions of alcohol and folate. J Nutr 2002;132(8S):2367S–2372S). Modeling both exposures together revealed highly significant, independent associations between alcohol and folate and DNA methylation profile. (Christensen BC et al. Breast Cancer DNA Methylation Profiles Are Associated with Tumor Size and Alcohol and Folate Intake. PLoS Genet 2010;6(7):e1001043.) A meta-analysis of 16 prospective studies with a total of 744,068 participants and 26,205 breast cancer patients and 26 case–control studies with a total of 16,826 cases and 21,820 controls that have evaluated the association between folate intake and breast cancer risk, suggested that folate may have preventive effects against breast cancer risk. Prospective studies indicated a U-shaped relationship for the dietary folate intake and breast cancer risk. Women with daily dietary folate intake between 153 and 400 mg showed a significant reduced breast cancer risk compared with those <153 mg, but not for those >400 mg. The case–control studies also suggested a significantly negative correlation between the dietary folate intake level and the breast cancer risk. (Chen P et al. Higher dietary folate intake reduces the breast cancer risk: a systematic review and meta-analysis. Br J Cancer 2014;110:2327-38.)
Coherence: “In short, the association we observe may be one new to science or medicine and we must not dismiss it too light-heartedly as just too odd. As Sherlock Holmes advised Dr Watson, ‘when you have eliminated the impossible, whatever remains, however improbable, must be the truth.’ On the other hand, the cause-and-effect interpretation of our data should not seriously conflict with the generally known facts of the natural history and biology of the disease – in the expression of the Advisory Committee to the Surgeon-General it should have coherence.”
Experiment: “Occasionally it is possible to appeal to experimental, or semi-experimental, evidence. For example, because of an observed association some preventive action is taken. Does it in fact prevent? The dust in the workshop is reduced, lubricating oils are changed, persons stop smoking cigarettes. Is the frequency of the associated events affected? Here the strongest support for the causation hypothesis may be revealed.”
Analogy: “In some circumstances it would be fair to judge by analogy. With the effects of thalidomide and rubella before us we would surely be ready to accept slighter but similar evidence with another drug or another viral disease in pregnancy.”
“Here then are nine different viewpoints from all of which we should study association before we cry causation. What I do not believe – and this has been suggested – is that we can usefully lay down some hard-and-fast rules of evidence that must be obeyed before we accept cause and effect. None of my nine viewpoints can bring indisputable evidence for or against the cause-and- effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question – is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect?” (Bradford Hill A. The Environment and Disease: Association or Causation? Proc R Soc Med 1965;58(5):295-300.)
Erik Skovenborg is a Danish physician with a special interest in the health benefits of moderate alcohol consumption. His published work includes In Vino Sanitas, 1990; Lead in Wine throughout the Ages, 1994; Wine and Health – Myths and Facts, 2000. Member of the Social, Scientific and Medical Council of AIM (Alcohol in Moderation) from 1992 and co-founder of the Scandinavian Medical Alcohol Board (SMAB) in 1994. Chairman of the 1996 Copenhagen “Health and Alcohol Symposium” and the 1998 Stockholm “Women and Alcohol Symposium”. For many years Erik Skovenborg has lectured extensively on alcohol and health to medical professionals and the general public and he is currently researching the effects of a moderate consumption of beer, wine and spirits.