Critique #285 – Alcoholic beverage consumption and female breast cancer risk: A systematic review and meta-analysis of prospective cohort studies

Authors

Sohi, I., Rehm, J., Saab, M., Virmani, L., Franklin, A., Sánchez, G., Jhumi, M., Irshad, A., Shah, H., Correia, D., Ferrari, P., Ferreira-Borges, C., Lauby-Secretan, B., Galea, G., Gapstur, S., Neufeld, M., Rumgay, H., Soerjomataram, I., Shield, K.

Citation

Alcohol: Clinical Experimental Research Alcohol Clin Exp Res. 2024;00:1–20. https://doi.org/10.1111/acer.15493

Author’s Abstract

Background Alcohol consumption is an established cause of female breast cancer. This systematic review examines in detail the association between alcohol and female breast cancer overall and among the described subgroups, using all of the evidence to date.

Methods A systematic review of PubMed and Embase was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search included articles published up to November 15, 2023. Meta-analyses and regressions were performed for alcohol consumption of less than 1 standard drink (10 g of ethanol) per day and for a range of alcohol consumption categories in relation to breast cancer. Analyses by menopausal status, hormone receptor status, human epidermal growth factor receptor 2 status, and molecular subtype were performed. The search yielded 5645 publications, of which 23 publications of individual and pooled studies examined the association between overall alcohol consumption and breast cancer incidence.

Results The meta-regression showed a positive association; relative risks (RR) of breast cancer were 1.05 (95% CI: 1.04, 1.06), 1.10 (95% CI: 1.08, 1.12), 1.18 (95% CI: 1.15, 1.21), and 1.22 (95% CI: 1.19, 1.25) for 0.5, 1, 2, and 3 standard drinks per day compared with nondrinking, respectively. A meta-analysis of nine studies indicated that for consumption of less than one standard drink per day, the RR estimate of breast cancer was 1.04 (95% CI: 1.01, 1.07) compared with nondrinking. Consumption of an additional 1 standard drink per day was associated with a higher risk of premenopausal (RR: 1.03 (95% CI: 1.01, 1.06)) and postmenopausal (RR: 1.10 (95% CI: 1.08, 1.12)) breast cancer.

Conclusions Alcohol consumption increases female breast cancer risk, even for women who consume one drink per day. Furthermore, alcohol consumption is associated with both pre- and postmenopausal breast cancer risk. These findings support evidence-based cancer prevention guidelines to reduce alcohol-related risks.

Forum Summary

This well-written review by Sohi et al. (2024) reports that breast cancer risk is increased even for women who consume one drink per day. The study, however, fails to highlight that breast cancer risk is non-linear, which means that the impact of an additional glass per day on the association with breast cancer risk diminishes or disappears after consumption levels of 20 g alcohol and higher/day. The review also shows that alcohol consumption increases the relative risk for breast cancer by a maximum of 20 to 25% for consumption levels up to 60 to 80 g alcohol/day.

Although a number of other risk factors for the alcohol-breast cancer risk association have been evaluated in this study, ISFAR forum members indicate various other non-evaluated confounding factors. These include, amongst others, socio-economic status, aspects of drinking patterns other than binge drinking and diet. Also, high variability between studies exists and suggests a limited impact of alcohol consumption on breast cancer risk.

The authors, unfortunately, fail to put their findings in context with all-cause mortality and cardiovascular disease. Cardiovascular disease kills more women than all types of cancer combined and cardiovascular disease risk is reduced in moderate alcohol consumers.

ISFAR forum members consider alcohol consumption a minor and less important risk factor for breast cancer, also because no clear mechanism of action for this lifestyle-disease association has been established.

Forum comments

Background

Breast cancer is the most prevalent kind of cancer in women and although treatment has advanced and is now relatively successful, it remains the second leading cause of cancer death in women (ACS 2023). Therefore, ISFAR regularly updates this topic and critically follows the most recent literature.

Two of the most recent ISFAR critiques were on breast cancer recurrence. In ISFAR critique #270, we evaluated a paper by Kwan et al. (Kwan et al., 2023) who showed that, whereas the positive association between alcohol consumption and breast cancer incidence is well-established, so is the absence of a positive association between pre-diagnosis and post-diagnosis alcohol consumption and breast cancer recurrence and breast cancer-specific mortality. In ISFAR critique #265, we evaluated the recommendation to the Japanese Breast Cancer Society Clinical Practice Guideline Committee (Nomura et al., 2023) that said alcohol consumption has a substantial effect on breast cancer risk but is unlikely to increase the relative risk of breast cancer recurrence and death from breast cancer.

This paper by Sohi et al. (2024) does not investigate breast cancer recurrence instead updating the alcohol consumption—breast cancer incidence association with specific attention to low alcohol consumption, viz 1 glass (10 g alcohol) or less per day.

It is important to realise that breast cancer is a multifactorial disease. This means that various factors will influence the risk for this disease. Some of the risk factors are modifiable and others are not. The main risk factors for breast cancer incidence are unfortunately not modifiable. Some of these non-modifiable risk factors include age, positive family history or genetics, early menarche, late menopause and having dense breasts (Fakhri et al., 2022). Indeed, age is the most significant factor for developing breast cancer, where approximately 75% of breast cancers are diagnosed after age 50, risk increases with age until approximately age 75 years[1]. Modifiable risk factors include the lifestyle factors of obesity, tobacco smoking, alcohol consumption, sedentary lifestyle, and hormone replacement therapy.

The relative importance of each of these modifiable and non-modifiable risk factors is not precisely established. The non-modifiable risk factors, however, contribute more than the modifiable risk factors. Genetic predisposition is, for example, an important contributor to the overall breast cancer risk. Although alcohol consumption was positively associated with risk of both oestrogen-receptor sensitivity (ER+) and ER- breast cancer (Jung et al., 2016), breast cancer is most prevalent in women with a high ER+ (Jiang et al., 2024). The decrease in the rate of breast cancer incidence around menopause and the subsequent increase post-menopause, suggests that ovarian and other female hormones in addition to oestrogen are involved in the development of breast cancer;[2] the level of circulating oestrogen is increased by alcohol consumption, and accordingly the risk of oestrogen-receptor sensitive breast cancer[3] (McDonald et al. 2023).

Within the modifiable risk factors, alcohol consumption is one of many as well. Obesity and tobacco smoking contribute most, whereas diet and alcohol consumption contribute, although to a lesser extent. Alcohol consumption appears positively and linearly associated with breast cancer. This means that the more a woman drinks the larger the risk associated. This paper is interesting since it is an update of the state-of-the-art with specific attention to low or very low alcohol consumption levels, dose-dependency of the association, and the effects of heavy episodic or binge drinking.

Critique

This paper re-evaluates the risks for breast cancer incidence associated with low alcohol consumption. Of the many papers concerned with the alcohol consumption—breast cancer association (692) numerous papers were excluded because of a wrong study design (not a longitudinal study), an erroneous outcome parameter (not concerning well-defined breast cancer incidence), and an erroneous exposure measure (no control group and no low alcohol consumption category included). This selection procedure resulted in 42 papers of which 23 were used for the overall risk association and nine for the risk associated with low alcohol consumption.

Older papers mentioned a linear increase of the relative risk of 10% with every extra standard glass of alcohol consumed every day (Smith-Warner et al., 1998). Later papers report a linearly increased risk of 3-6% per standard glass consumed (Seitz et al., 2012, Zhou et al., 2022). This paper reports a 10% increase with the first standard glass (10 g alcohol) per day, up to about an 18% relative risk increase at two standard glasses (20 g alcohol) per day. Additional drinking did increase the relative risk further but with low percentages. The relative risk for breast cancer is maximized at 20-25% for consumption levels up to 60 to 80 g alcohol/day. This means that the impact of an additional glass per day on the association with breast cancer risk diminishes or disappears after consumption levels of 20 g alcohol and higher/day. Such a non-linear relationship is new but has been shown previously by Jung et al.  (Jung et al., 2016); these authors reported an increasing relative risk of up to 40-50 g alcohol/day.

Sohi et al. (2024) do not emphasize this important finding. They instead focus on another finding, namely that even consuming only small quantities of alcohol, such as half a glass per day, will increase the relative risk for breast cancer. They also pay less attention to the differently shaped curve setting the maximum relative risk increase from alcohol consumption for breast cancer at 20-25%.

An increased relative risk is an adverse health effect, of course, but the size of the risk seems to be overestimated in the older studies. Such overestimation may relate to the improved estimation of potentially confounding factors. Whereas hormone sensitivity was not considered previously, later studies, as did this specific analysis by Sohi et al. (2024), corrected for oestrogen-receptor sensitivity and other genetic predispositions including progesterone-receptor status and human epidermal growth factor receptor 2 status.

Their discussion on the mechanism of action is interesting. These authors find a stronger association for those with a positive oestrogen-receptor sensitivity status, and a less strong and insignificant association with a negative oestrogen-receptor sensitivity status. The authors suggest that alcohol may have a mitogenic effect in addition to a hormone-regulating effect finally resulting in breast cancer initiation. This would mean that there is an indirect effect of alcohol on breast cancer risk rather than a direct effect of alcohol itself being the initiating carcinogenic compound.

Attention was paid to the contribution of heavy episodic drinking to breast cancer risk. Although a significant increase in the relative risk for breast cancer was observed with heavy episodic drinking, there was not a consistent increasing relative risk with increasing frequency of heavy episodic drinking. The authors argue that although heavy episodic drinking is positively associated with breast cancer risk, there may be an effect of drinking patterns on cancer risk. Acute heavy alcohol exposure may impact breast cancer risk differently than the same amount of alcohol consumed over a greater number of occasions. We fully support that concept, specifically when alcohol consumption occurs with meals. Drinking with meals results in significantly lowered blood alcohol concentrations attenuating potential adverse effects.

Overall, this is a well-performed study with an extensive discussion mentioning most of the factors that may have affected the results from the meta-analyses used and the potential confounders that may still affect the outcome of this meta-analysis. This makes the paper easy to read and understand, and well-balanced.

The public health implications paragraph, however, is quite lengthy and supports several of the possibilities to raise awareness of the alcohol consumption—breast cancer risk. It also indicates that alcohol control policies need to account for the applicable biologically relevant exposure period between alcohol consumption and breast cancer occurrence, as well as to manage the expectations of policymakers before and after policy changes have been implemented. The authors may be cognizant of the uncertainties in the alcohol consumption— breast cancer association, the limited effect size of that association, and the limited efficacy of public health measures such as health warning labelling and mass media campaigns (Zuckermann et al., 2024). In their conclusion, however, they fully support all these public health measures.

Furthermore, this study does not put the risk of breast cancer in context with all-cause mortality. Cardiovascular disease is still the primary cause of death in women worldwide (WHO, 2024), responsible for 35% of deaths in women each year (World Heart Federation, 2024). It can affect women of any age and more women also die from cardiovascular disease than all types of cancer combined. However, surveys show women tend to think they are more likely to die of cancer, particularly breast cancer (Bello and Cheng 2024). Cardiovascular disease continues to be under-diagnosed and under-treated in females, unfortunately, due to misconceptions and lack of awareness among both healthcare professionals and the general public which may result from the under-representation of women in clinical trials for cardiovascular disease in contrast to those for breast cancer.

Specific Comments from Forum Members

Forum Member Corder states that “this paper fails to mention the attached paper from the Nurses’ Health Study II (Kim et al., 2016) which reported that the association between (heavier) alcohol consumption and breast cancer risk was linked to family history and low folate diets.

Forum member de Gaetano muses that “the limitation of all studies like this is that they only measure a single clinical outcome, such as breast cancer, outside the general context of the individual and without considering the public health value at the population level (e.g., all-cause mortality). Are we sure that women who avoid drinking to reduce their risk of breast cancer also have fewer cardiovascular problems and ultimately live longer?”

He adds that “high adherence to a traditional Mediterranean diet, which includes regular moderate wine consumption with meals, was independently associated with a substantial reduction in all-cause mortality rates among cancer survivors, specifically in cardiovascular mortality. The latter observation is relevant because patients with cancer are considered a high cardiovascular disease risk population because of shared modifiable risk factors and, potentially, molecular mechanisms of disease, as postulated by the ‘common soil’ hypothesis (Bonaccio et al. 2024)”

Forum Member Waterhouse considers that “the study raises an important question about impact that policymakers might expect to see if alcohol consumption went down or to zero.  Clearly breast cancer would not go away, and my question is, would it go down by any significant amount on a population basis? “

“The association between drinking a moderately-heavy volume of alcohol (>2 drinks/day) is established with convincing evidence and probably causal,” suggests Forum Member Skovenborg.

“The question is whether there is convincing evidence that light drinking (less than one drink per day) is also associated with increased risk of breast cancer?  I have some comments on methodological issues that in my opinion question the evidence concerning light drinking.

An earlier meta-analysis conversely found that drinking up to 15 g alcohol/day is not associated with the incidence of the 20 most common cancer types in the Western World in contrast to higher consumption. It was noteworthy that the association with light and moderate alcohol consumption was negative for cancers such as (non)-Hodgkin lymphoma, leukaemia, lung and renal cancer (Hendriks and Calame, 2018).

• Heterogeneity: Study heterogeneity delineates the variability in study outcomes beyond what could be explained due to chance or measurement error. Differences between the results of studies may be so high that calculating an average effect size in a meta-analysis would make too little sense. Another current analysis of 122 systematic reviews and meta-analyses of causes and risk factors of breast cancer entitled What do we know for sure?, found many of the included studies investigating the same topics had confusing or conflicting results (Løyland et al. 2024). Three systematic reviews of alcohol use and breast cancer were included in this evidence synthesis with inconsistent findings. The conclusions varied from ‘there is an association’ between alcohol consumption and breast cancer risk, to ‘the association remains insufficient’, to ‘high intake of wine contributes’ to breast cancer risk, but ‘protection is exerted with low doses of wine’. Although one of these meta-analyses concluded with an association with an effect size of 1.28, the result did not qualify for the ‘top list’ of important findings because of high heterogeneity.

• Patterns of alcohol consumption: The volumes of alcohol intake listed as ‘light or moderate consumption’ do not represent a drinking pattern but are a categorization of drinking level by quantity. Most studies categorize light alcohol consumption as ≤ 1 drink (10 g/day), however, the ‘10 g/day category’ is an artifact produced by converting consumption data (e.g. alcohol intake/week) into daily averages. Very few cohort studies have information about drinking patterns, so it is not known whether consumption of, for example, 70 g alcohol/week is consumed as one drink per day spread over six to seven days or as binge drinking on weekends. There is no empirical justification for converting consumption data into daily averages, and study results suggest that the harm associated with relatively low weekly volumes of consumption may be largely attributable to the contribution of just a few heavy drinking days (Knupfer, 1987).

The authors acknowledge the importance of drinking patterns as a potential effect-modifying factor. ‘Patterns of alcohol consumption are hypothesized to modify the risk relationship between alcohol consumption and breast cancer,’ Shield et al. (2016) wrote in an earlier review of alcohol and breast cancer. They presented six studies with information about drinking pattern in the review, while three published studies were not noticed by the authors. Since 2016, four new studies with data on drinking patterns and cancer risk have been published. Overall, the findings provide evidence for an increased risk associated with heavy episodic drinking, especially among moderate lifetime drinkers. For example, Ma et al. (2021) defined a healthy drinking habit score (DHS) by regular drinking (frequency of alcohol intake ≥ 3 times per week) and by consuming alcohol with meals. One point was given for each favourable drinking habit (range 0-2). After adjustment for potential confounders and the amount of alcohol consumed, regular drinking was associated with an 8% lower risk of cancer mortality as compared with non-regular drinking. Compared with participants who consumed alcohol outside meals and those who had varying patterns, participants who consumed alcohol with meals had a 10% lower risk of cancer mortality. A positive linear association between alcohol consumption and cancer mortality was observed in participants with unfavourable DHS, whereas a U-shaped association was observed in participants with favourable DHS. Moderate alcohol consumption (50-200 g/week) was not associated with cancer mortality in participants with a favourable DHS.

• Underreporting of alcohol intake: Self-reported information on alcohol consumption is known to underestimate true consumption. Systematic under-reporting of consumption by both cases and controls would result in an overestimation of the relative risk of breast cancer for a given level of alcohol consumption. Moreover, the shape of the dose-response relationship could be changed if heavy drinkers were more likely to under-report intake than moderate drinkers. Taken together, these reporting errors imply that some uncertainty remains about the true quantitative effect of an intake of a fixed amount of alcohol on the risk of developing cancer. In a cohort study of cancer risk in participants reporting light to moderate drinking, the increased risk of cancer was concentrated in the stratum suspected of underreporting (Klatsky et al., 2014).

• Mendelian randomisation (MR) studies: Numerous MR studies did not find any compelling evidence in support of a causal relationship between genetically predicted alcohol consumption and the risk of breast cancer, such as Ingold et al., (2024), Zhou et al., (2022), Ong et al., (2021), Larsson et al., (2020) and Zhu et al., (2020)”.

For Forum Member Harding, “the problem with this paper is its clearly stated premise in the first paragraph of the abstract, ‘Alcohol consumption is an established cause of female breast cancer’.  This is followed by the first sentence of the second paragraph of the introduction, ‘The causal association between consumption of alcoholic beverages and female breast cancer risk was established by IARC in 2007’ (Bradford, 1965). 

As far as I can see, this conclusion was reached by the International Agency for Research on Cancer (IARC) solely based on epidemiological association, with no supporting evidence at all.  The assertion appears based on successive IARC publications, which cite each other in support.  We have the Bradford-Hill criteria (Bradford, 1965) to apply to help us establish whether an observed association is causal, but there is no mention of them in this paper, or in any of the IARC publications as far as I can tell.

The second of these criteria is consistency.  In the words of Sir Austin Bradford-Hill himself, ‘Has it been repeatedly observed by different persons, in different places, circumstances and times?’ Yes, it has, as seen below in Figure 2 from the paper itself.

I don’t think Sir Austin would have found that particularly convincing.  Many studies quoted in the 2010 IARC monograph show a reduction in risk with moderate consumption. Further, a 2007 study of 18,000 nurses over eight years found that those who drank moderately (up to 24 g/day) reduced their risk of breast cancer.  At higher consumption, breast cancer risk increased, and at even higher intakes decreased (Grønbaek et al., 2007). This finding was corroborated by a 2008 French study that found that none of the breast cancer cases appeared to have any association with alcohol consumption.  Indeed, consumption of up to 15 g/day alcohol reduced the risk by a dramatic 42%.  Higher consumption of wine did not increase cancer risk at all (Bressaoud et al., 2008), and a 2019 study based on UK Biobank data, suggested that in about half a million women found ‘no evidence of a causal association between alcohol consumption and breast cancer’ (Ingold et al., 2019).

Forum Member Corder cited a paper earlier, which concluded that alcohol consumption was not significantly associated with breast cancer risk overall but was associated with an increased risk of breast cancer among those with a family history and a low folate intake (Kim et al., 2017). So overall, the data fail the fifth Bradford Hill criterion too – the Biological Gradient – that is, greater exposure should lead to a greater incidence of the effect.  Thus, for these reasons, I do not think that the premise on which this paper is based can be justified.”

Concluding comments

This well-constructed and conducted study to assess alcohol consumption and female breast cancer risk, concludes that risk is increased even for women who consume one drink per day.

The study, however, fails to highlight in their conclusions that risk is non-linear, such that the relative risk for breast cancer is maximized at 20-25% for consumption levels up to 60 to 80 g alcohol/day. This means that the impact of an additional glass per day on the association with breast cancer risk diminishes or disappears after consumption levels of 20 g alcohol and higher/day.

These findings do not, however, strongly support evidence-based cancer prevention guidelines to reduce alcohol-related risks, given that this study does not put the risk of breast cancer in context with all-cause mortality. Cardiovascular disease is still the primary cause of death in women, although surveys show women tend to think they are more likely to die of cancer, particularly breast cancer. The most important thing to remember is that cardiovascular disease kills more women than all types of cancer combined.

Indeed, Forum Member Ellison concludes that “while I have always been intrigued by the findings that the diagnosis of breast cancer seems to be slightly increased among women who consume even moderate amounts of alcohol, seldom is there an increase in breast cancer mortality among moderate drinkers.  Further, women with diagnosed breast cancer who continue to drink have lower mortality than those who stop drinking.  There may still be residual confounding in many studies, as women with higher socioeconomic status (SES) who tend to be moderate drinkers, may have more mammograms and earlier diagnosis of breast cancer than women with lower SES who are more likely to be non-drinkers.

In any case, moderate drinking appears to be a minor contributor to breast cancer occurrence in women. In epidemiologic studies for decades, those who choose to drink moderately have been found to have longer lifespans than non-drinkers.  On the other hand, the assessment of risk for this cancer is very difficult, and few very strong risk factors have been identified; thus, continued research on this association may be useful.”

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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Henk Hendriks, PhD, Netherlands

Creina Stockley, PhD, MBA, Independent consultant and Adjunct Senior Lecturer in the School of Agriculture, Food and Wine at the University of Adelaide, Australia

Roger Corder, PhD, Emeritus Professor of Experimental Therapeutics, Centre: Translational Medicine and Therapeutics, UK

Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy

Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis, USA

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

Richard Harding, PhD, Formerly Head of Consumer Choice, Food Standards and Special Projects Division, Food Standards Agency, UK

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

R. Curtis Ellison, MD, Section of Preventive Medicine/Epidemiology, Boston University School of Medicine, Boston, MA, USA

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[1] https://www.breastscreen.org.au/breast-cancer-and-screening/your-breast-cancer-risk/

[2] https://www.canceraustralia.gov.au/sites/default/files/publications/breast-cancer-risk-factors-review-evidence/pdf/rfrw-breast-cancer-risk-factors-a-review-of-the-evidence_1.15.pdf

[3] https://www.breastcancer.org/risk/risk-factors/drinking-alcohol