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CORK Bibliography: Breast Cancer and Alcohol Use

102 citations. January 1997 to present

Prepared: March 2008

Ballagh SA. Alcohol: The link between hormone replacement and breast cancer risk. Women's Health Issues 9(6): 338-342, 1999. (19 refs.)

Many women avoid or discontinue hormone replacement therapy due to the fear of breast cancer. They have read studies linking hormone use with increased breast cancer incidence. The Link between alcohol use and breast cancer risk, in contrast, is at least as strong as that of hormone replacement therapy (HRT), yet little publicity has reached practicing physicians or patients. A new study by Ginsburg, suggests that women who use hormone replacement therapy experience an elevation in estradiol levels exceeding the ovulatory range (>300 pg/ml) with prolonged elevation for four hours, after consumption of a moderate amount of alcohol (2 to 4 ounces or .07 grams/kg). This provides a plausible explanation for the observation of increased breast cancer among women who drink alcohol regularly and suggests that a synergism between the two products may be possible. All of the epidemiologic data to date would suggest than an exposure threshold exists for hormone therapy or alcohol use. Existing literature was evaluated to identify studies that simultaneously measure alcohol and HRT exposure in relation to breast cancer incidence. Two epidemiologic studies analyzed both exposures together. The adjustment for alcohol intake in HRT users by Kaufman eliminated any breast cancer risk associated with HRT (Relative Risk: 0.9, 95% Confidence Interval: 0.7-1.1). By subdividing the Iowa Women's Health Study Cohort, Gapstur found that breast cancer risk was confined to women who used HRT and reported drinking at least 5 grams of alcohol per day. While more study is appropriate, these data are reminiscent of the link that was ultimately identified between the combination of oral contraceptives and smoking on arterial thrombosis. Alcohol and hormone exposure together may act synergistically to create increased breast cancer risk. Given the prolonged elevation of estradiol levels in women who use hormones and consume moderate amounts of alcohol, new guidelines should be established to counsel women who choose to use HRT. They should be informed about the effect of moderate alcohol intake. More importantly, the women who choose to avoid alcohol while they use hormones can be reassured that there is little evidence to suggest that their risk of breast cancer is increased in any way.

Baumgartner KB; Annegers JF; McPherson RS; Frankowski RF; Gilliland FD; Samet JM. Is alcohol intake associated with breast cancer in Hispanic women? The New Mexico Women's Health Study. Ethnicity & Disease 12(4): 460-469, 2002. (54 refs.)

A New Mexico statewide, bi-ethnic study was conducted to determine whether moderate or heavy alcohol consumption is associated with breast cancer in Hispanic women. Data on alcohol use, medical history, energy intake, and breast cancer risk factors were gathered from women with breast cancer (n = 712) and healthy controls (n = 844) by in-person interview. Analysis of the data showed an association between the highest level of recent alcohol intake and breast cancer risk for postmenopausal Hispanic and non-Hispanic White women. Lower recent alcohol intake was associated with reduced breast cancer risk for non-Hispanic White women. The latter finding was independent of hormone-receptor status and was true for both premenopausal and postmenopausal White women. No trends were found for past alcohol use. It is concluded that alcohol use apparently is not consistently or significantly associated with breast cancer.

Beral V; Hamajima N; Hirose K; Rohan T; Calle EE; Heath CW Jr et al. Alcohol, tobacco and breast cancer: Collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease. British Journal of Cancer 87(11): 1234-1245, 2002. (73 refs.)

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58515 women with invasive breast cancer and 95067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19 - 1.45, P < 0.00001) for an intake of 35 - 44 g per day alcohol, and 1.46 (1.33 - 1.61, P < 0.00001) for greater than or equal to 45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1 % per 10 g per day, P < 0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers= 1.03, 95% CI 0.98 - 1.07, and for current smokers=0.99, 0.92 - 1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.

Boffetta P; Hashibe M. Alcohol and cancer. (review). Lancet Oncology 7(2): 149-156, 2006. (73 refs.)

A causal association has been established between alcohol consumption and cancers of the oral cavity, pharynx, larynx, oesophagus, liver, colon, rectum, and, in women, breast; an association is suspected for cancers of the pancreas and lung. Evidence suggests that the effect of alcohol is modulated by polymorphisms in genes encoding enzymes for ethanol metabolism (eg, alcohol dehydrogenases, aldehyde dehydrogenases, and cytochrome P450 2E1), folate metabolism, and DNA repair. The mechanisms by which alcohol consumption exerts its carcinogenic effect have not been defined fully, although plausible events include: a genotoxic effect of acetaldehyde, the main metabolite of ethanol; increased oestrogen concentration, which is important for breast carcinogenesis; a role as solvent for tobacco carcinogens; production of reactive oxygen species and nitrogen species; and changes in folate metabolism. Alcohol consumption is increasing in many countries and is an important cause of cancer worldwide.

Bosetti C; Altieri A; La Vecchia C. Diet and environmental carcinogenesis in breast/gynecological cancers. Current Opinion in Obstetrics & Gynecology 14(1): 13-18, 2002. (62 refs.)

This paper reviews recent advances (published since 2000) on the relation between diet, other environmental factors and breast and gynecological cancers. Other lifestyle and environmental factors, including alcohol drinking, tobacco smoking, body mass index, physical activity, and the use of anti-inflammatory drugs, are also mentioned. Despite considerable research the issue remains still unsettled. The protective effect of a diet rich in vegetables and fruit, and thus selected (antioxidant) micronutrients, is not consistently reported in various studies. Though alcohol consumption has been implicated in increased risk for breast or gynecological cancer, the possible relationship between fats and breast and female genital tract neoplasms remains unconfirmed. A case-control study in Canada within a cohort of women suggested that elevated alcohol consumption might be associated with an increased risk of breast cancer (Risk Ratio 1.70, 95 percent Confidence Interval 9.97-2.98, for consumption of 50 grams alcohol a day). A population-based case-control study conducted in Germany among women up to the age of 50 years, also found an Odds Ratio of 1.94 (95 percent CI 1.18-3.20) for consumption of 31 grams or more per day of alcohol. The potential benefits of physical activity remains unquantified. Nonetheless, there has been research indicating that physical activity is associated with a reduced risk of breast and gynecological cancers. Alcohol appears to be related to the risk of breast cancer and overweight is associated with post-menopausal breast cancer and is strongly related to the risk of endometrial cancer.

Bowlin SJ; Leske MC; Varma A; Nasca P; Weinstein A; Caplan L. Breast cancer risk and alcohol consumption: Results from a large case-control study. International Journal of Epidemiology 26(5): 915-923, 1997. (28 refs.)

Background. Alcohol use is associated with breast cancer in many epidemiological studies. Most, however, have measured risk from recent consumption patterns, and only a few include analyses for duration of drinking or age that a woman started to drink. The authors studied the effect of these variables, as well as of recent alcohol consumption patterns, on breast cancer risk. Methods. Data from a large case-control study conducted in Long Island, New York from 1 January 1984 to 31 December 1986 were used. A total of 1214 women aged 20-79 years with incident breast cancer were interviewed. A control was selected for each case from driver's license files, and matched on age and county of residence. Alcohol consumption was measured as: ever versus never, grams of alcohol per day, age started drinking, and total years drinking. Results. After adjustment for breast cancer risk factors, the odds ratio for ever versus never drinking was 1.40 (95% confidence interval [CI] 1.09-1.79); odds ratios for >0-5 and greater than or equal to 5 grams of alcohol use per day, as compared to nondrinkers, were 1.29 (95% CI : 1.00-1.65) and 1.46 (95% CI : 1.13-1.89), respectively. Age when drinking began was not related to breast cancer risk, but the greater the total years of drinking, up to 40 years (odds ratio 1.48, 95% CI : 1.13-1.93), the greater the risk. However, when grams per day and duration of drinking were simultaneously included in the multivariate model, duration was not important as a risk factor. This suggests that intensity of drinking may be the important factor for breast cancer risk. After covariate adjustment, risk from alcohol intake did not differ between pre-and postmenopausal women. Conclusions. These data support the belief that alcohol is associated with breast cancer risk.

Bradlow HL; Sepkovic DW. Diet and breast cancer. Annals of the New York Academy of Sciences 963: 247-267, 2002. (132 refs.)

The preponderance of evidence suggests a role for fat and alcohol as risk factors for breast cancer. The role of milk is more controversial with some studies suggesting that milk is a risk factor and others that consumption of milk is protective against breast cancer. No other major nutrient appears to play a significant role in increasing breast cancer risk. On the other hand, there is increasing evidence that a variety of micronutrients and hormones appear to have significant anti-cancer activity. These range from steroids such as dehydroepiandrosterone (DHEA) and its analysis, to indoles, isothiocyanates, and isoflavone derivatives. These compounds act directly by interfering with cyclins and promoting apoptosis as well as indirectly by altering estrogen metabolism in a favorable direction. These effects are not merely theoretical actions in cell culture and tissue explants; they have been demonstrated in human patients in a range of studies.

Brekelmans CTM. Risk factors and risk reduction of breast and ovarian cancer. Current Opinion in Obstetrics & Gynecology 15(1): 63-68, 2003. (61 refs.)

Purpose of review. Breast and ovarian cancer remain a significant burden for women living in the Western world. This paper reviews the risk factors and current strategies to prevent these diseases. Recent findings. Established factors associated with the risk of breast cancer include family history, reproductive factors and lactation, as well as age at menarche and menopause. Hormone replacement therapy increases the risk, whereas oral contraceptives probably confer no increased risk. Alcohol moderately increases the risk, whereas a diet rich in folate and carotenoids might be protective. The role of other dietary factors, smoking and physical exercise remain unclear. Important risk factors for ovarian cancer are reproductive factors and possibly the long-term use of hormone replacement therapy. The risk is decreased by oral contraceptives. In carriers of a BRCA1 or BRCA2 gene mutation, prophylactic surgery can significantly reduce the risk of breast as well as ovarian cancer. Tamoxifen may be considered as a chemopreventive agent in women with a high risk of breast cancer, including carriers of a BRCA2 mutation, but is probably not effective in BRCA1 carriers. Summary. During the period of this review, the importance of several known risk factors was confirmed, whereas the effects of other factors became more clear. Chemoprevention and prophylactic surgery have emerged as preventative options that can reduce the risk of breast and ovarian cancer.

Brienza RS; Stein MD. Alcohol use disorders in primary care: Do gender-specific differences exist? (review). Journal of General Internal Medicine 17(5): 387-397, 2002. (142 refs.)

OBJECTIVE: To describe how alcohol use disorders (AUDs) affect women, focusing on gender-specific Implications for primary care physicians (PCPs). DESIGN: An overview of literature from 1966 to 2000 Identified by a MEDLINE, PsychINFO and HealthSTAR/Ovid Healthstar database search using key words "women," "alcohol" and "alcoholism." MEASUREMENTS AND MAIN RESULTS: Although the prevalence of AUDs is greater in men than in women, women with AUDs are more likely to seek help, but less likely to be identified by their physicians. Psychiatric comorbidities (especially depression and eating disorders) are more common in women with AUDs than in men with AUDs. A past history of sexual and/or physical abuse places a woman at Increased risk for AUDs. Women have a greater sensitivity to alcohol, have an accelerated progression from alcohol toxicity, and have increased mortality at lower levels of consumption compared to men. Women and men who are light-to-moderate drinkers have lower coronary artery disease mortality than do abstainers or heavy drinkers. Risk of breast cancer is increased in women who drink greater than or equal to1 drinks daily. Common barriers to treatment include: fear of abandonment by partner; fear of loss of children; and financial dependency. Brief interventions have been shown to be effective in reduction of alcohol consumption in women with at-risk drinking. It is unclear if women-only treatment programs improve outcomes. CONCLUSION: PCPs should be alert to gender-specific differences for women with AUDs.

Byrne C; Webb PM; Jacobs TW; Peiro G; Schnitt SJ; Connolly JL et al. Alcohol consumption and incidence of benign breast disease. Cancer Epidemiology, Biomarkers & Prevention 11(11): 1369-1374, 2002. (22 refs.)

We evaluated whether moderate alcohol consumption is associated with increased risk of developing benign breast disease (BBD), a potential "precursor" or marker for breast cancer development. This study evaluated associations between reported alcohol consumption and BBD diagnosis among 75,826 women in the Nurses' Health Study II. Between 1989 and 1997, 16,035 women reported a first diagnosis of BBD (317/10,000 person-years), of which 2,999 diagnoses were confirmed by tissue biopsy (59/10,000 person-years). Of the pathology specimens reviewed, 532 were nonproliferative benign breast conditions, and 932 were proliferative conditions. Person-time models provided estimates of the rate ratio (RR) and 95% confidence interval (CI). Reported recent adult consumption of alcohol was not associated with increased BBD incidence. Compared with women who did not drink alcohol, the age- and body mass index (BMI)-adjusted RRs for any reported BBD were 0.98 (95% CI, 0.95-1.02) for those who consumed <5 g/day, 0.93 (95% CI, 0.89-0.98) for those who consumed 5-14.9 g/day, and 0.90 (95% CI, 0.83-0.98) for those who consumed; greater than or equal to15 g/day. The adjusted RRs for biopsy confirmed BBD and any proliferative benign condition were similar. However, reported alcohol consumption of 2:15 g/day between ages 18 and 22 years was associated with higher rates of biopsy-confirmed BBD (age- and body mass index-adjusted RR = 1.14; 95% CI, 1.00-1.30), nonproliferative BBD (RR = 1.46; 95% CI, 1.09-1.96), and any proliferative BBD (RR = 1.33; 95% CI, 1.05-1.69), but not atypical hyperplasia. In this study, recent alcohol consumption was associated with slightly lower rates of reported BBD. However, greater alcohol consumption earlier in life (ages 18-22 years) was associated with higher proliferative BBD rates, suggesting that timing of exposure may be relevant to disease incidence.

Carney CP; Jones LE. The influence of type and severity of mental illness on receipt of screening mammography. Journal of General Internal Medicine 21(10): 1097-1104, 2006. (45 refs.)

BACKGROUND: Women with mental illness may be at risk for failure to receive recommended preventive services such as mammography. Little is known about whether the type or severity of mental illness influences receipt of preventive services. OBJECTIVES: To measure the influence of type and severity of mental illness on receipt of mammography. DESIGN: Retrospective study of administrative claims data, 1996 to 2001. SUBJECTS: Privately insured women age 40 to 64 years, with and without claims for mental illness, and who were eligible for mammography between 1996 and 2001. MEASUREMENTS: Odds ratios (OR) for receipt of screening mammography, any mammography, and follow-up mammography, adjusted for age, rural location, utilization of nonmental health services, and severity and type of the mental disorder. Severity measures were based on utilization of outpatient and inpatient mental health services and presence of comorbid substance use disorder. RESULTS: Women with any mental disorder were significantly less likely to receive mammography than controls. This was strongly influenced by severity of mental illness (any mammography: moderate severity OR 0.62; confidence interval [CI] 0.59 to 0.66: high severity OR 0.38; CI 0.33 to 0.43). Whereas severity contributed to lower receipt of mammography among women with mood and anxiety disorders, women with psychotic, alcohol, and substance abuse disorders had decreased odds for receipt of mammography regardless of severity. CONCLUSIONS: Women with mental disorders are at risk for failure to receive mammography, a recommended preventive service. Women with severe mental illness or psychotic and substance abuse disorders should be targeted to ensure delivery of mammography.

Chen WY; Colditz GA; Rosner B; Hankinson SE; Hunter DJ; Manson JE; Stampfer MJ; Willett WC; Speizer FE. Use of postmenopausal hormones, alcohol, and risk for invasive breast cancer. Annals of Internal Medicine 137(10): 798-804, 2002. (28 refs.)

Background: Physiologic evidence suggests that use of alcohol increases the risk for breast cancer through a hormonal mechanism, but the relationship among breast cancer, alcohol, and postmenopausal hormones (PMH) remains unclear. Objective: To examine the relation between concurrent use of alcohol and PMH and invasive breast cancer. Design: Prospective cohort study Setting: Nurses' Health Study. Participants: 44187 postmenopausal women. Measurements: Self-reported data on PMH use and breast cancer obtained from biennial questionnaires completed from 1980 to 1994 and average alcohol consumption in 1980, 1984, 1986, and 1990. Results: 1722 women developed invasive breast cancer. Risk for breast cancer was elevated in women who currently used PMH for 5 or more years and did not drink alcohol (relative risk, 1.32 [95% CI, 1.05 to 1.66]) and those who never used PMH but drank 20 or more g (1.5 to 2 drinks) of alcohol daily (relative risk, 1.28 [Cl, 0.97 to 1.69]). Current users of PMH for 5 or more years who consumed 20 or more g of alcohol daily had a relative risk for breast cancer nearly twice (1.99 [Cl, 1.42 to 2.79]) that of non-drinking nonusers of PMH. A hypothetical postmenopausal woman whose lifetime risk for breast cancer is 4% could increase her risk to 8% with 5 or more years of current PMH use and consumption of more than one alcoholic drink daily. Conclusions: Both alcohol consumption and PMH use were associated with an increased incidence of breast cancer. Women who are currently taking PMH may want to consider the added risks of regular alcohol consumption.

Choi JY; Abel J; Neuhaus T; Ko Y; Harth V; Hamajima N; Tajima K et al. Role of alcohol and genetic polymorphisms of CYP2E1 and ALDH2 in breast cancer development. Pharmacogenetics 13(2): 67-72, 2003. (13 refs.)

Objective: We examined the potential association between alcohol consumption and genetic polymorphisms in the alcohol metabolizing enzymes, CYP2E1 and ALDH2, in individual susceptibility to breast cancer in a Korean study population. Methods Three hundred and forty-six histologically confirmed breast cancer patients and 377 controls with no present or previous history of cancer were recruited from several teaching hospitals in Seoul during 1995-2001. The CYP2E1 RsaI polymorphism was determined by a real time PCR method, and the ALDH2 Glu(487) Lys polymorphism was determined by a PCR method with confronting two-pair primers (PCR-CTPP). Results The drinking women had a 1.4-fold risk for breast cancer (95% CI = 0.99-2.11) compared to never drinkers after adjustment for age and family history of breast cancer. No statistically significant overall differences were seen in the genotype frequencies between breast cancer cases and controls. However, the 'ever'-drinking women with the CYP2E1 c2 allele containing genotypes had a 1.9-fold risk (95% CI = 0.99-3.83) for developing breast cancer compared to non-drinkers with the CYP2E1 c1/c1 genotype (P for interaction = 0.043). Conclusion This study therefore suggests that the CYP2E1 c2 allele may influence the individual susceptibility to breast cancer in alcohol-consuming women.

Clarke CA; Purdie DM; Glaser SL. Population attributable risk of breast cancer in white women associated with immediately modifiable risk factors. BMC Cancer 6: article 170, 2006. (33 refs.)

Background: Estrogen/progestin replacement therapy (EPRT), alcohol consumption, physical activity, and breast-feeding duration differ from other factors associated with breast cancer in being immediately modifiable by the individual, thereby representing attractive targets for future breast cancer prevention efforts. To justify such efforts, it is vital to quantify the potential population-level impacts on breast cancer considering population variations in behavior prevalence, risk estimate, and baseline incidence. Methods: For each of these four factors, we calculated population attributable risk percents (PARs) using population-based survey ( 2001) and cancer registry data (1998-2002) for 41 subpopulations of white, non-Hispanic California women aged 40-79 years, and ranges of relative risk (RR) estimates from the literature. Results: Using a single RR estimate, subpopulation PARs ranged from 2.5% to 5.6% for hormone use, from 0.0% to 6.1% for recent consumption of >=2 alcoholic drinks daily, and 4.6% to 11.0% for physical inactivity. Using a range of RR estimates, PARs were 2-11% for EPRT use, 1-20% for alcohol consumption and 2-15% for physical inactivity. Subpopulation data were unavailable for breastfeeding, but PARs using published RR estimates ranged from 2% to 11% for lifetime breastfeeding >=31 months. Thus, of 13,019 breast cancers diagnosed annually in California, as many as 1,432 attributable to EPRT use, 2,604 attributable to alcohol consumption, 1,953 attributable to physical inactivity, and 1,432 attributable to never breastfeeding might be avoidable. Conclusion: The relatively feasible lifestyle changes of discontinuing EPRT use, reducing alcohol consumption, increasing physical activity, and lengthening breastfeeding duration could lower population breast cancer incidence substantially.

Dorgan JF; Baer DJ; Albert PS; Judd JT; Brown ED; Corle DK et al. Serum hormones and the alcohol-breast cancer association in postmenopausal women. Journal of the National Cancer Institute 93(9): 710-715, 2001. (61 refs.)

Background: Alcohol ingestion is associated with an increased risk of breast cancer in most epidemiologic studies. Results, however, are heterogeneous at lon er levels of alcohol intake, and a biologic mechanism for the association has not been clearly identified. To determine whether alcohol consumption by postmenopausal women elevates serum levels of hormones associated with an increased risk of breast cancer, we performed a controlled feeding study, Methods: Participants were 51 healthy postmenopausal women not using hormone replacement therapy. Each participant rotated through three 8-week dietary periods in which she consumed 15 or 30 g of alcohol per day or an alcohol-free placebo beverage. The order of assignment to the three alcohol levels was random. During the dietary periods, all food and beverages were supplied by the study, and energy intake mas adjusted to keep body weight constant. Levels of estradiol, estrone. estrone sulfate, testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenediol were measured by radioimmunoassays in serum collected at the end of each dietary period. AII statistical tests are two- sided. Results: When women consumed 15 or 30 g of alcohol per day, respectively, estrone sulfate concentrations increased by 7.5% (95% confidence interval [CI] = -0.3% to 15.9%; P =.06) and 10.7% (95% CI = 2.7% to 19.3%; P =.009) and DHEAS: concentrations increased by: 5.1% (95% CI = 1.4% to 9.0%; P =.008) and 7.5% (95% CI = 3.7% to 11.5%; P<.001) relative to levels when women consumed placebo. None of the other hormones measured changed statistically significantly when women consumed alcohol. Conclusions: Results suggest a possible mechanism by which consumption of one or two alcoholic drinks per day by postmenopausal women could increase their risk of breast cancer.

Public Domain

Dumeaux V; Lund E; Hjartaker A. Use of oral contraceptives, alcohol, and risk for invasive breast cancer. Cancer Epidemiology, Biomarkers & Prevention 13(8): 1302-1307, 2004. (36 refs.)

The aim of our study was to examine how the use of oral contraceptives (OCs) interact with alcohol on breast cancer risk within the large prospective follow-up study, Norwegian Women and Cancer Study. Between 1991 and 1997, women aged 30 to 70 years were drawn at random from the central person register and mailed an invitation. Follow-up information was collected throughout 2001 by linkage to national registries. Only women (n = 86,948) with complete information on alcohol consumption and duration of OC use were included in the present analysis. A total of 1,130 invasive breast cancers were diagnosed during 618,638 person-years of follow-up. Consumption of greater than or equal to10.0 g/d alcohol was associated with a breast cancer relative risk (95% confidence interval) of 1.69 (1.32-2.15), consistent with a linear relationship (P for trend < 0.0001). Among alcohol consumers, an excess risk of breast cancer was observed for total duration of OC use only among women who consumed <5 g/d alcohol (P for trend = 0.0009). We observed a negative interaction between duration of OC use and alcohol consumption effects (P for interaction = 0.01). After stratification on menopausal status, the association between high alcohol intake and breast cancer was more prominent among postmenopausal women than among premenopausal women (P for heterogeneity = 0.01). No interaction between alcohol and duration of OC use were significant after stratification on menopausal status. Our findings in conjunction with biological data imply that alcohol and OCs have antagonistic effects on breast cancer risk through a common pathway. Whether the interactive effect differs according to menopausal status remains unclear and needs further investigations.

Ebrahim SH; Anderson AL; Floyd RL. Alcohol consumption by reproductive-aged women in the USA: An update on assessment, burden and prevention in the 1990s. (review). Prenatal and Neonatal Care 4(6): 419-430, 1999. (80 refs.)

Because of alcohol's effects on maternal, fetal and child health, the public health implications of alcohol abuse by women are potentially greater than those of alcohol abuse by men. This report provides a summary of developments in the field of alcohol use and women's health in the 1990s. During the 1990s, the prevalence of alcohol consumption, including binge drinking, appears to have increased among pregnant women, whereas there was little change among non-pregnant women of childbearing age. The prevalence of alcohol use among women under 21 years of age, for whom alcohol should be inaccessible, is equal to or greater than that in older age groups. Adverse effects have been detected among pregnant women who consume more than three drinks per week on average. Alcohol may impair fertility and increase the risk for breast cancer. The national burden from all effects of alcohol on women's health has not been assessed. The available brief screening instruments to detect alcohol use do not detect moderate alcohol consumption or binge drinking by pregnant women. Brief primary care clinic-based behavioral interventions and some medications have been shown to decrease alcohol use and subsequent problems among women who are problem drinkers. To prevent alcohol-exposed pregnancies, researchers need to study the feasibility of these interventions for pregnant women including moderate drinkers, as well as interventions that enhance the use of contraception among women who misuse alcohol and are at risk for pregnancy. Attempts to reduce alcohol-exposed pregnancies should begin prior to conception. Primary care providers for women, including obstetricians, general practitioners, family planning advisers and school health-care providers can play an important role in the prevention of all adverse effects of alcohol consumption by women.

Ellison RC; Zhang YQ; McLennan CE; Rothman KJ. Exploring the relation of alcohol consumption to risk of breast cancer. American Journal of Epidemiology 154(8): 740-747, 2001. (100 refs.)

There are lingering questions regarding the relation between alcohol consumption and breast cancer risk in women. The authors performed a meta-analysis of epidemiologic studies carried out through 1999 to examine the dose-response relation and to assess whether effect estimates differed according to various study characteristics. Overall, there was a monotonic increase in the relative risk of breast cancer with alcohol consumption, but the magnitude of the effect was small; in comparison with nondrinkers, women averaging 12 g/day of alcohol consumption (approximately one typical drink) had a relative risk of 1.10 (95% confidence interval (Cl): 1.06, 1.14). Estimates of relative risk were 7% greater in hospital-based case- control studies than in cohort studies or community-based case- control studies, 3% greater in studies published before 1990 than in studies published later, and 5% greater in studies conducted outside of the United States than in US studies. The findings of five US cohort studies published since 1990 yielded a relative risk of 1.06 (95% Cl: 1.00, 1.11) for consumers of 12 g/day, as compared with nondrinkers. Cohort studies with less than 10 years of follow-up gave estimates 11% higher than cohort studies with longer follow-up periods. No meaningful difference was seen by menopausal status or type of beverage consumed.

Enger SM; Ross RK; Paganini-Hill A; Longnecker MP; Bernstein L. Alcohol consumption and breast cancer oestrogen and progesterone receptor status. British Journal of Cancer 79(7-8): 1308-1314, 1999. (26 refs.)

We examined the role of alcohol on the risk of breast cancer by the joint oestrogen receptor (ER) and progesterone receptor (PR) status or the tumour using data from two case-control studies conducted in Los Angeles County, USA. Eligible premenopausal patients were 733 women aged less than or equal to 40 years and first diagnosed from 1 July 1983 to 1 January 1989. Eligible postmenopausal patients were 1169 women aged 55-64 years and first diagnosed from 1 March 1987 to 31 December 89. Patients were identified by the University of Southern California Cancer Surveillance Program. Neighbourhood controls were individually matched to patients by parity (premenopausal patients) and birth date (+/- 3 years). ER and PR status were obtained from medical records for 424 premenopausal and 760 postmenopausal patients. The analyses included 714 premenopausal and 1091 postmenopausal control subjects. Alcohol use was generally not associated with premenopausal risk of breast cancer, regardless of hormone-receptor status. Among the postmenopausal women, those who consumed, on average, greater than or equal to 27 g of alcohol/d experienced an odds ratio (OR) of 1.76 [95% confidence interval (CI) 1.14-2.71] for ER-positive/PR-positive breast cancer relative to women who reported no alcohol consumption. Alcohol use was less clearly associated with risk of other receptor types among postmenopausal women. These data suggest that alcohol may preferentially increase risk of ER-positive/PR-positive breast cancer in postmenopausal women.

Fan SJ; Meng QH; Gao B; Grossman J; Yadegari M; Goldberg ID; Rosen EM. Alcohol stimulates estrogen receptor signaling in human breast cancer cell lines. Cancer Research 60(20): 5635-5639, 2000. (26 refs.)

Epidemiological studies suggest that moderate alcohol consumption increases the risk of breast cancer, and that alcohol combined with estrogen replacement therapy may synergistically enhance the risk, However, the mechanism(s) of alcohol-induced mammary cancer is unknown. In human breast cancer cell lines, we found that ethanol (EtOH) caused a dose-dependent increase of up to 10- to 15-fold in the transcriptional activity of the liganded estrogen receptor (ER- alpha), but did not activate the nonliganded receptor. Significant stimulation of ER-alpha activity was observed at EtOH concentrations comparable with or less than blood alcohol levels associated with intoxication and at doses below the threshold for ill vitro cytotoxicity. These findings may be explained, in part, by an EtOH- induced down-regulation of the expression of BRCA1, a potent inhibitor of ER-alpha activity, and, in part, by a modest increase in the ER-alpha levels. Our findings suggest that inactivation of BRCA1 and increased estrogen-responsiveness might contribute to alcohol-induced breast cancer.

Feigelson HS; Calle EE; Robertson AS; Wingo PA; Thun MJ. Alcohol consumption increases the risk of fatal breast cancer (United States). Cancer Causes and Control 12(10): 895-902, 2001. (29 refs.)

Objective: To investigate the hypothesis that alcohol consumption increases the risk of breast cancer mortality. Methods: We examined breast cancer mortality in relation to self- reported alcohol consumption in women from the American Cancer Society Cancer Prevention Study (CPS)-II. After 14. years of follow-up, 1,442 eligible breast cancer deaths were observed among 242,010 women. Cox proportional hazards models were constructed for total alcohol consumption and for beer, wine, and liquor separately. Results: Total alcohol consumption was associated with increased risk of fatal breast cancer among post- but not pre- or perimenopausal women. Even less than one drink/day was associated with up to a 30% increase in breast cancer mortality among postmenopausal women compared to non-drinkers (RR = 1.3, 95% CL 1.1-1.6 for women drinking 0.26- <1 drink/day). When examined separately, consumption of beer, wine, and liquor each increased the risk of breast cancer among postmenopausal women. We found no evidence that alcohol consumption was more deleterious among women at high risk for breast cancer compared to average-risk women. Conclusion: This study adds to the evidence that postmenopausal women can reduce their risk of breast cancer by avoiding or minimizing their use of alcohol.

Feigelson HS; Jonas CR; Robertson AS; McCullough ML; Thun MJ; Calle EE. Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiology, Biomarkers & Prevention 12(2): 161-164,, 2003. (19 refs.)

The relationship between risk of breast cancer and alcohol consumption was studied with a focus on the protective effects of adequate folate intake. The research sample included 66,561 postmenopausal women in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Cox proportional hazards models and stratified analysis were used to examine the relationship between alcohol, dietary and total folate intake, multivitamin use, dietary methionine, and breast cancer. The following results of the study were seen: (1) a total of 1,303 incident cases of breast cancer occurred during the first 5 years of follow-up; (2) an increasing risk of breast cancer with increasing alcohol consumption; (3) in the highest category of consumption (15 or more grams of ethanol/day) a risk of breast cancer of 1.26 compared with nonusers; (4) observation of this association with higher alcohol consumption for in situ, localized, and regional disease; (5) no association between risk of breast cancer and dietary folate, total folate, multivitamin use, or methionine intake; (6) no evidence of an interaction between levels of dietary folate or total folate and alcohol; and (7) no evidence of an interaction between alcohol consumption and recent or long-term multivitamin use. It is concluded that the results support a positive association with alcohol but do not support an association with folate or methionine intake or an interaction between folate and alcohol intake on risk of breast cancer.

Ferraroni M; Decarli A; Franceschi S; La Vecchia C. Alcohol consumption and risk of breast cancer: A multicentre Italian case-control study. European Journal of Cancer 34(9): 1403-1409, 1998. (42 refs.)

The relationship between alcohol consumption and breast cancer risk was investigated using data from a co-operative case-control study conducted in Italy between 1991 and 1994 on 2569 incident, histologically confirmed breast cancer cases and 2588 controls in hospital for acute, non-neoplastic, non-hormone related conditions. Overall, 915 (38%) cases and 1048 (43%) controls were abstainers. Compared with them, the odds ratio (OR), adjusted only for age, was 1.31 (95% confidence interval (CI) 1.13-1.53) for drinkers and became 1.39 (95% CI 1.(1)21-1.60) after correction for measurement error. The multivariate OR was 1.21 for drinkers of less than or equal to 5.87 g/day and 1.23, 1.19, 1.21, 1.41 for drinkers of 5.88-13.40, 13.41-24.55, 24.56-27.60, >27.60g/day, respectively. The trend in risk was significant (chi(2) = 12.28, P< 0.0005). The association was apparently stronger in premenopausal women (OR = 1.80 for >27.60g/day). Considering the different types of alcoholic beverages (wine, beer, digestives, grappa and other spirits), a significant direct trend in breast cancer risk was seen for wine with an OR of 1.27 (95% CI 1.06-1.53) for the category >26.34g/day. The ORs were also above unity for beer, grappa, digestives and spirits drinkers. No appreciable interaction was observed between alcohol drinking and body mass index, smoking, or any other covariate considered. Thus, the present data, based on a validated alcohol consumption questionnaire and on a population characterised by a relatively high alcohol consumption in women, confirmed that alcohol drinking is moderately related to breast cancer risk. If causal, this association could explain 12% (95% CI, 5-19%) of breast cancers in Italy, thus representing one of the major avoidable risk factor for breast cancer.

Fredman L; Sexton M; Cui YD; Althuis M; Wehren L; Hornbeck P; Kanarek N. Cigarette smoking, alcohol consumption, and screening mammography among women ages 50 and older. Preventive Medicine 28(4): 407-417, 1999. (36 refs.)

Background. The associations among cigarette smoking and alcohol consumption with recent screening mammograms were evaluated among women ages 50 years and older. Methods. The sample included 946 white and African-American women ages 50 years and older from the 1995 Maryland Behavioral Risk Factor Survey. Bivariate and logistic regression analyses were performed to evaluate the associations between current cigarette smoking and alcohol consumption in the past month (none, 1-7 drinks, >7 drinks) with obtaining a screening mammogram in the past 2 years (recent mammogram), controlling for sociodemographic and health variables. Results. Seventy-eight percent of respondents had recent mammograms, 15% smoked cigarettes, 18% reported 1-7 drinks, and 12% reported >7 drinks in the past month. Smokers had lower mammography rates than nonsmokers (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.30-0.75). Women who drank alcoholic beverages had higher mammography rates than nondrinkers (OR = 1.37, 95% CI = 1.03-1.83). Smokers had the lowest mammography rates, regardless of their consumption of alcohol. An interaction was observed among white but not African-American women: nonsmokers who consumed moderate amounts of alcohol (1-7 drinks) had the highest mammography rates in this subgroup. Conclusions. To reduce breast cancer mortality, it is important to increase screening mammography among all women over age 50 and especially among smokers and the oldest women.

Freudenheim J. Lifetime Alcohol Exposure and Breast Cancer Risk. Fort Detrick MD: US Army Medical Research and Materiel Command, 2001. (6 refs.)

This is one of three reports provided to the U.S. Army that funded this research. This is a case-control study was an examination of breast cancer risk in relation to lifetime alcohol consumption. We interviewed 1,181 women with breast cancer (295 pre- and 886 post-menopausal women), age 35-79, from Erie and Niagara counties in New York State, all with incident, pathologically confirmed breast cancer. A total of 2,181 controls were interviewed; controls were randomly selected and frequency matched to cases on age, race and county of residence. Participants complete a computerized interview, which focused on in-depth lifetime alcohol consumption history. Potential confounding factors were also assessed. A specimen bank is being used to store biological samples for future research of serum and urinary markers of hormones, hormone metabolites, vitamins, genetic polymorphisms and blood levels of antioxidants and oxidative stress. At the completion of the study, 969 blood samples were stored for cases and 2,016 for controls. Data collection has been completed. Some data analysis has been completed as well and preliminary findings are included. Data analysis will continue to utilize this excellent resource.

Public Domain

Freudenheim JL; Bonner M; Krishnan S; Ambrosone CB; Graham S; McCann SE et al. Diet and alcohol consumption in relation to p53 mutations in breast tumors. Carcinogenesis 25(6): 931-939, 2004. (59 refs.)

There is evidence linking alcohol consumption to p53 mutations in tumors, considerable evidence linking alcohol consumption with risk of breast cancer and some evidence that alcohol and folate consumption interact to affect risk. Further, while there is some indication that oxidation may play a role in breast cancer etiology, there has been little examination of an association of oxidative stress with p53 mutations. We examined several dietary components related to one-carbon metabolism and antioxidants to determine if these factors were related to the prevalence of p53 mutations in breast tumors. We conducted a case-control study of primary, histologically confirmed breast cancer in western New York. Controls <65 were selected from drivers license lists; those greater than or equal to65 were selected from Health Care Finance Administration lists. p53 mutations in archived tumor blocks were identified in exons 2-11 and flanking intron sequences. Usual dietary intake was assessed by interview regarding intake in the previous 2 years; alcohol consumption was queried for 2, 10 and 20 years in the past. Our data were consistent with increased likelihood of tumors with p53 mutations for premenopausal breast cancer with increased alcohol intake 10 or 20 years previous; for intake of 16 or more drinks per month in the period 20 years before the interview compared with non-drinkers, the OR was 5.25, 95% CI 1.48-18.58. For postmenopausal women, there was increased likelihood of tumors with p53 mutations among women with higher folate. Antioxidant nutrients were not differentially related to p53 mutations. These results indicate that there may be heterogeneity in breast tumors, as indicated by differences in associations for those with or without p53 mutations, and that causal pathways for these nutrients may vary for pre- and postmenopausal women. For premenopausal women, alcohol consumption in the past was associated with p53 mutations.

Furberg AS; Veierod MB; Wilsgaard T; Bernstein L; Thune I. Serum high-density lipoprotein cholesterol, metabolic profile, and breast cancer risk. Journal of the National Cancer Institute 96(15): 1152-1160, 2004. (48 refs.)

Background: The prevalence of metabolic syndrome (obesity, glucose intolerance, low serum high-density lipoprotein cholesterol [HDL-C], high serum triglycerides, hypertension) is high and increasing in parallel with an increasing breast cancer incidence worldwide. HDL-C represents an important aspect of the syndrome, yet its role in breast cancer is still undefined. Methods: In two population-based screening surveys during 1977-1983 and 1985-1987, serum HDL-C was assayed enzymatically among 38 823 Norwegian women aged 17-54 years at entry. Height, weight, blood pressure, serum lipids, fat and energy intake, physical activity, parity, oral contraceptive use, hormone therapy use, alcohol intake, and tobacco use were also assessed. We used Cox proportional hazards modeling to estimate the relative risk (RR) of breast cancer associated with serum HDL-C levels and to adjust for potential confounding variables. We performed stratified analyses to evaluate effect modification by body mass index (BMI) and menopausal status. All statistical tests were two-sided. Results: During a median follow-up of 17.2 years, we identified 708 cases of invasive breast cancer. In multivariable analysis, the risk of postmenopausal breast cancer was inversely related to quartile of HDL-C (P-trend = .02). Among women with HDL-C above 1.64 mmol/L (highest quartile) versus below 1.20 mmol/L (lowest quartile), the relative risk was 0.75 (95% confidence interval [CI] = 0.58 to 0.97). The HDL-C association was confined to women in the heavier subgroup (BMI greater than or equal to25 kg/m(2)), for whom the relative risk of postmenopausal breast cancer in those with HDL-C above 1.64 mmol/L versus below 1.20 mmol/L was 0.43 (95% CI = 0.28 to 0.67; P-trend < .001; P-interaction = .001). Conclusion: Low HDL-C, as part of the metabolic syndrome, is associated with increased postmenopausal ;breast cancer risk.

Garland M; Hunter DJ; Colditz GA; Spiegelman DL; Manson JE; Stampfer MJ; Willett WC. Alcohol consumption in relation to breast cancer risk in a cohort of United States women 25-42 years of age. Cancer Epidemiology, Biomarkers & Prevention 8(11): 1017-1021, 1999. (17 refs.)

We evaluated current and past alcohol consumption prospectively in relation to breast cancer risk among 116,671 women ages 25-42 years old at enrollment in 1989. During 6 years of follow-up, 445 cases of invasive breast cancer were identified. For alcohol consumption in the previous year, the multivariate relative risk associated with more than 20 g/day (approximately 10 drinks/week) was 1.23 (95% confidence interval, 0.68-2.21); the P for trend was 0.85. For average lifetime alcohol consumption, the multivariate relative risk associated with consumption of 10 or more drinks/week was 1.20 (95% confidence interval, 0.69-2.11); the P for trend was 0.18. We examined drinking in several time periods of life; only drinking at ages 23-30 was significantly positively associated with risk. Although this may represent a chance finding, it merits further study. Because drinking levels in this population were low, we had limited information on heavier drinking. Our results suggest that there is unlikely to be a large effect of moderate alcohol consumption on breast cancer risk among young women, although a modest effect cannot be excluded. The association between alcohol consumption and breast cancer is unlikely to be substantially stronger among premenopausal women than among postmenopausal women.

Gavaler JS; Deal SR; Rosenblum ER. Directions for unraveling the issue of alcohol and health disparities: Findings from the Postmenopausal Health Disparities Study. Alcohol 32(1): 69-75, 2004. (46 refs.)

The Postmenopausal Health Disparities Study (PHD Study) is a model for unraveling the underlying factors that may play a role in the health status and life expectancy disparities among racial and ethnic groups, with particular attention to effects of alcoholic beverage consumption. The study is bioepidemiologic; underlying mechanisms, rather than end points per se, are evaluated. The design is cross-sectional with historical prospective elements. Data were collected from responses to three questionnaires and examination findings from a clinic visit. There were significant differences among racial and ethnic groups in patterns of alcoholic beverage consumption and selected demographic factors, body mass index, measures of physical activity and fitness, and nutritional factors. Predictors of body mass index included both moderate drinking and hormonal factors. To address the current controversy about risks and benefits of hormone replacement therapy (HRT) we examined the predictors of control-based categories of estradiol among treated women; predictors included drinking of alcohol, hormonal variables, and being Caucasian. In addition, a substantial proportion of the variables examined differed significantly between alcohol drinkers and abstainers. The significant differences between alcohol drinkers and abstainers, and among racial and ethnic groups, demonstrate the value of studying multiple racial and ethnic groups simultaneously. The PHD Study provides a unique and productive model that can be used in other populations.

Gerber B; Muller H; Reimer T; Krause A; Friese K. Nutrition and lifestyle factors on the risk of developing breast cancer. (review). Breast Cancer Research and Treatment 79(2): 265-276, 2003. (135 refs.)

Aspects of nutrition and lifestyle may be largely responsible for the development of common cancers in Western countries, as indicated by the large differences in breast cancer rates between countries, the striking changes in these rates among migrating populations, and the rapid changes over time within countries. The better informed and increasingly health-conscious population of the present day are intensively seeking to identify and eliminate these putative carcinogenic risk factors and to exploit the preventive effects that have been attributed to certain dietary components. Nutrition and 'lifestyle' may exert its carcinogenic effects indirectly by cell stimulations (alcohol, hormone therapy in postmenopause), inhibition of DNA-repair mechanisms (lack of vitamins), effecting estrogen metabolism (phytoestrogenes), or as promotors to enhance growth of tumours (body mass index). Some 'substances' may act as a carcinogenic itself, for example, aromatic hydrocarbons in tobacco or increased polycyclic aromatic hydrocarbons in well done meat. Individual differences in the effects of nutritional factors on mammary epithelia could be caused by genetic polymorphisms. In this critical review, we focus on current data regarding the effect of nutrition and lifestyle, on the risk of developing breast cancer. A health lifestyle, consisting of 'healthy diet', physical activity, renunciation of stimulants, is recommended from childhood throughout life.

Gomes ALRR; Guimaraes MDC; Gomes CC; Chaves IG; Gobbi H; Camargos AF. Risk factors for breast cancer among pre- or post-menopausal women in Belo Horizonte, Brazil. Gynecologic and Obstetric Investigation 52(3): 173-179, 2001. (33 refs.)

Although breast cancer is an important cause of death among women in Brazil, few studies have compared risk factors in premenopausal and postmenopausal breast cancer. This case-control study examined whether selected socioeconomic and reproductive risk factors for breast cancer differed between pre-menopausal and post-menopausal women. The cases were women (n = 300) with breast carcinoma. The controls were women (n = 600) with other benign diseases matched for age and date of diagnosis who were admitted to the same hospital during the same period as the cases (1978-1987). Univariate and multivariate conditional logistic regression analyses were performed. Multivariate analysis revealed no differences in breast cancer risk in pre- and post-menopausal women (risk factors were similar in direction and magnitude). Both groups had similar associations with occupation, irregular menstrual cycles, parity, history of breast cancer in at least one first-degree female relative, oral contraceptive use, and alcohol use. The results indicate that risk profiles are similar in pre- and postmenopausal breast cancer.

Guenel P; Cyr D; Sabroe S; Lynge E; Merletti F; Ahrens W et al. Alcohol drinking may increase risk of breast cancer in men: A European population-based case-control study. Cancer Causes and Control 15(5): 571-580, 2004. (29 refs.)

Objective: It has been estimated that alcohol drinking increases the risk of breast cancer in women by approximately 7% for each increment of 10 g alcohol per day. However, the few studies conducted on breast cancer among men have failed to detect an association with quantitative measures of alcohol drinking, even if the alcohol intake is generally higher in men than in women. On the other hand, increased risks of male breast cancer were inconsistently reported in alcoholics or patients with liver cirrhosis. We have investigated the role of alcohol drinking in male breast cancer using data collected in a population-based case-control study on seven rare cancers, conducted in Denmark, France, Germany, Italy, and Sweden. Methods: The cases were 74 histologically verified male breast cancer patients aged 35-70 years. The controls (n = 1432) selected from population registers, and frequency-matched to the cases by age group and geographic area. To check for consistency, a separate analysis was conducted using as controls the patients with a rare cancer other than the breast recruited simultaneously in the European study (n = 519 men). Results: Based on population controls, the risk of developing breast cancer in men increased by 16% (95% CI: 7-26%) per 10, g alcohol/day (p < 0.001). An odds ratio of 5.89 (95% CI: 2.21-15.69) was observed for alcohol intake greater than 90 g per day, as compared with light consumers (< 15 g per day). Similar associations were observed when other rare cancers patients were used as controls. Conclusion: We found that the relative risk of breast cancer in men is comparable to that in women for alcohol intakes below 60 g per day. It continues to increase at high consumption levels not usually studied in women.

Holmes MD; Willett WC. Does diet affect breast cancer risk? (review). Breast Cancer Research 6(4): 170-178, 2004. (103 refs.)

The role of specific dietary factors in breast cancer causation is not completely resolved. Results from prospective studies do not support the concept that fat intake in middle life has a major relation to breast cancer risk. However, weight gain in middle life contributes substantially to breast cancer risk. Alcohol is the best established dietary risk factor, probably by increasing endogenous estrogen levels. Hypotheses relating diet during youth to risk decades later will be difficult to test. Nevertheless, available evidence is strong that breast cancer risk can be reduced by avoiding weight gain during adult years, and by limiting alcohol consumption.

Horn-Ross PL; Canchola AJ; West DW; Stewart SL; Bernstein L; Deapen D et al. Patterns of alcohol consumption and breast cancer risk in the California Teachers Study cohort. Cancer Epidemiology, Biomarkers & Prevention 13(3): 405-411, 2004. (19 refs.)

Alcohol consumption of approximately two drinks or more per day has been associated with elevated breast cancer risk in the California Teachers Study cohort as well as in many other populations. The objective of this analysis is to examine effects of age at drinking and drinking patterns and to identify effect modifiers. Of the 103,460 at-risk cohort members, age <85, who resided in California and completed the baseline alcohol assessment, 1,742 were diagnosed with invasive breast cancer after joining the cohort and before January 2001. Incident breast cancers were identified through the California Cancer Registry and follow-up for death and confirmation of continued California residence used various sources. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RRs). Elevated breast cancer risk was most evident for recent drinking [RR = 1.28, 95% confidence interval (CI): 1.06-1.54 for >20 g/day versus nondrinkers], with no clear pattern for consumption during earlier periods of life. This elevation in risk was 32% among postmenopausal women (95% CI: 1.061.63) and 21% among pre/perimenopausal women (95% CI: 0.76-1.92). Highest risks associated with heavy alcohol consumption were observed among postmenopausal women with a history of biopsy-diagnosed benign breast disease (RR = 1.97, 95% Cl: 1.39-2.79 compared to nondrinkers without benign breast disease) or who had used combination hormone replacement therapy (HRT) (RR = 2.24, 95% CI: 1.59-3.14 compared to nondrinkers who never used HRT). Recent alcohol consumption equivalent to two or more drinks per day increases the risk of invasive breast cancer, with the greatest RRs observed among heavy drinkers who are also postmenopausal and have a history of benign breast disease or who use HRT.

Horn-Ross PL; Hoggatt KJ; West DW; Krone MR; Stewart SL; Anton-Culver H et al. Recent diet and breast cancer risk: The California Teachers Study (USA). Cancer Causes and Control 13(5): 407-415, 2002. (41 refs.)

Objective: The impact, if any, on breast cancer risk of modifying adult dietary intake is an area of much interest. We take the opportunity to address the relationship between recent adult diet and breast cancer risk during the first two years of follow-up of the large California Teachers Study cohort. Methods: Of the 111,526 at-risk cohort members who resided in California and completed a baseline dietary assessment, 711 were diagnosed with invasive breast cancer after joining the cohort and before January 1998. Average daily nutrient intake was computed based on a food-frequency questionnaire assessing usual dietary intake and portion size during the year prior to joining the cohort. Incident breast cancers were identified through the California Cancer Registry and follow-up for death and confirmation of continued California residence utilized a variety of data sources. Cox proportional hazards models were used to calculate relative hazards. Results: The following components of recent dietary intake were not associated with breast cancer risk: energy, fat, fiber, antioxidant vitamins, and phytoestrogens. Only recent average alcohol consumption of 20 or more grams per day (approximately two or more glasses of wine) was associated with increased risk (RR = 1.5, 95% CI: 1.2-2.0 compared to non-drinkers; p(trend) = 0.01 across quintiles). Conclusion: With the exception of alcohol consumption, this study provides no evidence that recent macro- or micronutrient composition of adult diet is likely to have a direct effect on breast cancer risk. Some reduction of alcohol consumption among those consuming more than one drink per day may be beneficial.

Izevbigie EB; Ekunwe SI; Jordan J; Howard CB. Ethanol modulates the growth of human breast cancer cells in vitro. Experimental Biology and Medicine 227(4): 260-265, 2002. (36 refs.)

The role of ethanol or its metabolites on breast neoplasm has not been characterized. We hypothesized that ethanol may alter the growth rate of human breast tumor epithelial cells by modulating putative growth-promoting signaling pathways such as p44/42 mitogen-activated protein kinases (MAPKs). The MCF-7 cell line, considered a suitable model, was used in these studies to investigate the effects of ethanol on [H-3]thymidine incorporation, cell number, and p44/42 MAPK activities in the presence or absence of a MAPK or extracellular signal-regulated kinase ERK-1, and (MEK1) inhibitor (PD098059). Treatment of MCF-7 cells with a physiologically relevant concentration of ethanol (0.3% or 65 mM) increased p44/42 activities by an average of 400% (P < 0.02), and subsequent cell growth by 200% (P < 0.05) in a MEK1 inhibitor (PD098059)-sensitive fashion, thus suggesting that the Ras/MEK/MAPK signaling pathways are crucial for ethanol-induced MCF-7 cell growth.

Jain MG; Ferrence RG; Rehm JT; Bondy SJ; Rohan TE; Ashley MJ; Cohen JE; Miller AB. Alcohol and breast cancer mortality in a cohort study. Breast Cancer Research and Treatment 64(2): 201-209, 2000. (28 refs.)

Available epidemiological evidence indicates that alcohol intake is associated with a higher risk of developing breast cancer. Plausible biological pathways include its effect on levels of estrogens, cell membrane integrity and cell-to-cell communication, inhibition of DNA repair, and congener effect. The present study evaluated the impact of alcohol on mortality from breast cancer, an area with relatively few studies in the literature. The subjects were participants in a Canadian prospective cohort study, the National Breast Screening Study (NBSS). Women were enrolled in the cohort from 1980 to 1985 to evaluate the efficacy of mammographic screening. Information on usual diet and alcohol intake at enrolment and other epidemiological variables was collected by means of a mailed, self-administered questionnaire. Mortality from breast cancer during follow- up to 31 December, 1993 was ascertained by record linkage to the Canadian Mortality Data Base maintained by Statistics Canada. During the follow-up period of 1980-1993 (average 10.3 years), 223 deaths from breast cancer were identified for this analysis. The hazard ratios for the risk of death from breast cancer increased with intakes of total alcohol of 10-20 g/day (1.039, 1.009-1.071) and > 20 g/day (1.063, 1.029-1.098). This increase was contributed largely by the intake of wine, a 15% increase in risk at intakes higher than 10 g/day of alcohol from wine. Alcohol from spirits was associated with a small decrease in risk of death (hazard ratio at 10 g/day, 0.945, 0.915-0.976). The effect of alcohol from beer was not significant in the two categories studied. Although our results were statistically significant, the magnitude of the change in risk was small.

Janssens JP; Shapira N; Debeuf P; Michiels L; Putman R; Bruckers L et al. Effects of soft drink and table beer consumption on insulin response in normal teenagers and carbohydrate drink in youngsters. European Journal of Cancer Prevention 8(4): 289-295, 1999. (37 refs.)

There is ample evidence that breast cancer susceptibility is induced during the developmental stages of the human breast where, in a manner related to sex-steroid hormones, insulin plays an important role. In turn, nutrition might be implicated. Regular soft drinks and table beer, both carbohydrate-containing drinks, are candidates affecting insulin concentrations. Eleven teenagers, between the ages of 13 and 17 years, consumed a soft drink and a table beer in a crossover study. The blood levels of insulin and glucose were related to antropomorphometric and endocrine factors. In contrast to table beer, consumption of regular soft drinks induced a fast and dramatic increase in both glucose and insulin concentration within a maximum 1/2 hour after consumption. The insulin response was linearly correlated to the body mass index (BMI). Children with a small increase in BMI are highly sensitive to regular soft drinks with regard to glucose and insulin response. The finding suggests a vicious circle of high caloric drinks, increase in BMP and insulin response. It is one of the nutritional pathways which might affect susceptibility for breast cancer in youngsters. Table beer, a drink with fermented sugars, does not share these effects on carbohydrate metabolism.

Key J; Hodgson S; Omar RZ; Jensen TK; Thompson SG; Boobis AR et al. Meta-analysis of studies of alcohol and breast cancer with consideration of the methodological issues. Cancer Causes and Control 17(6): 759-770, 2006. (38 refs.)

Objective: To give an up-to-date assessment of the association of alcohol with female breast cancer, addressing methodological issues and shortfalls in previous overviews. Methods: Meta-analysis of studies (any language) providing original data on incidence of first primary breast cancer and alcohol. Two reviewers independently extracted data. Study quality assessed by objective criteria including degree of control for confounding; funnel plots examined for publication bias; meta-regression techniques to explore heterogeneity. Risks associated with drinking versus not drinking and dose-response not constrained through the origin estimated using random effects methods. Results: Ninety-eight unique studies were included, involving 75,728 and 60,653 cases in drinker versus non-drinker and dose-response analyses, respectively. Findings were robust to study design and analytic approaches in the meta-analyses. For studies judged high quality, controlled for appropriate confounders, excess risk associated with alcohol drinking was 22% (95% CI: 9-37%); each additional 10 g ethanol/day was associated with risk higher by 10% (95% CI: 5-15%). There was no evidence of publication bias. Risk did not differ significantly by beverage type or menopausal status. Estimated population attributable risks were 1.6 and 6.0% in USA and UK, respectively. Conclusions: Taking account of shortcomings in the study base and methodological concerns, we confirm the alcohol-breast cancer association. We compared our results to those of an individual patient data analysis, with similar findings. We conclude that the association between alcohol and breast cancer may be causal.

Key TJ; Allen NE; Spencer EA; Travis RC. Nutrition and breast cancer. Breast 12(6): 412-416, 2003. (47 refs.)

The major risk factors for breast cancer are hormone-related, and the only well-established diet-related risk factors for breast cancer are obesity and alcohol consumption. Obesity increases breast cancer risk in postmenopausal women by around 30%, probably by increasing serum concentrations of bioavailable oestradiol. Moderate alcohol intakes increase breast cancer risk by about 7% per alcoholic drink per day, perhaps also by increasing oestrogen levels. Populations with high fat intakes generally have high rates of breast cancer, but studies of individual women have not confirmed an association of high fat diets with breast cancer risk. Phyto-oestrogens can affect hormone metabolism, but data on phyto-oestrogen consumption and breast cancer risk are inconsistent. Nutrition might affect breast cancer risk by altering levels of growth factors such as insulin-like growth factor-I. Current dietary advice should be to avoid obesity, limit alcohol intake, and maintain a varied diet.

Kinney AY; Millikan RC; Lin YH; Moorman PG; Newman B. Alcohol consumption and breast cancer among black and white women in North Carolina (United States). Cancer Causes and Control 11(4): 345-357, 2000. (48 refs.)

Objective: The purpose of this study was to investigate the effects of alcohol consumption on breast cancer risk in black and white women. Methods: We used data from the Carolina Breast Cancer Study, a population-based, case-control study of black and white women in North Carolina. Interviews were conducted with 890 cases and 841 controls frequency-matched on age and race. Results: Overall, the prevalence of moderate to high levels of alcohol consumption was low. Compared with abstainers, the multivariate odds ratio for recent intake of one or two drinks per day was 1.4 (95% CI = 0.9-2.1) and two or more drinks a day was 1.0 (95% CI = 0.6-1.6); increasing consumption was not associated with risk (p for trend = 0.6). The associations were similar, but somewhat weaker, for average lifetime consumption. Among women who consumed 91 g/week or more of alcohol, a nonsignificant increased risk of breast cancer was observed for women reporting binge drinking (OR = 1.5; 95% CI = 0.9-2.3), but not for those who consumed less than 91 g/week reporting binge drinking (OR = 1.0; 95% CI = 0.6-1.5). Odds ratios did not differ meaningfully by race, age, menopausal status, exogenous hormone use, or body mass index. Conclusions: These data provide little evidence for an association between alcohol consumption and risk of breast cancer among either black or white women.

Klatsky AL. Could abstinence from alcohol be hazardous to your health? (commentary). International Journal of Epidemiology 30(4): 739-742, 2001. (30 refs.)

In considering the relationship of cardiovascular disease and drinking patterns, the author considers what recommendations might be made, noting that the "debate about causality will long continue, but practical decisions about advice must often be made without certainty of knowledge. In considering what recommendations should be made, the author sets forth the following: "Cultural context clearly influences attitudes. The need for great care is universally recognised. It is essential to avoid any inducement or even rationalization of heavy drinking. Much media dissemination about the possible CHD benefits of moderate alcohol drinking and of red wine, in particular, has occurred. This has resulted in increased red wine sales in the U.S., but it is not clear what, if any effect has occurred upon individual drinking habits. The general public is becoming increasingly sophisticated about health matters. Partially because of media presentation of conflicting reports, the public is also increasingly sceptical. Risk of progression to problem drinking is the major health risk of moderate drinking. Other possible, but unproven, risks of moderate drinking include fetal alcohol syndrome, haemorrhagic stroke, large bowel cancer, and female breast cancer. The most troublesome data are those about moderate drinking and possible increased risk of breast cancer, especially since women <50 years of age are generally at very low CHD risk. One widely used definition of a 'safe limit' is no more than two drinks per day for men or one per day for women, amounts associated with evidence of lower risk of CHD. Both the number and the size of drinks compromising the safe limit should always be specified. One thread which has emerged with increasing consistency in the medical literature is the need to individualize advice. Age, sex, family and personal history of drinking, and specific medical history all must be known to make a judgement about the individual risk benefit equation.27-30 It is easier and more satisfactory for a knowledgeable health practitioner to advise his or her patient than to formulate rules for all. In the end, the responsibility to give wise and honest counsel falls upon the shoulders of the professional."

Kropp S; Becher H; Nieters A; Chang-Claude J. Low-to-moderate alcohol consumption and breast cancer risk by age 50 years among women in Germany. American Journal of Epidemiology 154(7): 624-634, 2001. (51 refs.)

Studies of the association between alcohol drinking and breast cancer show a tendency towards an increase in risk for high consumption levels but yield less consistent results for low-to-moderate levels, particularly among premenopausal women. In a population-based case- control study in Germany, the authors determined the effect of alcohol consumption at low-to-moderate levels on breast cancer risk among women up to age 50 years. The study included 706 case women whose breast cancer had been newly diagnosed in 1992-1995 and 1, 381 residence- and age-matched controls. In multivariate conditional logistic regression analysis, the adjusted odds ratios for breast cancer were 0.71 (95% confidence interval (CI): 0.54, 0.91) for average ethanol intake of 1-5 g/day, 0.67 (95% CI: 0.50, 0.91) for intake of 6-11 g/day, 0.73 (95% CI: 0.51, 1.05) for 12-18 g/day, 1.10 (95% CI: 0.73, 1.65) for 19-30 g/day, and 1.94 (95% CI: 1.18, 3.20) for greater than or equal to 31 g/day. The association with high daily ethanol intake of greater than or equal to 19 g was modified by educational level, such that odds ratios were 3.7, 1.6, and 0.7 for women with low, moderate, and high levels of education, respectively. These data suggest that low-level consumption of alcohol does not increase breast cancer risk in premenopausal women.

Kuper H; Ye W; Weiderpass E; Ekbom A; Trichopoulos D; Nyren O; Adami HO. Alcohol and breast cancer risk: The alcoholism paradox. British Journal of Cancer 83(7): 949-951, 2000. (22 refs.)

A population-based cohort study of 36 856 women diagnosed with alcoholism in Sweden between 1965 and 1995 found that alcoholic women had only a small 15% increase in breast-cancer incidence compared to the general female population. It is therefore apparent, contrary to expectation, that alcoholism does not increase breast-cancer risk in proportion to presumed ethanol intake.

Lagiou P; Ye W; Wedren S; Ekbom A; Nyren O; Trichopoulos D et al. Incidence of ovarian cancer among alcoholic women: A cohort study in Sweden. International Journal of Cancer 91(2): 264-266, 2001. (23 refs.)

Utilizing a nationwide Inpatient register database in Sweden, this study examined the incidence of ovarian cancer among 36,856 women diagnosed with alcoholism between 1965 and 1994. Mean duration of follow-up was 9.6 years, for a total of 317,518 person-years at risk. The expected number of cases of ovarian cancer was calculated by multiplying the number of person-years by 5-year age group and calendar year-specific incidence rates of ovarian cancer in Sweden. The effect measure was the standardized incidence ratio (SIR), with 95 percent confidence intervals (CIs). Overall results indicated a deficit of cases of ovarian cancer of about 14 percent among women with a diagnosis of alcoholism. This deficit is particularly strong and statistically significant among alcoholic women younger than 60 years (SIR = 0.76, 95 percent CI, 0.58-1.00). This deficit is compatible with the reported reduction of gonadotrophin levels among alcoholic women younger than 60 years and with the hypothesis invoking these gonadotrophins in the etiology of ovarian cancer. There appears to be an inverse association between alcoholism and the incidence of ovarian cancer, concentrated among women younger than 60 years old. The decrease of ovarian cancer among alcoholic women in Sweden contrasts with the increase of breast cancer in the same cohort of women. These findings appear to be more compatible with the gonadotrophin hypothesis, which also fits with the established effects of parity, oral contraceptive use and the reported consequences of taking fertility drugs.

Lenz SK; Goldberg MS; Labreche F; Parent ME; Valois MF. Association between alcohol consumption and postmenopausal breast cancer: Results of a case-control study in Montreal, Quebec, Canada. Cancer Causes and Control 13(8): 701-710, 2002. (55 refs.)

Objectives: To determine the association between postmenopausal breast cancer and prior consumption of alcoholic beverages.Methods: This case-control study, conducted in all Montreal hospitals between 1996 and 1997, included 556 postmenopausal women (age 50-75 years) who had a new histologically confirmed diagnosis of primary, malignant breast cancer. Control subjects (577) were selected from other histologically confirmed sites of cancer. A detailed history of alcohol consumption and other risk factors was obtained by interview. Indices reflecting alcohol consumption were developed and unconditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).Results: Current regular drinkers of any type of alcohol were at an increased risk of breast cancer (OR = 1.5; 95% CI 1.0-2.2). For all beverages considered, current regular drinkers showed higher risks than ever regular drinkers. The risk of breast cancer was highest among women who reported exclusive drinking of wine on a weekly or daily basis (e.g. current regular drinking: OR = 2.3; 95% CI 1.2- 4.3). Women who started to drink wine on or before the age of 40 were at a 2.5 times increased risk (95% CI 1.4-4.4).Conclusions: Our findings provide further support for a positive association between the risk of postmenopausal breast cancer and alcohol consumption.

Levi F; Pasche C; Lucchini F; La Vecchia C. Alcohol and breast cancer in the Swiss Canton of Vaud. European Journal of Cancer 32A(12): 2108-2113, 1996. (35 refs.)

The relationship between alcoholic beverage drinking and the risk of breast cancer was considered using data from a case-control study of breast cancer conducted between 1990 and 1995 in the Swiss Canton of Vaud on 230 incident cases of breast cancer below age 75 years, linked with the Vaud Cancer Registry, and 507 controls admitted to the same network of hospitals for a wide spectrum of acute, non-neoplastic, non-hormone related conditions. Overall, 70.4% of cases versus 57.4% of controls consumed alcohol, corresponding to a multivariate odds ration (OR) of 1.5 (95% confidence interval: 1.1-2.22). The ORs were 1.3 for < 1 drink per day, 1.8 for 1 to 2, 1.5 or 2 to 4, and 2.7 for > 4 drinks per day, and the trend in risk with dose was significant. The association was consistent for wine (OR=2.0), beer (OR=2.6) and spirits (OR=2.0), and was apparently stronger in premenopausal women, whereas no noticeable interaction was observed with any of the hormonal or reproductive risk factors for breast cancer. The alcohol-related risk was unrelated to duration; the OR was 1.8 for women who started drinking at the prior to age 30 and was 1.4 for those who began drinking at age 30 or older. Thus, the present study confirms that alcohol is a correlated of breast cancer risk in this European population, where alcohol drinking among women is common and relatively high. Assuming that this association reflects causality, in terms of attributable risk, alcohol could explain 25% (8-42%) of breast cancer cases.

Longnecker MP. Invited commentary: The Framingham results on alcohol and breast cancer. (commentary). American Journal of Epidemiology 149(2): 102-104, 1999. (32 refs.)

Marcus PM; Newman B; Millikan RC; Moorman PG; Baird DD; Qaqish B. The associations of adolescent cigarette smoking, alcoholic beverage consumption, environmental tobacco smoke, and ionizing radiation with subsequent breast cancer risk (United States). Cancer Causes and Control 11(3): 271-278, 2000. (43 refs.)

Objectives: Studies of breast cancer among survivors of the World War II atomic bomb blasts over Japan suggest that the adolescent breast may be particularly sensitive to carcinogenic insult. To further explore that possibility we examined the relationships of cigarette smoking, alcohol consumption, environmental tobacco smoke (ETS) exposure, and medical treatment with ionizing radiation during adolescence with subsequent breast cancer risk. Methods: Data from the Carolina Breast Cancer Study, a population-based, case-control study of breast cancer in North Carolina women aged 20-74 years (864 cases, 790 controls), were analyzed. Results: A modest increase in breast cancer risk was suggested for women who began to smoke cigarettes between the ages of 10 and 14 years (OR: 1.5, CI: 0.9-2.5), and for women exposed to ionizing radiation between ages 10 and 19 years to treat or monitor a medical condition (OR: 1.6, CI: 0.5-2.5). Neither exposure to ETS at home prior to age 18 years (OR: 1.1, CI: 0.9-1.3) nor initiation of alcoholic beverage consumption between ages 10 and 15 years (OR: 1.1, CI: 0.6-1.8) appeared to increase risk. Conclusions: Our results are consistent with previous evidence suggesting that some adolescent exposures could influence future breast cancer risk.

Mattisson I; Wirfalt E; Wallstrom P; Gullberg B; Olsson H; Berglund G. High fat and alcohol intakes are risk factors of postmenopausal breast cancer: A prospective study from the Malmo diet and cancer cohort. International Journal of Cancer 110(4): 589-597, 2004. (63 refs.)

Associations between intakes of relative fat, total alcohol and alcoholic beverages and risk of breast cancer were examined in a subsample of 11,726 postmenopausal women from the MDC cohort. The MDC conducted baseline examinations from 1991 to 1996; the end of follow-up was 31 December 2001. Data were obtained by an interview-based diet history method, a structured questionnaire, anthropometric measurements and national and regional cancer registries. During 89,602 person-years of follow-up, 342 incident cases were documented. Cox regression analysis examined breast cancer risks adjusted for potential confounders. Two energy-adjustment approaches (i.e., adjusting for total energy vs. adjusting for nonalcohol energy) were used. High total alcohol intake was associated with a nonsignificantly elevated risk. High wine intake was associated with a significantly elevated breast cancer risk (relative risk = 2.12, 95% CI 1.24-3.60). There were significant trends of increased breast cancer risk across quintiles of relative fat intake. Mutual adjustment did not affect risk estimates for total alcohol or relative fat intakes. The specific energy-adjustment approach did not influence associations differentially.

McDonald PAG; Williams R; Dawkins F; Adams-Campbell LL. Breast cancer survival in African American women: Is alcohol consumption a prognostic indicator? Cancer Causes and Control 13(6): 543-549, 2002. (48 refs.)

Objective: Compromised breast cancer survival in African American women is well established. Factors associated with poorer survival in this group are not fully elucidated. This analysis examined the influence of alcohol consumption on breast cancer survival in African American women accrued to a hospital-based study. Methods: One hundred twenty-five postmenopausal women (mean age = 64.2 +/- 12.2 years) diagnosed with invasive breast carcinoma between August 1989 and December 1994, and accrued to a hospital-based study of the disease, were followed for survival through December 1998. Cox proportional hazards regression models, adjusted for cigarette smoking, summary stage of disease, and treatment explored the association between alcohol use and breast cancer survival. Results: Premorbid alcohol consumption of at least one drink per week was associated with 2.7-fold increase in risk of death (95% CI 1.3- 5.8). Conclusions: This study suggests compromised breast cancer survival among postmenopausal women who reported drinking at least one alcoholic beverage per week, a preliminary finding that warrants further investigation.

McPherson K. Alcohol and breast cancer. (editorial). European Journal of Cancer 34(9): 1307-1308, 1998. (13 refs.)

Meng Q; Gao B; Goldberg ID; Rosen EM; Fan SJ. Stimulation of cell invasion and migration by alcohol in breast cancer cells. Biochemical and Biophysical Research Communications 273(2): 448-453, 2000. (30 refs.)

Increasing epidemiological studies suggest that alcohol consumption confers a high risk for development of breast cancer. In this study, we found that biologically relevant concentrations of alcohol elicited a significant stimulation of cell adhesion, migration, and invasion in MCF-7 human breast cancer cells. Moreover, the promotion of invasion and migration potential by alcohol was associated with the significant decrease of E-cadherin, alpha, beta, and gamma three major catenin, and BRCA1 expression. In addition, an enhanced expression of BRCA1 significantly blocked alcohol-stimulated cell invasion. Thus, our present study suggests that alcohol as a breast cancer risk factor plays an important role not only in carcinogenesis, but also in promotion of cell invasion and migration.

Messina CR; Kabat GC; Lane DS. Perceptions of risk factors for breast cancer and attitudes toward mammography among women who are current, ex- and non-smokers. Women & Health 36(3): 65-82, 2002. (39 refs.)

Understanding risk perceptions for breast cancer among women smokers is important because smokers tend to underutilize breast cancer screening. Perceptions of the relative importance of a variety of factors which may increase breast cancer risk and the benefits/barriers of mammography, were examined among women who were current (n = 185), ex- (n = 632) and never (n = 623) smokers. Participants were a subset of women taking part in a project to increase mammography utilization among women aged 50 and over. Current smokers, but not ex-smokers, were significantly less likely than never smokers to agree that health risk behaviors most frequently seen in smokers (e.g., smoking cigarettes, high-fat diet, low intake of fruits and vegetables, physical inactivity, drinking alcohol) may increase risk for breast cancer. Current smokers, but not ex-smokers, perceived more barriers and fewer benefits of mammography, than never smokers.

Nagata C; Kabuto M; Takatsuka N; Shimizu H. Associations of alcohol, height, and reproductive factors with serum hormone concentrations in postmenopausal Japanese women: Steroid hormones in Japanese postmenopausal women. Breast Cancer Research and Treatment 44(3): 235-241, 1997. (31 refs.)

We measured serum levels of estradiol (E-2), sex hormone-binding globulin SHBG), progesterone, and dehydroepiandrosterone sulfate (DHEAS) in 61 postmenopausal women drawn from female residents in a community in Japan to evaluate the relationships between these hormone levels and potential breast cancer risk factors. The information on reproductive history, body size, alcohol use, and physical activity was obtained by means of a self-administered questionnaire. There was a significant trend in increasing E-2 level with increasing height after taking account of age and body mass index (BMI) (p for trend = 0.04). BMI was inversely associated with SHBG level after controlling for age (p for trend = 0.01). Decreasing progesterone with increasing BMI was observed after controlling age and history of hysterectomy (P = 0.05). Alcohol consumption was positively associated with E-2 level and there was a strong linear trend after controlling for age, height, and BMI (p for trend = 0.001). Trend for increasing DHEAS with alcohol consumption was also statistically significant after controlling for age and history of hysterectomy (p for trend = 0.01). Reproductive factors as well as physical activity were not related to any of the hormone levels.

Newcomb PA; Trentham-Dietz A; Storer BE. Alcohol consumption in relation to endometrial cancer risk. Cancer Epidemiology, Biomarkers & Prevention 6(10): 775-778, 1997. (30 refs.)

We analyzed data from a population-based case-control study of Wisconsin women to evaluate the relationship of alcohol consumption to endometrial cancer risk, Cases (n = 739) were identified from a statewide tumor registry; controls (n = 2313) were selected randomly from driver's license lists and Medicare beneficiary files. Alcohol consumption and other factors were ascertained by telephone interview. Compared with abstainers, the multivariable relative risk for recent consumption of two or more drinks per day was 1.27 [95% confidence interval (CI) 0.78-2.07]; increasing consumption was not associated with risk of disease (P for trend, 0.82). The relative risk for early adulthood consumption of two or more drinks per day was 1.00 (95% CI, 0.58-1.73), with no suggestion of a trend (P = 0.26). Although the sample size was limited, a significant inverse association was suggested in premenopausal women consuming one drink per day or more (0.20, 95% CI 0.06-0.71). Beverage-specific consumption was not associated with risk. This study suggests that, unlike breast cancer, endometrial cancer is not positively associated with alcohol intake.

Okasha M; McCarron P; Gunnell D; Smith GD. Exposures in childhood, adolescence and early adulthood and breast cancer risk: A systematic review of the literature. (review). Breast Cancer Research and Treatment 78(2): 223-276, 2003. (243 refs.)

A growing body of work indicates that exposures over the life course have important roles to play in the aetiology of breast cancer. This review synthesises the literature that has been published in the area of early life events and female breast cancer risk. The review finds some evidence, primarily from cohort studies on the relationship between birthweight and breast cancer, to suggest that in utero events are related to breast cancer risk in adulthood. Strong evidence to support a positive association between height and breast cancer exists. Postulated mechanisms for this relationship include the role of early diet in subsequent disease risk, and the influence of endogenous growth factors mediating the relationship. There is some evidence to suggest that leg length is the component of height which is generating the observed associations between height and breast cancer. There is no consistent pattern of association between relative weight in childhood or adolescence and risk of breast cancer. The evidence to suggest an association between physical activity in early life and breast cancer risk is convincing from case-control studies, but is not fully substantiated by the results of three cohort studies. There are inconsistent results regarding the association between smoking at a young age and breast cancer risk. There is little evidence for an association between passive smoking in early life and breast cancer risk. No clear association between early drinking and breast cancer risk exists. These results are discussed in relation to possible underlying mechanisms and health promotion strategies which could reduce breast cancer risk.

Petri AL; Tjonneland A; Gamborg M; Johansen D; Hoidrup S; Sorensen TIA et al. Alcohol intake, type of beverage, and risk of breast cancer in pre- and postmenopausal women. Alcoholism: Clinical and Experimental Research 28(7): 1084-1090, 2004. (30 refs.)

Background: Most studies of the relation between alcohol consumption and breast cancer have shown a modestly increased risk, although the results are still conflicting. Methods: The aim of this prospective population-based cohort study was to assess the influence of alcohol intake and type of beverage (beer, wine, or spirits) on breast cancer risk in relation to menopausal status. Among 13,074 women aged 20 to 91 years, we examined the relationship between breast cancer risk, total alcohol intake, and type of alcohol in relation to menopausal status. The women were classified as premenopausal or as postmenopausal at younger than 70 years or 70 years or more. Results: During follow-up, 76 premenopausal and 397 postmenopausal women developed breast cancer. Premenopausal women who had an intake of more than 27 drinks per week had a relative risk of breast cancer of 3.49 (95% confidence limits, 1.36-8.99) compared with light drinkers (p = 0.011), whereas there were no differences in risk in the lower-intake categories. The increased risk of breast cancer among premenopausal women was independent of the type of alcohol. Postmenopausal women older than 70 years of age who had an intake of more than six drinks per week of spirits had a relative risk of breast cancer of 2.43 (95% confidence limits, 1.41-4.20) compared with women who consumed less than one drink of spirits per week (p = 0.0014). Conclusions: Total alcohol intake of more than 27 drinks per week increases breast cancer risk in premenopausal women independently of the type of alcohol. Among postmenopausal women, an intake of spirits of more than six drinks per week increases breast cancer risk.

Pike MC; Kolonel LN; Henderson BE; Wilkens LR; Hankin JH; Feigelson HS et al. Breast cancer in a multiethnic cohort in Hawaii and Los Angeles: Risk factor-adjusted incidence in Japanese equals and in Hawaiians exceeds that in Whites. Cancer Epidemiology, Biomarkers & Prevention 11(9): 795-800, 2002. (20 refs.)

The extent to which differences in breast cancer risk between racial-ethnic groups are explained by differences in their distribution of risk factors was determined for African-American (AA), native Hawaiian (NH), Japanese-American (JA), Latina-US-born (L-US), Latina-non-US-born (L-NUS), and white (W) women using prospective incidence data on 88,712 postmenopausal women recruited in 1993-1996. There were 1,757 incident breast cancer cases through 1999 among these women (1,116 cases after excluding women with a simple hysterectomy or missing risk factor data). Data were available on seven "known" risk factors: ages at menarche and first birth, parity, age at and type of menopause, weight, hormone replacement therapy use, and alcohol consumption. The relative risks (RRs) of breast cancer (with the RR in Ws set to 1.0) for the groups were as follows: W = 1.0; AA = 0.78; NH = 1.33; JA = 0.99; L-US = 0.77; and L-NUS 0.60. After adjustment for the risk factors, the RRs were as follows: W = 1.0; AA = 0.98; NH = 1.65; JA = 1.11; L-US = 0.95; and L-NUSB = 0.84. The slightly greater risk of the JAs compared with the Ws is in sharp contrast to the very low breast cancer rates that were observed in traditional Japanese women and in early Japanese migrants. The adjusted RR of NHs is 65 percent greater than that of Ws, and that of migrant Latinas is 16 percent lower than that of Ws. The authors are now attempting to elucidate the causes of the high breast cancer rates in NH women.

Purohit V. Moderate alcohol consumption and estrogen levels in postmenopausal women: A review. Alcoholism: Clinical and Experimental Research 22(5): 994-997, 1998. (22 refs.)

This report reviews the literature to evaluate association between moderate alcohol consumption and estrogen levels in healthy postmenopausal women. Of the eight studies available in literature on postmenopausal women who were not on estrogen therapy, two analyzed urine samples and six analyzed blood samples for estrogen levels. Of the two urine sample studies, only one reported positive association (p < 0.05) between alcohol consumption and estrogen (estrone and estradiol) levels that increased by 16 to 20%. Of the six blood sample studies, only two- one in American women and one in European women-reported significant increases (p < 0.05) in estradiol levels in response to alcohol consumption. In the American women study, estradiol levels increased only with wine and not with beer or whiskey. In the European women study, estradiol levels increased in Danish and Portuguese women, but not in Spanish women. Thus, further studies are required to establish correlation between moderate alcohol consumption and estrogen levels in postmenopausal women. Of the two studies on postmenopausal women who were on estrogen replacement therapy, one administered estradiol through transdermal patch (0.15 mg) and one orally (1 mg/day). In both studies, blood estradiol levels were measured after administering a single dose of ethanol orally (0.7-0.75 g/kg of body weight). Estradiol levels were increased by 22 and 300% in the transdermal patch and oral studies, respectively. These results suggest that alcohol consumption may increase blood estradiol levels in postmenopausal women who are on estrogen replacement therapy, and this may increase the risk of breast cancer.

Purohit V; Khalsa J; Serrano J, eds. Mechanism of alcohol-associated cancers. Alcohol 35(3): 155-279 (entire issue), 2005. (article refs.)

This journal issue, the proceedings of a symposium, deals with the mechanisms of alcohol-associated cancers. Following an introduction and summary, there are 13 articles dealing with -- The epidemiology of alcohol-associated cancers; Alcohol and oral cancer; Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers; DNA adducts from acetaldehyde and the implications for alcohol-related carcinogenesis; Alcohol and liver cancer; Alcohol and pancreatic cancer; The etiology of alcohol-induced breast cancer; The role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer; The effects of alcohol on folate metabolism and the implications for carcinogenesis; Alcohol, iron-associated oxidative stress, and the relation to cancer; Alcohol, vitamin A, and cancer; Nicotine and gastric cancer; and An epidemiologic review of marijuana use and cancer risk.

Rohan TE; Jain M; Howe GR; Miller AB. Alcohol consumption and risk of breast cancer: A cohort study. Cancer Causes and Control 11(3): 239-247, 2000. (39 refs.)

Objectives: To study the association between alcohol consumption and breast cancer risk. Methods: A case-cohort analysis was undertaken within the cohort of 56,837 women who were enrolled in the Canadian National Breast Screening Study (NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40-59 at recruitment.) The cohort was recruited between 1980 and 1985, and during follow-up to the end of 1993 a total of 1469 women in the dietary cohort were diagnosed with biopsy-confirmed incident breast cancer. For comparative purposes a subcohort consisting of a random sample of 5681 women was selected from the full dietary cohort. After exclusions for various reasons the analyses were based on 1336 cases and 5238 noncases. Results: When compared to nondrinkers the adjusted incidence rate ratios (95% confidence intervals) for those consuming > 0 and less than or equal to 10 g of alcohol/day, > 10 and less than or equal to 20 g/day, > 20 and less than or equal to 30 g/day, > 30 and less than or equal to 40 g/day, > 40 and less than or equal to 50 g/day, and > 50 g/day were 1.01 (0.84-1.22), 1.16 (0.91-1.47), 1.27 (0.91-1.78), 0.77 (0.51-1.16), 1.00 (0.57-1.75), and 1.70 (0.97-2.98), respectively; the associated p value for the test for trend was 0.351. Similar findings were obtained when analyses were conducted separately in the screened and control arms of the NBSS, in premenopausal and postmenopausal women, for screen-detected and interval-detected breast cancer, and by levels of other breast cancer risk factors. Conclusions: The results of this study suggest that alcohol consumption might be associated with increased risk of breast cancer at relatively high levels of intake.

Royo-Bordonada MA; Martin-Moreno JM; Gualler E; Gorgojo L; van't Veer P; Mendez M et al. Alcohol intake and risk of breast-cancer: The Euramic Study. Neoplasma 44(3): 150-156, 1997. (42 refs.)

To evaluate the association of alcohol intake with the risk of breast cancer in post-menopausal women, we analyzed the data from an international case-control study conducted in five European countries, (FRG, Switzerland, Northern Ireland, the Netherlands, and Spain). Information on alcohol intake was available in 315 cases and 364 controls. Medians for the tertiles of alcohol intake among current drinkers were 1.7, 6.0, and 20.0 g/day. Adjusted relative risk (and 95% confidence intervals) of breast cancer for each tertile of intake in current drinkers compared to never drinkers, were 1.00 (0.6-1.67), 1.01 (0.6-1.73), and 1.18 (0.69-2.03). The adjusted relative risk for ex-drinkers was 1.73 (1.07-2.79). Among both current drinkers and ex-drinkers, the relative risk was higher for those with body mass above the median compared to those with body mass index below the median. These results do not support a dose-response effect of alcohol on breast cancer risk, although consumption levels were too low to exclude increased risk for high regular intake. Further research is necessary to evaluate the risk of developing breast cancer among ex-drinkers and potential interaction between body mass index and alcohol drinking.

Sarkar DK; Liehr JG; Singletary KW. Role of estrogen in alcohol promotion of breast cancer and prolactionomas. Alcoholism: Clinical and Experimental Research 25(5): 230s-236s, 2001. (116 refs.)

The role of estrogen in alcohol promotion of breast cancer and prolactinomas is discussed. It is noted that two endocrine disorders prevalent in alcoholics are breast cancers and hyperprolactinemia. Hyperprolactinemia is a condition in which plasma prolactin (PRL) levels are elevated above normal, resulting in reproductive dysfunction such as amenorrhea, galactorrhea, and infertility in women; gynecomastia, impotence, decreased libido, and reduced reproductive hormone levels in men. In most cases, hyperprolactinemia is due to the presence of prolactinomas, pituitary tumors of the prolactin-secreting lactotropes. Estrogen is considered a risk factor for breast cancer and prolactinomas. Recent studies suggest that alcohol consumption elevates blood levels of estrogen as well as increases the incidence of breast cancer and hyperprolactinemia. This symposium evaluates the relationship between the ovarian hormone levels and risk factors for these diseases in alcohol-drinking humans and animals. The data indicate that chronic alcoholism increases the risk for breast cancers and hyperprolactinemia. Presentations include: (1) Dual role of estrogen as hormone and carcinogen in mammary carcinogenesis; (2) Alcohol and breast cancer -- studies using animals; and (3) Evaluation of the role of estrogen in mediation of ethanol effect on prolactinoma -- studies using animals.

Seitz H; Poschl G. Alcohol and gastrointestinal cancer: Pathogenetic mechanisms. Addiction Biology 2(1): 19-33, 1997. (155 refs.)

This article reviews literature on alcohol and gastrointestinal cancer, with particular attention to epidemiological studies and studies of the pathogenesis of cancer in the upper respiratory tract and rectum. Chronic heavy alcohol consumption is associated with a significantly increased risk of oropharyngeal, laryngeal, and esophageal cancer, and liver cirrhosis from chronic alcohol abuse is a precursor of hepatocellular cancer. Recent epidemiological studies also show that regular consumption of alcohol, even in low amounts, is associated with increased risk of rectal and breast cancer. Although alcohol by itself is not a carcinogen, it can, through a variety of mechanisms, increase the susceptibility of various organs to chemicals that are carcinogenic. Among the possible mechanisms are increased activation of procarcinogens through induction of microsomal enzymes, altered metabolism and distribution of carcinogens, interference with repair mechanisms for deoxyribonucleic acid damaged caused by alkylation by carcinogens, damage to mucosal tissue leading to stimulation of cellular regeneration, and alcohol-related malnutrition. Acetaldehyde and free radical production resulting from alcohol consumption may lead to tissue damage and secondary hyper-regeneration in the upper gastrointestinal tract. The co-carcinogenic process may also involve local mechanisms. Acetaldehyde appears to be an important factor in carcinogenesis in the rectum and may be produced mainly by fecal bacteria.

Sellers TA; Kushi LH; Cerhan JR; Vierkant RA; Gapstur SM; Vachon CM et al. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 12(4): 420-428, 2001. (36 refs.)

Low B-vitamin intake may increase risk of breast cancer through decreased DNA repair capacity. Alcohol intake increases risk for breast cancer, with evidence from prospective studies of an interaction between alcohol and folate, We explored dietary intake of folate and other B vitamins with risk of breast cancer in a cohort study of 34, 387 postmenopausal women. To measure diet, we mailed a food frequency questionnaire; we estimated nutrient intakes and categorized them into four levels: < 10th, 11th-30th, 31st-50th, and > 50th percentiles. Through 12 years of follow-up. we identified 1, 586 cases of breast cancer in the cohort at risk. We estimated relative risks (RRs) and 95% confidence intervals (CIs) through Cox regression models adjusted for age, energy, and other risk factors. Women in the lowest 10th percentile of folate intake from diet alone were at modestly increased risk of breast cancer relative to those above the 50th percentile: RR = 1.21 (95% CI = 0.91-1.61). We examined the joint association of folate intake and alcohol use on risk of breast cancer, with the reference group defined as women with high folate (> 50th percentile) and no alcohol use. The RRs of breast cancer associated with low dietary folate intake were 1.08 (95% CI = 0.78-1.49) among nondrinkers, 1.33 (95% CI = 0.86-2.05) among drinkers of less than or equal to4 gm per day, and 1.59 (95% CI = 1.05-2.41) among drinkers of >4 gm per day. These results suggest that the risks of postmenopausal breast cancer may be increased among women with low intakes of folate if they consume alcohol-containing beverages.

Sellers TA; Vierkant RA; Cerhan JR; Gapstur SM; Vachon CM; Olson JE et al. Interaction of dietary folate intake, alcohol, and risk of hormone receptor-defined breast cancer in a prospective study of postmenopausal women. Cancer Epidemiology, Biomarkers & Prevention 11(10 Part 1): 1104-1107, 2002. (26 refs.)

Alcohol intake is an established risk factor for breast cancer, but the underlying mechanism remains unknown. Four recent studies have described interactions of alcohol and low folate intake. We examined this interaction on the risk of postmenopausal breast cancer stratified by tumor receptor status for estrogen (ER) and progesterone (PR). The Iowa Women's Health Study is a prospective cohort study of 34,393 at-risk women. Alcohol use and folate intake from diet and supplements were estimated at baseline in 1986 through a semiquantitative food frequency questionnaire. Through 1999, 1,875 cases of breast cancer were identified through linkage to the Iowa Surveillance, Epidemiology, and End Results registry. Compared with nondrinkers with folate intakes above the 50(th) percentile, women with low folate and high alcohol were at 1.43-fold greater risk (1.02- 2.02). When stratified by tumor receptor status for ER or PR, the risks for low folate/high alcohol were 2.1 (1.18-3.85), 1.0 (0.76- 1.42), 1.2 (0.88-1.70), and 1.2 (0.69-2.02) for ER-, ER+, PR+, and PR- tumors, respectively. Because the results were limited primarily to ER- tumors, one plausible interpretation of these data is that alcohol influences breast cancer through its metabolite, acetaldehyde, rather than through effects on ER levels and receptor- mediated pathways.

Silva ID. Alcohol, tobacco and breast cancer: Should alcohol be condemned and tobacco acquitted? (editorial). British Journal of Cancer 87(11): 1195-1196, 2002. (8 refs.)

Singletary K. Ethanol and experimental breast cancer: A review. Alcoholism: Clinical and Experimental Research 21(2): 334-339, 1997. (61 refs.)

There is considerable evidence from epidemiological studies to support a positive association between alcohol intake and risk for breast cancer. Yet, experimental evidence has provided less convincing evidence to support this relationship, although much less attention has been focused on elucidating the effect of ethanol on breast carcinogenesis in animal models. Although the number of reports are limited, information on the effect of ethanol on mammary carcinogenesis in spontaneous, chemically induced and metastatic models has been published. In addition, a small number of reports provide insights into an influence of ethanol on the physiological processes associated with the initiation, promotion, and progression stages of breast carcinogenesis in animals, as well as on the growth of human breast cancer cells. This information from the literature is summarized, and specific recommendations put forth so that greater progress can be made in this controversial and complex research area.

Singletary KW; Frey RS; Yan W. Effect of ethanol on proliferation and estrogen receptor-alpha expression in human breast cancer cells. Cancer Letters 165(2): 131-137, 2001. (36 refs.)

This study examined a direct effect of ethanol exposure on the proliferation and intracellular content of cyclic AMP (cAMP) in two estrogen receptor-positive (ER+) and two estrogen receptor-negative (ER-) human mammary cancer cell lines (BT-20 and MDA-MB-231), and investigated whether an effect of ethanol on ER+ breast cancer cells is associated with changes in the ERalpha levels. Treatment of ER+ human breast cancer cells (MCF-7 and ZR75.1) with ethanol at concentrations between 10 and 100 mM was associated with increased cell numbers compared to controls. The ERalpha content and the amount of intracellular cAMP also increased in ER+ cells exposed to ethanol, compared to controls. On the other hand, ethanol treatment did not increase cell proliferation or cAMP levels in the ER- (BT-20 and MDA-MB-231z) human breast cancer cells. The capacity of ethanol to stimulate proliferation of specific types of human breast cancer cells, rather than all breast cancer cells, might partly explain the generally modest increases in breast cancer risk reported in epidemiological studies, since an increased development of breast tumors may only be apparent for a subset of tumors with specific hormone receptor characteristics. The mechanism for the selective effect of ethanol on human breast cancer cell proliferation, cAMP content, and ER levels warrants further study.

Singletary KW; Gapstur SM. Alcohol and breast cancer: Review of epidemiologic and experimental evidence and potential mechanisms. Journal of the American Medical Association 286: 2143-2151, 2001. (221 refs.)

This report summarizes information on the association of alcohol consumption with increased risk for breast cancer from human and animal investigations, with particular reference to epidemiologic data published since 1995. The association has been a consistent finding in a majority of epidemiologic studies during the past 2 decades. Increased estrogen and androgen levels in women consuming alcohol appear to be important mechanisms underlying the association. Other plausible mechanisms include enhanced mammary gland susceptibility to carcinogenesis, increased mammary carcinogen DNA damage, and greater metastatic potential of breast cancer cells, processes for which the magnitude likely depends on the amount of alcohol consumed. Susceptibility to the breast cancer-enhancing effect of alcohol may also be affected by other dietary factors (such as low folate intake), lifestyle habits (such as use of hormone replacement therapy), or biological characteristics (such as tumor hormone receptor status). Additional progress in understanding alcohol's enhancing effect on breast cancer will depend on a better understanding of the interactions between alcohol and other risk factors and on additional insights into the multiple biological mechanisms involved.

Smith-Warner SA; Spiegelman D; Yaun SS; van den Brandt PA; Folsom AR; Goldbohm RA et al. Alcohol and breast cancer in women: A pooled analysis of cohort studies. (review). Journal of the American Medical Association 279(7): 535-540, 1998. (75 refs.)

Objective.-To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption and to evaluate whether dietary and nondietary factors modify the association. Data Sources.-We included in these analyses 6 prospective studies that had at least 200 incident breast cancer cases, assessed long-term intake of food and nutrients, and used a validated diet assessment instrument. The studies were conducted in Canada, the Netherlands, Sweden, and the United States. Alcohol intake was estimated by food frequency questionnaires in each study. The studies included a total of 322 647 women evaluated for up to 11 years, including 4335 participants with a diagnosis of incident invasive breast cancer. Data Extraction.-Pooled analysis of primary data using analyses consistent with each study's original design and the random-effects model for the overall pooled analyses. Data Synthesis.-For alcohol intakes less than 60 g/d (reported by >99% of participants), risk increased linearly with increasing intake; the pooled multivariate relative risk for an increment of 10 g/d of alcohol (about 0.75-1 drink) was 1.09 (95% confidence interval [CI], 1.04-1.13; P for heterogeneity among studies, .71). The multivariate-adjusted relative risk for total alcohol intakes of 30 to less than 60 g/d (about 2-5 drinks) vs nondrinkers was 1.41 (95% CI, 1.18- 1.69), Limited data suggested that alcohol intakes of at least 60 g/d were not associated with further increased risk. The specific type of alcoholic beverage did not strongly influence risk estimates. The association between alcohol intake and breast cancer was not modified by other factors. Conclusions.-Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women. Among women who consume alcohol regularly, reducing alcohol consumption is a potential means to reduce breast cancer risk.

Stevens RG; Cohen RD; Terry MB; Lasley BL; Siiteri P; Cohn BA. Alcohol consumption and serum hormone levels during pregnancy. Alcohol 36(1): 47-53, 2005. (42 refs.)

Factors that change sex hormone levels during pregnancy may have long-term health consequences for the offspring, including changes in breast cancer risk. A cross-sectional analysis of alcohol consumption and hormone levels in 339 pregnant women sampled from the Child Health and Development Study cohort was undertaken. Alcohol intake was queried from 1959 to 1966, long before any hazards of drinking during pregnancy were publicized. Third trimester serum hormone levels including estradiol and testosterone were analyzed. Among 339 pregnant women, 196 reported some alcohol consumption during pregnancy. The drinkers were divided into three groups with intake levels of 0.2-0.5, 0.6-2.0, and 2.1-12.5 ounces of ethanol per week. The second group corresponds to a median intake of similar to 2 drinks per week, and the last group corresponds to a median intake of similar to 1 drink per day, which is considered "light" to "moderate" drinking. Maternal estradiol levels were not associated with alcohol intake during pregnancy. However, serum testosterone was significantly lower, by 12.2%, in the latter two groups of drinking pregnant women, [confidence interval (CI) = -3.0 to 25.2] and 25.6% (CI = 9.2-39.5), respectively. The alcohol intakes reported are far below those shown to cause fetal alcohol syndrome, or any of the fetal alcohol effects so far studied. Light alcohol intake during pregnancy is associated with lower maternal testosterone. The health implications are uncertain, but may include an increased breast density in the daughters of drinking mothers.

Stevens RG; Hilakivi-Clarke L. Alcohol exposure in utero and breast cancer risk later in life. (letter). Alcohol and Alcoholism 36(3): 276-277, 2001. (28 refs.)

The relationship between alcohol exposure in utero and risk of breast cancer later in life is discussed in this letter to the editor. It is noted that there is considerable evidence suggesting that moderate-to-heavy alcohol consumption increases the risk of breast cancer in women, with a possible mechanism being alcohol's effects on circulating hormone levels. In addition to affecting estrogen levels, alcohol appears to effect melatonin, reducing the nocturnal rise in serum melatonin in rats as well as in humans. The authors suggest that the increase in circulating estradiol levels and the reduction in melatonin levels after alcohol exposure may be related: alcohol ingestion may lower melatonin levels, which may lead to elevated circulating estradiol levels in blood. Both high estrogen levels and low melatonin levels have been thought to increase the risk of developing breast cancer. The authors further suggest that these observations can be considered in the context of the hypothesis than an elevated exposure to estrogens in utero will increase the lifetime risk of breast cancer by changing normal breast development. They conclude that ingestion of even moderate amounts of alcohol by pregnant women may lead to elevated circulating estradiol levels which may then affect developing mammary tissue in such a way that the lifetime risk of breast cancer is raised in their daughters.

Stoll BA. Alcohol intake and late-stage promotion of breast cancer. (review). European Journal of Cancer 35(12): 1653-1658, 1999. (83 refs.)

Breast cancer risk in women rises with increasing alcohol intake and is widely assumed to be mediated by increased oestrogen concentrations. However, observations that mechanisms and risk are likely to differ between pre- and postmenopausal women suggest that the postmenopausal disease in particular, may involve a promoting role for concomitants of hyperinsulinaemia which is commonly associated with alcoholic cirrhosis of the liver. The MEDLINE database and ongoing studies were examined for clinical, epidemiological and laboratory data on; (a) alcohol-related increase in the incidence of breast cancer in relation to menopausal status, oestrogen concentrations and the oestrogen receptor (ER) status of the tumour; (b) activation of insulin-like growth factor 1 receptor (IGF1R) in mammary tissue by alcohol-related hyperinsulinaemia; (c) interaction between ER and IGF1R in breast cancer cell systems. Epidemiological association between alcohol intake and increased breast cancer risk is more clearly seen in postmenopausal than premenopausal women, and a significant risk is associated with intake of more than two drinks (over 30 g) daily over a period of years. Alcohol-related hyperinsulinaemia is reported to increase with increasing degrees of cirrhosis and damage to liver function. Laboratory evidence suggests that hyperinsulinaemia can stimulate express