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Luangkaew: Alcohol Intake and Breast Cancer Prevention 1

Alcohol Intake and Breast Cancer Prevention in Women Ages 45 or Older

Peter S. Luangkaew

Biology department, University of Nebraska Kearney

Luangkaew: Alcohol Intake and Breast Cancer Prevention 2

Abstract

Moderate alcohol intake is associated with around 30-50% high risks in breast cancers. Cohort

and case-control studies provided data to support modest increases. Recent epidemiologic and

molecular cancer biology studies have crucial evidence that supports the association between

alcohol intake and breast cancer risk is real and not endorsed by correlation of the studies'

exposures, factors, and outcomes. The reviews of women who carried BRCA1 and 2 gene

mutations are not at increased risk of breast cancer. Heart disease incidence is more significant

than breast cancer. Modest alcohol intake could reduce the risk of heart diseases; the latest

evidence to evaluate if alcohol intake reduction and prevention should focus on women at

increased risk of breast cancer. Most evidence has shown the effects of alcohol intake on breast

tumor recurrence and survival rates for patients diagnosed with breast cancer.

Luangkaew: Alcohol Intake and Breast Cancer Prevention 3

Introduction

Breast cancers are diseases in breast cells that grow uncontrollably and are many subtypes of

breast cancer, based on specific cells in the breasts develop into cancers. The breasts have three

main parts: ducts, lobules, and connective tissue (U.S. Department of Health and Human

Services 2020). Breast cancers may form in different parts of the breast. Moreover, breast

cancers have occurred in women 45 years old or older and grow in the ducts or lobules. The two

primary common types of breast cancers are invasive ductal carcinoma and invasive lobular

carcinoma. Invasive ductal carcinoma cells can extend outside the ducts into other parts of the

breast tissues and metastasize to other organs' parts of the body.

Invasive lobular carcinoma cells grow from the lobules to the breast tissues locally and spread to

other body organs. Each year in the U.S., approximately 250,000 breast cancer cases are newly

diagnosed in women, and about 42,000 die each year from breast cancers. African American

women have higher rates of death than White women from breast cancers. Studies have shown

that women's risks for breast cancers are factors, including getting older, being a woman, and

alcohol intake (U.S. Department of Health and Human Services 2020).

Alcohol intake is associated with breast cancer risks with a 7-10 percent increase in risk for

each 10g (~1 drink) daily alcohol intake by women over 45. Breast cancer risk significantly

increases by 4-15 percent for a small number of alcohol intakes (≤1 drink per day or ≤12.5g per

day) that do not increase cancer risks in other organs in women (McDonald et al. 2004).

Alcohol intake raises both public health and medical concerns because almost half of the women

of childbearing age drink alcoholic beverages and 15 percent of female drinkers at these ages

have at least four or more drinks at a time. Around 4-10 percent of female breast cancers in the

U.S. are attributable to alcohol intake, accounting for 9000-23,000 newly diagnosed invasive

Luangkaew: Alcohol Intake and Breast Cancer Prevention 4

breast cancers every year. Having risk factors does not reply; an individual will have a disease,

and all risk factors do not have the same effects (Morch et al. 2007).

Therefore, a better understanding of how alcohol intake may increase breast cancer risk is

needed to prevent breast cancers in these groups.

Alcohol Intake Related to Genes and Breast Cancers

Ethanol can metabolize by alcohol dehydrogenase (ADH) to Acetaldehyde (AA) and can

remove by aldehyde dehydrogenase (ALDH) to acetate. The genes, which encode for ALDH and

ADH are polymorphic. The enzymes they encode to determine a rate of ethanol metabolisms and

concentrations of intermediate metabolites, including a carcinogenic AA (Scoccianti et al. 2014).

Suppose associations between alcohol intake and breast cancer are attributable to an unmeasured

confounder. In that case, we could not expect the strength of alcohol intake and breast cancer

association to change based on the genotype of enzymes that regulate ethanol metabolisms

unless a confounder is also mapped to a genotype. Modifications of alcohol intake and breast

cancer association by enzymes' activities could support evidence that associations are causal

(Chen et al. 2011).

Moreover, AA could play a crucial role in alcohol-related carcinogenesis. Activities of gene

encoding ADH determine levels. Some studies evaluated the effect modification of the

association of breast cancer risk and alcohol intake by genes encoding ADH isozymes (Suzuki et

al. 2005).

There are many classes of ADH genes in humans. It is a class I ADH isozymes that are involved

in ethanol oxidations. Several genes, which encode these certain enzymes are ADH1A, ADH1B,

Luangkaew: Alcohol Intake and Breast Cancer Prevention 5

and ADH1C. ADH1B polymorphism is found mostly in Asians, and the genetic variants ADH1B

have nearly 40 times more enzymatic activities than a wild-type ADH1B.

Therefore, having ADH1B causes prolonged exposure to AA and is thought to increases breast

cancer risks. Some studies have reported that a type of ADH1B allele present modifies the

association between alcohol intake and breast cancer (Coronado et al. 2011).

However, AA is responsible for side effects related to alcohol intake. Therefore, the homozygous

recessive carrier of ADH1B has severe side effects from alcohol intake. They are alcohol

abstainers, making this genotype less studied due to small numbers of alcohol intake.

(Tjonneland et al. 2004). In addition to ADH1B, ADH1C also affects enzymatic activities, but to

a lesser extent: ADH1C alleles have nearly 2.5 times more enzymatic activity than ADH1C.

Polymorphisms in the ADH1C genes are mostly found in Whites than polymorphisms in

ADH1B; they have been more studied in the US population.

In a population-based study, Terry et al. (2006) stated that there were 1,047 breast cancer

patients and 1,101 controls; the authors found that ADH1C carriers who had moderate alcohol

intake (15-30 grams per day) were at nearly two times risk of having breast cancer that to

nondrinkers (OR 1.97, 95% CI 1.10-3.54). These findings show the interaction of the ADH1C

genotype with the alcohol-breast cancer association support that this association is causal.

Alcohol Intake and Breast Density

In addition to their metabolites' carcinogenesis roles, alcohol may alter estrogen levels,

causing to change in breast density, resulting in breast cancer risks. The breast cancer risks

related to breast cancer hormone are mammographic density, connective and epithelial tissues in

the breast. Greater density means a 4-6-fold increase in breast cancer risks. Additionally, alcohol

intake has been linked to modifying the mammographic density in dose-response ways.

Luangkaew: Alcohol Intake and Breast Cancer Prevention 6

The correlations between alcohol intake and breast density provide more evidence that alcohol is

linked to breast cancer.

Epidemiologic studies have applied different parameters to assess mammographic densities

with previous research using qualitative measures, such as the Wolfe parenchymal patterns

(Conroy et al. 2012).

Some frequently used qualitative measures in recent studies are BI-RADS (breast imaging

reporting and data system) or applying the computer-based threshold measure program ranging

from 0-100%. We can categorize breast density using Wolfe patterns into four types:

• N1 (predominately fat)

• P1 (ductal prominence in <25 percent of the breast)

• P2 (ductal prominence in >25 percent of the breast)

• DY (extensive dysplasia)

Previous studies have assessed breast densities using Wolfe patterns; one study by Jeon et al.

(2011) stated a 30 percent prevalence rate related to high density and high alcohol intake.

Another study by Yaghjyan et al. (2012) showed that the prevalence rate was 21percent (Table

1). The Wolfe patterns reflect significantly much more significant changes in density than other

quantitative measures.

Table 1

Table1 shows study findings of an association between alcohol intake and mammographic

density.

Authors

and Year

Recruite

d Year

Study

Population

Age N Prevalence Results Adjustment

Luangkaew: Alcohol Intake and Breast Cancer Prevention 7

Jeon et

al.

2011

2008 Mammograph

y

Screening

(Korea)

40-

80

mea

n

50.6

516 30% of

current/pas

t

users

Outcomes:

BI-RADS

(III/IV

versus I/II)

Versus

nonusers:

Current/pas

t users OR

1.36, 95%

CI 0.87-

2.14

BMI, age,

Menopausal

status,

Family

history,

Ages

at menarche,

parity, OC

use, and

Educational

background

Yaghjya

n et al.

al. 2012

1990-

2008

Fernald

Community

Cohort (USA)

mea

n

51.3

112

5

21% users Outcomes:

BI-RADS

(IV versus

I)

Versus

nonusers:

users OR

2.0, 95%

CI 1.4-2.8

BMI, Age at

mammogra

m,

menopausal

status, age

at menarche,

age at first

birth, family

history, and

smoking

history

Some previous studies examined alcohol intake, and breast density has found a positive

association. The Minnesota breast cancer family study stated that a positive association between

alcohol and high-density (Jeon et al. 2011).

In their study, Yaghjyan et al. (2012), the longitudinal Fernald Community cohort (N=1,125)

study, using BIRADS to measure breast density, (N=11125). They found that breast density was

linked to BMI at mammogram (P for trend<0.001), and parity (P for trend=0.02) and related to

alcohol intake (users vs. nonusers: odds ratio 2.0, 95 percent confidence interval was 1.4-2.8).

Alcohol intake was associated with breast density positively. The association was more

significant in women with a family history of breast cancers (P<0.001) and women with previous

HRT (hormone replacement therapy) (P<0.001). Parity was associated with breast density in

most subsets, except premenopausal women and women with non-family history. The parity

Luangkaew: Alcohol Intake and Breast Cancer Prevention 8

associations with breast density were greater in women with HRT history (P<0.001).

Consideration on Alcohol Intake for Breast Cancer Prevention

According to the Healthy People 2020 initiative goals, one is to decrease an average alcohol

intake annually by 10% over ten years. To meet a goal, public health and medical workers will

need to develop an effective strategy to adjust alcohol drinking behaviors in women who drink

over one drink per day. The national epidemiologic survey on alcohol intake and associated

conditions (NESARC) reported that over three years, female drinkers were at baseline, 11

percent reported abstaining from alcohol intake in three years of study. In current woman

drinkers who did not exceed drinking limits at baseline, 20 percent stated exceeding drinking

limits in the past year. These results reflect that though alcohol intake trends may appear stable,

women may change drinking habits. Epidemiologic evidence, complemented further by genetic

factor studies and intermediate markers, suggests that alcohol intake may increase breast cancer

risk. High alcohol intake has been linked to other health conditions, including liver diseases such

as alcoholic hepatitis and cirrhosis, high blood pressure and cardiomyopathy, and various types

of cancers, such as pharynx, mouth, esophagus, larynx, and colon (Li et al. 2010)

Alcohol abuse could lead to crimes, accidents, and mental health issues. However, modest

alcohol intake has lined to a low risk of CHD (coronary heart disease). In a meta-analysis,

woman drinkers had a 29 percent reduced risk of CHD incidence and a 21 percent reduced risk

of CHD mortality rate than non-drinkers.

According to the 2009-2010 NHANES study, over fifty percent of U.S. women were drinkers

who had more than 12 drinks in the past year. Forty-one percent were moderate drinkers (≤7

drinks per week), and ten percent were heavy drinkers (>7 drinks per week). The prevalence rate

of heavy drinking was greater in non-Hispanic white women (12%) compared to Non-Hispanic

Luangkaew: Alcohol Intake and Breast Cancer Prevention 9

Black (7%) or Hispanic women (4%). In non-Hispanic Black and Hispanic groups, young adult

women (20-39 years) tended to consume alcohol more than older women (≥60 years). Moreover,

the prevention challenges in those women at great risk of breast cancer are that cardioprotective

benefits of alcohol among women could be fewer consequences; however, the evidence has not

supported that increased risk women of breast cancer who drink alcohol are at higher risk

because of their alcohol intake (Li et al. 2010).

Furthermore, BRCA1 and 2 are the most well-known studies of genes affected by hereditary

breast and ovarian cancers. BRCA1 and 2 genes may protect the individual from having a

particular type of cancers; however, mutations in BRCA1 and 2 genes cause them not to work

correctly; consequently, if a person inherits one of these gene mutations, you are more likely to

have breast, ovarian cancers.

More studies have focused on women with BRCA1 or BRCA2 gene mutations. In a large

case-control study conducted in postmenopausal BRCA1 or BRCA2 gene carriers (N=1,925),

alcohol intake was not related to BRCA-associated with breast cancer (McCarty et al. 2012).

The BRCA gene studies have been retrospective, depending on their samplings, which could be

affected by survivor bias. The low prevalence of BRCA gene carriers could limit the ability to

detect alcohol and carrier status associations. Although the empirical evidence does not suggest

that high-risk women have an increased risk of breast cancer from alcohol intake, prospective

confirmation of study findings across women at a higher continuum of risk, including BRCA1 &

2 gene carriers, is needed.

Conclusion

Alcohol intake is associated with an increase in breast cancer risk. The association has been

studied in cohort studies and case-control, reducing the likelihood of explaining selection biases.

Luangkaew: Alcohol Intake and Breast Cancer Prevention 10

Effect modifications of this relationship by the ADH1C genotype, and the associations between

alcohol intake and high breast density, provide more evidence to support the causal effect.

Although all recent studies do not support increased breast cancer risks with heavy alcohol intake

in women at high risk of breast cancer, prospective studies are needed to rule out biases. The

well-known evidence suggests that increased risk women are not at increased risk from moderate

alcohol intake. With the prevalence of alcoholic drinking in U.S. women, many could benefit

from staying within the drinking guidelines of ≤1 drink per day for overall health to reduce

breast cancer risk in 45 or older women.

Luangkaew: Alcohol Intake and Breast Cancer Prevention 11

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