Critique 015: Moderate drinking does not increase risk of breast cancer among women with BRCA gene mutations

Critique 015                                                                                                    22 August 2010 

Dennis J, Ghadirian P, Little J, Lubinski J, Gronwald J, Kim-Sing C, Foulkes W, Moller P, Lynch HT, Neuhausen SL, Domchek S, Armel S, Isaacs C, Tung N, Sweet K, Ainsworth P, Sun P, Krewski D, Narod S; the Hereditary Breast Cancer Clinical Study Group.  Alcohol consumption and the risk of breast cancer among BRCA1 and BRCA2 mutation carriers.  The Breast 2010;e-pub.

Authors’ Abstract:  Alcohol consumption increases the risk of breast cancer among women in the general population, but its effect on women who carry a BRCA gene mutation is unclear.  We conducted a case-control study of 1,925 matched pairs of predominantly premenopausal women who carry a BRCA1 or a BRCA2 mutation.  Information on current alcohol consumption was obtained from a questionnaire administered during the course of genetic counseling or at the time of enrollment.  A modest inverse association between breast cancer and reported current alcohol consumption was observed among women with a BRCA1 mutation (OR = 0.82, 95% CI 0.70-0.96), but not among women with a BRCA2 mutation (OR = 1.00; 95% CI 0.71-1.41).  Compared to non-drinkers, exclusive consumption of wine was associated with a significant reduction in the risk of breast cancer among BRCA1 carriers (p-trend = 0.01).  Alcohol consumption does not appear to increase breast cancer risk in women carrying a BRCA gene mutation.

Forum Comments:  Most prospective observational studies suggest a slight increase in the risk of women’s breast cancer for the consumption of alcohol, with an increase often seen at low levels of alcohol intake.  Several studies, but not all, suggest that an increase may not be seen for wine consumption.  Little is known about the association between alcohol and breast cancer risk among women with specific genetic mutations that affect risk.

This study is particularly important as it compared the effects of alcohol among women carrying either a BRCA1 or a BRCA2 gene mutation, both of which markedly increase the risk of breast cancer.  Because the analysis was based on subjects from 54 participating centers in eight countries, the number of women with these genetic mutations was very large.  The comparisons were between women with a gene mutation who had developed invasive breast cancer matched with women with the same gene mutation who had not developed breast cancer.  After a number of appropriate exclusions, there were 1,480 matched pairs with BRCA1 mutations and 445 pairs with BRCA2 mutations.

Comments on the present study:  The large majority of subjects were from Canada, Poland, or the US; in each country, there was a good distribution of non-drinkers and drinkers.  The self-reports of alcohol intake of the women came more than 6 years after the diagnosis of cancer for the cases; previous alcohol consumption was not assessed.  Most drinkers consumed small amounts of alcohol (< 3% consumed 10 or more drinks per week).  Other factors known to relate to breast cancer risk (ethnicity, menopausal status, oral contraceptive use, HRT use, smoking oophorectomy, BMI, and parity) were adjusted for in the analyses. 

As stated in the abstract, for women with a BRCA1 mutation, the OR for breast cancer for consumers of alcohol was 0.82 (95% CI 0.70-0.96) in comparison with non-drinkers, with a significant trend of decreasing risk with increasing drinks per week (p for trend = 0.03).  For women with BRCA2, the odds ratio was 1.00 (95% CI 0.71-01.41) in comparison with non-drinkers.  While there was not a clear dose-response curve for risk according to categories of alcohol intake, the lowest risk was generally among women in the highest alcohol category (≥ 10 drinks/week); however, the numbers of subjects in these categories were small.

The type of alcohol consumed was known for 1,141 case-control pairs.  Among BRCA1 subjects, consumers of wine exclusively had a significantly reduced risk of breast cancer compared with non-drinkers (OR=0.64, CI 0.47-0.87), but this was not seen for consumers of other beverages.  For BRCA2 subjects the OR for breast cancer for exclusive wine drinkers in comparison with non-drinkers was 1.01 (CI 0.61-1.69). 

Previous research on the topic:  Women with BRCA1 or BRCA2 gene mutations are known to be at very increased risk of breast and other cancers1.  However, data on the effects of alcohol on breast cancer risk for women with these mutations are quite limited.  In a previous study based on women less than 50 years old in Australia, Canada, and the USA, McGuire et al2 reported that there was no increase in breast cancer risk from alcohol consumption among women with BRCA1 or BRCA2 mutations.  Those investigators did a case-control comparison between 195 cases and 302 controls with BRCA1 mutations and 128 cases and 179 controls with BRCA2 mutations.  They reported that compared with never users of alcohol, ever users were not at increased risk for breast cancer regardless of whether they were BRCA1 carriers (OR, 1.06; 95% CI, 0.73-1.52) or BRCA2 carriers (OR, 0.66; 95% CI, 0.45-0.97).  There was no evidence for a linear trend in risk with drink-years among BRCA1 carriers (P = 0.5) or BRCA2 carriers (P = 0.4).  Similarly, there was no evidence for a linear trend in risk with increasing rates of alcohol consumption measured as grams daily (P = 0.4 and 0.9 for BRCA1 and BRCA2 carriers, respectively)2.

McGuire et al2 did find that modest alcohol intake (<4 grams daily) was associated with a significant decrease in breast cancer risk among women with the BRCA2 mutation (OR, 0.41; 95% CI, 0.22-0.77).  (This association is different from the reduction associated with wine in the present study3, which was among women with the BRCA1 mutation but not the BRCA2 mutation.)  McGuire et al reported that they “observed no significant differences in risks by type of alcohol (beer, wine, or spirits)”, but detailed data were not provided in that article2

Is there a threshold for alcohol’s effects on breast cancer risk?  For women in general (not just those with a BRCA mutation), a specific threshold level for drinking that may be associated with breast cancer has not been clearly identified.  In a very large study from the US, Li et al4 found there was a significant increase in risk of breast cancer for total alcohol consumption starting at 1-2 drinks/day.  However, to screen for possible underestimation of drinking among persons reporting alcohol in this category, these investigators included in some models a “possible under-reporter” variable, representing persons judged by inference more likely to be under-estimators because they reported heavy intake on another occasion or because they received at any time an in-patient or out-patient diagnosis of an alcohol-related condition.  These authors state, “Among women reporting < 1 drink per day there was an increased breast cancer risk among those suspected of under-reporting, but no such relation among the remainder.  This suggests a risk threshold somewhere in the broad 1–2 drinks/day category, but exactly where cannot be determined”4.

Bessaoud et al5, in a study from Southern France, estimated a threshold for increase in breast cancer risk to be at about 1.5 to 2 drinks/day or more.  They found that frequent (6 or 7 days/week) drinking of any type of beverage did not show an increase in breast cancer risk.  For wine drinkers, these investigators found lower risk of breast cancer for light drinking than for non-drinkers.5

Potential mechanisms:  The reasons that an increase in breast cancer risk was not seen in the present study or others of women with BRCA mutations may relate to the fact that alcohol consumption appears to be more strongly related to ER-positive tumors4.  Previous reports show that the large majority of tumors among BRCA1 mutation carriers are ER-negative6.  Further, the women in both studies on this topic1,3 were young and mainly pre-menopausal.

Differences according to type of beverage:  A potential reduction in risk for consumers of wine has been found in a number of previous studies5,7.  Further, a large number of experimental studies have shown that resveratrol and other polyphenols in wine may block the initiation or growth of breast cancer cells.  In particular, as the authors of the present study describe, “As a phyto-estrogen, resveratrol binds to the estrogen receptor and up-regulates transcription of BRCA1 and BRCA1-associated proteins in human breast cancer cell lines8,9.”  They add that “in mouse models, resveratrol is a potent inhibitor of the initiation and progression of BRCA1 mutant cancer, suggesting that resveratrol may be a potential chemopreventive agent for women with BRCA1 mutations”10.

Summary:  The data from this large study support an earlier report suggesting no increase in breast cancer risk from alcohol intake for women with a BRCA1 or a BRCA2 gene mutation.  In the previous study on this topic2, a slight lowering of breast cancer risk was noted with light drinking among women with a BRCA2 mutation but not among those with a BRCA1 mutation.  In the present study3, a possible reduction in risk of breast cancer was seen for moderately drinking women with a BRCA1 mutation, but not with a BRCA2 mutation.  In this study, the reduction in risk of breast cancer was seen only for wine consumption.  One should not over-interpret epidemiologic data in the absence of identified biologic mechanisms.  However, there have been a very large number of experiments showing that certain polyphenols present in wine actively impede the initiation and growth of cancer cells. 

Overall, current scientific data suggest that alcohol in moderation does not increase risk among women with BRCA mutations and wine may be somewhat protective.  If this is indeed the case and given the high risk associated with these genetic mutations, it would be important to inform women with such mutations that moderate alcohol does not appear to increase their risk of breast cancer. 

References from Forum review:

1.  Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al.  Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117e30.

2.  McGuire V, John EM, Felberg A, Haile RW, Boyd NF, Thomas DC, et al.  No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years.  Cancer Epidemiol Biomarkers Prev 2006;15:1565e7.

3.  Dennis J, Ghadirian P, Little J, et al; the Hereditary Breast Cancer Clinical Study Group.  Alcohol consumption and the risk of breast cancer among BRCA1 and BRCA2 mutation carriers.  The Breast 2010;e-pub xxx:1-5.

4.  Li Y, Baer D, Friedman GD, Udaltsova N, Shim V, Klatsky AL.  Wine, liquor, beer and risk of breast cancer in a large population.  Eur J Cancer 2009;45:843-850.

5.  Bessaoud F, Daurés JP.  Patterns of alcohol (especially wine) consumption and breast cancer risk: A case-control study among a population in southern France.  Ann Epidemiol 2008;18:467-475.

6.  Foulkes WD, Metcalfe K, Sun P, Hanna WM, Lynch HT, Ghadirian P, etal.  Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type.  Clin Cancer Res 2004;10:2029e34.

7.  Zhang SM, Lee IM, Manson JE, Cook NR, Willett WC, Buring JE. Alcohol consumption and breast cancer risk in the Women’s Health Study. Am J Epidemiol 2007;165:667e76.

8.  LeCorre L, Fustier P, Chalabi N, Bignon YJ, Bernard-Gallon D. Effects of resveratrol on the expression of a panel of genes interacting with the BRCA1 oncosuppressor in human breast cell lines.  Clin Chim Acta 2004;344:115e21.

9.  Fustier P, LeCorre L, Chalabi N, Vissac-Sabatier C, Communal Y, Bignon YJ, et al. Resveratrol increases BRCA1 and BRCA2 mRNA expression in breast tumour cell lines.  Br J Cancer 2003;89:168e72

10.  Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis.  Mol Cell 2008;32:11e20.

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Contributions to these comments from the International Scientific Forum on Alcohol Research were from the following:

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

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Francesco Orlandi, MD, Dept. of Gastroenterology, Università degli Studi di Ancona. Italy

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

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

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