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Updated Evidence for the Effect

of Alcohol and Breast Cancer

Seung Pil Jung

Department of Surgery,

Korea University Medical Center

Welcome to Songdo

Contents

1. Short-term and long-term effect of alcohol

2. Cancer and Alcohol

3. Hypothetic mechanism of breast carcinogenesis

4. Clinical evidence of breast cancer and alcohol

5. Alcohol and breast cancer recurrence

• Alcoholic drink

: contains ethanol,

- a type of alcohol produced by fermentation of grains, fruits,

or vegetables

Alcohol

• Alcoholic drink

: intentionally fermented drinks existed from stone age (10,000 BC).

: one of the most widely used recreational drugs

: plays an important social role in many cultures.

: about 33% of people being current drinkers

: US women on average drink 0.7 drinks and males 1.7 drinks a day

G.Max Lancet 2018 (22); 392:1015-35

Alcohol

• From stomach

: quickly passed into the blood stream

: in a few minute, travel to every part of the body, including brain

Short-term effect of alcohol

• Low doses

: alters neuron’s membranes and ion channels,

: slows the function of the central nervous system

: increases dopamine

causes euphoria, reduces anxiety, and improves sociability

Short-term effect of alcohol

• High doses

: drunkenness, stupor, unconsciousness, anterograde amnesia

vomiting, aspiration, respiratory depression, even death

• Hangover

: unpleasant effects following consumption of alcohol

: headache, drowsiness, dry mouth, fatigue, gastrointestinal distress…

: dehydration, metabolic acidosis, increased cardiac output,

vasodilation, sleep deprivation, acetaldehyde accumulation.

Short-term effect of alcohol

• ADH metabolizes alcohol to acetaldehyde

: a toxic substance and known carcinogen

: cause of hangover

• acetaldehyde is further metabolized down to acetate

: finally broken down into water and carbon dioxide

Alcohol metabolism

Patrick N Alcohol Clin Exp Res. 1995 Aug;19(4):1055-60

• Toxic byproduct

: intermediate byproduct

: potential to cause significant damage

: in the liver, where the bulk of alcohol metabolism takes place.

- some alcohol metabolism also occurs in pancreas, brain, G-I tract

and breast tissue causing damage to cells and tissues

Acetaldehyde

Patrick N Alcohol Clin Exp Res. 1995 Aug;19(4):1055-60O’Connor, S, Alcohol Clin Exp Res. 1998 22:202-210

• Cardio-vascular disease

: hypertension, peripheral vascular disease, and stroke, atrial fibrillation

• Hepatobiliary disease

: Liver cirrhosis, HCC, gallstone, pancreatitis

• Renal dysfunction

• Osteoporosis

• DM

• Dementia

• Accidents, violence

Long-term effect of Alcohol

• Cancer

IARC declared alcohol as Group I (carcinogenic to human) carcinogen.

“ Alcohol consumption has been shown to cause cancers of the oral cavity, pharynx, larynx,

oesophagus, colorectum, liver and female breast and pancrease. The relative risk of breast

cancer increases with increasing alcohol intake by about 10% per 10g/day.”

Long-term effect of Alcohol

Bagnardi et al., 2015; IARC, 2009; IARC, 2007; Hill, 2003

Bagnardi et al., 2015; IARC, 2009; IARC, 2007; Hill, 2003

Cancer risk are associated with average daily alcohol consumption

• Carcinogenesis of alcohol

: acetaldehyde can damage both DNA and proteins

: reactive oxygen species can damage DNA, proteins, and lipids

via oxidation

: increasing blood levels of estrogen

: a variety of carcinogenic contaminants during fermentation

(nitrosamines, asbestos fibers, phenols, and hydrocarbons)

Alcohol and cancer

Bagnardi et al., 2015; IARC, 2009; IARC, 2007; Hill, 2003

• Alcohol consumption is associated with increased risk for breast cancer.

• The proportion of breast cancer attributable to alcohol consumption

is 2.1% - 10%.

Breast cancer and alcohol

Petri, A. Alcohol Clin Exp Res 2004(28):1084-1090Singletary K. JAMA 2001(286) 2143-2151

Mechanism of Carcinogenesis

Ramona G Alcohol 2005 (35), 213-225

E

T

H

A

N

O

L

Estrogen metabolismCellular response and proliferation

DNA damage and mutagenesis

B

R

E

A

S

T

C

A

N

C

E

R

Oxidation and free radicals

One carbon metabolism

(folate, B6 and B12)

Acetaldehyde mutagenesis

• Ethanol metabolism

Mechanism

Helmut K, NIAAA publication

• Toxic compound

: acetaldehyde binds to cellular proteins and DNA, leading to protein

adducts and to DNA adducts

acetaldehyde causes DNA cross-linking, micronuclei, aneuploidy,

and chromosomal aberrations

Acetaldehyde

Helmut K, NIAAA publicationNakamura, K , Arch Toxicol 2003, 77, 591–593.

• Acetaldehyde acetate

by ALDH, xanthine oxidoreductase (XOR)

and aldehyde oxidase (AOX).

- Both XOR and AOX enzymes

can generate reactive oxygen species (ROS).

Helmut K, NIAAA publication, RICHARD M. Free Radical Biology & Medicine,1999 (26) 348–354

Reactive oxygen species

• Ethanol generates lipid peroxidation products

: malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE)

: aggravates DNA and protein adducts synthesis

: contribute to breast carcinogenesis

Lipid peroxidation products

Ishii, H., Kurose, I., & Kato, S.1997J Gastroenterol Hepatol, 1999(12), S272.Li, D. Cancer Detect Prev 1999 (23), 454–462.

• Mitochondrial damage induced by ethanol

: impair mitochondrial function

: increasing the oxidative stress to cell

: mitochondrial DNA (mtDNA) is a target for oxidative stress

: ethanol can lead to mitochondrial structural and functional disturbances

Oxidative stress and mitochondria

Tan, D.-J Cancer Res 2002 (62) 972–976Kim SJ, Int J Mol Sci 2015 (16) 21486

• Alcohol interferes estrogen pathways

: decreased menstrual cycle variability

: increased serum and urinary estrogen metabolites

: down-regulate the expression of the normal BRCA1

• Ethanol stimulates proliferation, ER-a, and aromatase

expression in breast cell.

Alcohol drinking and estrogen

Verkasalo, P. Cancer Causes Control 2110 (12), 47–59Fan, S. Cancer Res 2000 (60), 5635–5639, Etique Int J Mol Med (2004) 13, 149–155

• Estrogen receptor mediated hormonal activity

- promoting cellular proliferation

- accumulation of the genetic damage

• Activation of the cytochrome P450 metabolic pathways

- increase the mutation rates

• induction of aneuploidy

Increased estrogen level

makes and aggravates breast carcinogenesis

Estrogen induced breast carcinogenesis

Russo & Russo, Trends Endocrinol Metab 2004 (15), 211–214.

• Alcohol consumption

: negatively affect folate status in tissues

: diminish serum vit B6 and B12 concentrations

• Vit B6, B12 and folate

: required for DNA methylation and nucleotide synthesis.

• Folate, Vit B6 and B12 deficiency

: increase the risk of malignancy by causing

- DNA hypomethylation, deficiency in the DNA repair process

and DNA strand breaks

one-carbon metabolism

Zhang, Curr Opin Obstet Gynecol 2004(16), 19–25Friso, S.Proc Natl Acad Sci U S A 2002 (99) 5606–5611.

• Alcohol can contribute to breast carcinogenesis

1) ethanol metabolite acetaldehyde

2) oxidative damage

3) one-carbon metabolism pathways through reduced folic acid intake

4) perturbation of estrogen metabolism and response

Summary

Epidemiologic studies

Samir Zakhari Cancers 2018, 10, 349

Meta-analysis studies

Samir Zakhari Cancers 2018, 10, 349

YJ Choi, Cancer Res Treat. 2018;50(2):474-487

Meta-analysis studies

meta-analysis from 60 cohort studies

total of 9,428,076 participants

Meta-analysis

YJ Choi, Cancer Res Treat. 2018;50(2):474-487

YJ Choi, Cancer Res Treat. 2018;50(2):474-487

Site of cancerTotal No. of

studies

Very light drinking (≤ 0.5 drink/day)

Light drinking (≤ 1 drink/day)

Moderate drinking (1-2 drinks/day)

No. of studies

RR (95% CI)No. of studies

RR (95% CI)No. of studies

RR (95% CI)

Head and neck 2 1 1.11 (0.75-1.65) 2 1.00 (0.75-1.33) 2 1.18 (0.67-2.07)

Stomach 11 3 1.00 (0.78-1.30) 7 1.00 (0.95-1.07) 6 0.91 (0.78-1.06)

1 1.11 (0.71-1.73) 0 NA 0 NA

2 1.04 (0.66-1.64) 2 1.01 (0.92-1.11) 2 0.91 (0.68-1.20)

Colorectum 16 6 1.10 (0.94-1.28) 14 1.04 (1.01-1.06) 10 1.10 (1.03-1.19)

2 0.92 (0.78-1.08) 7 1.02 (0.98-1.06) 5 1.04 (0.95-1.13)

3 1.31 (0.92-1.86) 6 1.06 (1.01-1.11) 6 1.19 (1.06-1.35)

Lung 10 3 0.89 (0.84-0.93) 10 0.91 (0.90-0.94) 8 0.98 (0.91-1.07)

2 0.82 (0.70-0.95) 4 0.90 (0.87-0.94) 4 1.05 (0.99-1.11)

1 0.86 (0.71-1.03) 3 0.91 (0.90-0.95) 4 0.98 (0.82-1.16)

Breast (female) 34 20 1.04 (1.01-1.07) 25 1.09 (1.06-1.12) 15 1.13 (1.11-1.15)

Endometrium 9 6 0.95 (0.80-1.12) 7 0.98 (0.93-1.03) 4 0.93 (0.84-1.04)

Ovary 5 2 1.00 (0.82-1.22) 5 1.02 (0.88-1.20) 4 1.20 (0.92-1.56)

Cervix and uterus 2 NA NA 2 1.02 (0.88-1.19) 2 0.99 (0.83-1.17)

Association between very light, light and moderate alcohol drinking and cancer incidence

YJ Choi, Cancer Res Treat. 2018;50(2):474-487

Site of cancerTotal No. of

studies

Very light drinking (≤ 0.5 drink/day)

Light drinking (≤ 1 drink/day)

Moderate drinking (1-2 drinks/day)

No. of studies

RR (95% CI)No. of studies

RR (95% CI)No. of studies

RR (95% CI)

Head and neck 2 1 1.11 (0.75-1.65) 2 1.00 (0.75-1.33) 2 1.18 (0.67-2.07)

Stomach 11 3 1.00 (0.78-1.30) 7 1.00 (0.95-1.07) 6 0.91 (0.78-1.06)

1 1.11 (0.71-1.73) 0 NA 0 NA

2 1.04 (0.66-1.64) 2 1.01 (0.92-1.11) 2 0.91 (0.68-1.20)

Colorectum 16 6 1.10 (0.94-1.28) 14 1.04 (1.01-1.06) 10 1.10 (1.03-1.19)

2 0.92 (0.78-1.08) 7 1.02 (0.98-1.06) 5 1.04 (0.95-1.13)

3 1.31 (0.92-1.86) 6 1.06 (1.01-1.11) 6 1.19 (1.06-1.35)

Lung 10 3 0.89 (0.84-0.93) 10 0.91 (0.90-0.94) 8 0.98 (0.91-1.07)

2 0.82 (0.70-0.95) 4 0.90 (0.87-0.94) 4 1.05 (0.99-1.11)

1 0.86 (0.71-1.03) 3 0.91 (0.90-0.95) 4 0.98 (0.82-1.16)

Breast (female) 34 20 1.04 (1.01-1.07) 25 1.09 (1.06-1.12) 15 1.13 (1.11-1.15)

Endometrium 9 6 0.95 (0.80-1.12) 7 0.98 (0.93-1.03) 4 0.93 (0.84-1.04)

Ovary 5 2 1.00 (0.82-1.22) 5 1.02 (0.88-1.20) 4 1.20 (0.92-1.56)

Cervix and uterus 2 NA NA 2 1.02 (0.88-1.19) 2 0.99 (0.83-1.17)

Association between very light, light and moderate alcohol drinking and cancer incidence

YJ Choi, Cancer Res Treat. 2018;50(2):474-487

Site of cancerTotal No. of

studies

Very light drinking (≤ 0.5 drink/day)

Light drinking (≤ 1 drink/day)

Moderate drinking (1-2 drinks/day)

No. of studies

RR (95% CI)No. of studies

RR (95% CI)No. of studies

RR (95% CI)

Head and neck 2 1 1.11 (0.75-1.65) 2 1.00 (0.75-1.33) 2 1.18 (0.67-2.07)

Stomach 11 3 1.00 (0.78-1.30) 7 1.00 (0.95-1.07) 6 0.91 (0.78-1.06)

1 1.11 (0.71-1.73) 0 NA 0 NA

2 1.04 (0.66-1.64) 2 1.01 (0.92-1.11) 2 0.91 (0.68-1.20)

Colorectum 16 6 1.10 (0.94-1.28) 14 1.04 (1.01-1.06) 10 1.10 (1.03-1.19)

2 0.92 (0.78-1.08) 7 1.02 (0.98-1.06) 5 1.04 (0.95-1.13)

3 1.31 (0.92-1.86) 6 1.06 (1.01-1.11) 6 1.19 (1.06-1.35)

Lung 10 3 0.89 (0.84-0.93) 10 0.91 (0.90-0.94) 8 0.98 (0.91-1.07)

2 0.82 (0.70-0.95) 4 0.90 (0.87-0.94) 4 1.05 (0.99-1.11)

1 0.86 (0.71-1.03) 3 0.91 (0.90-0.95) 4 0.98 (0.82-1.16)

Breast (female) 34 20 1.04 (1.01-1.07) 25 1.09 (1.06-1.12) 15 1.13 (1.11-1.15)

Endometrium 9 6 0.95 (0.80-1.12) 7 0.98 (0.93-1.03) 4 0.93 (0.84-1.04)

Ovary 5 2 1.00 (0.82-1.22) 5 1.02 (0.88-1.20) 4 1.20 (0.92-1.56)

Cervix and uterus 2 NA NA 2 1.02 (0.88-1.19) 2 0.99 (0.83-1.17)

Association between very light, light and moderate alcohol drinking and cancer incidence

YJ Choi, Cancer Res Treat. 2018;50(2):474-487

Site of cancerTotal No. of

studies

Very light drinking (≤ 0.5 drink/day)

Light drinking (≤ 1 drink/day)

Moderate drinking (1-2 drinks/day)

No. of studies

RR (95% CI)No. of studies

RR (95% CI)No. of studies

RR (95% CI)

Head and neck 2 1 1.11 (0.75-1.65) 2 1.00 (0.75-1.33) 2 1.18 (0.67-2.07)

Stomach 11 3 1.00 (0.78-1.30) 7 1.00 (0.95-1.07) 6 0.91 (0.78-1.06)

1 1.11 (0.71-1.73) 0 NA 0 NA

2 1.04 (0.66-1.64) 2 1.01 (0.92-1.11) 2 0.91 (0.68-1.20)

Colorectum 16 6 1.10 (0.94-1.28) 14 1.04 (1.01-1.06) 10 1.10 (1.03-1.19)

2 0.92 (0.78-1.08) 7 1.02 (0.98-1.06) 5 1.04 (0.95-1.13)

3 1.31 (0.92-1.86) 6 1.06 (1.01-1.11) 6 1.19 (1.06-1.35)

Lung 10 3 0.89 (0.84-0.93) 10 0.91 (0.90-0.94) 8 0.98 (0.91-1.07)

2 0.82 (0.70-0.95) 4 0.90 (0.87-0.94) 4 1.05 (0.99-1.11)

1 0.86 (0.71-1.03) 3 0.91 (0.90-0.95) 4 0.98 (0.82-1.16)

Breast (female) 34 20 1.04 (1.01-1.07) 25 1.09 (1.06-1.12) 15 1.13 (1.11-1.15)

Endometrium 9 6 0.95 (0.80-1.12) 7 0.98 (0.93-1.03) 4 0.93 (0.84-1.04)

Ovary 5 2 1.00 (0.82-1.22) 5 1.02 (0.88-1.20) 4 1.20 (0.92-1.56)

Cervix and uterus 2 NA NA 2 1.02 (0.88-1.19) 2 0.99 (0.83-1.17)

Association between very light, light and moderate alcohol drinking and cancer incidence

YJ Choi, Cancer Res Treat. 2018;50(2):474-487

Association between light alcohol drinking (≤1 drink/day) and

the risk of female breast cancer in a random-effects meta-analysis.

SY J Int J Epidemiology. 2016;916-928

meta-analysis from 20 studies

total of 1,089,273 participants during a 6-18 years of follow-up

SY J Int J Epidemiology. 2016;916-928CUP Report 2018, Diet, nutrition, physical activity and breast cancer

Multivariable relative risks (95% CIs) for 5 g/d

categories of alcohol consumption

and total breast cancer, compared with non-

drinkers.

Alcohol (as

ethanol) (g/day)RR (95%CI)

0 1

2.5 1.02 (1.02-1.02)

5.1 1.04 (1.04-1.05)

10 1.08 (1.07-1.10)

15 1.13 (1.11-1.14)

22 1.18 (1.16-1.20)

31.2 1.26 (1.23-1.28)

43.8 1.36 (1.31-1.41)

55 1.46 (1.39-1.54)

Relative risk of breast cancer and

alcohol estimated using non-linear

models

SY J Int J Epidemiology. 2016;916-928

Pooled multivariable relative risks for categories of total alcohol intake and breast

cancer overall and by hormone receptor status

Total alcohol intake (g/day) P-value,

test for trendNon-

drinkers>0–<5 5–< 15 15–< 30 ≤ 30

Total breast

cancer

No. of cases 13255 12202 6235 2686 1805

RR (95% CI) 1 1.03 (1.00–1.06) 1.10 (1.06–1.14) 1.19 (1.14–1.25) 1.32 (1.23–1.41) <0.001

By ER status

ER+ No. of cases 7829 6965 3748 1618 1042

RR (95% CI) 1 1.04 (0.99–1.08) 1.12 (1.07–1.18) 1.27 (1.17–1.39) 1.35 (1.23–1.48) <0.001

ER- No. of cases 1836 1677 924 335 212

RR (95% CI) 1 1.08 (1.01–1.16) 1.19 (1.08–1.31) 1.17 (1.04–1.33) 1.28 (1.10–1.49) <0.001

By PR status

PR+ No. of cases 6424 5694 3022 1315 839

RR (95% CI) 1 1.03 (0.98–1.08) 1.13 (1.08–1.18) 1.28 (1.16–1.42) 1.36 (1.21–1.54) <0.001

PR- No. of cases 2781 2606 1446 532 351

RR (95% CI) 1 1.09 (1.01–1.17) 1.17 (1.09–1.26) 1.17 (1.06–1.30) 1.30 (1.16–1.46) <0.001

• Continuous Update Project by World cancer research fund network

meta-analysis from 23 studied (98,046 cases) about alcohol and breast cancer

Pooled meta-analysis

CUP Report 2018, Diet, nutrition, physical activity and breast cancer

• the dose-response meta-analysis from 10 studies (n=4,227 cases)

: 5 % increased risk per 10 g of ethanol/day (RR 1.05 (95% CI 1.02-1.08))

Premenopausal

CUP Report 2018, Diet, nutrition, physical activity and breast cancer

• the dose-response meta-analysis from 18 studies (n=4,426 cases)

: no significant increased risk per 10g of ethanol/day (RR 1.03 (0.99-1.07))

Premenopausal

CUP Report 2018, Diet, nutrition, physical activity and breast cancer

• the dose-response meta-analysis from 22 studies (n=35,221 cases)

: 9 % increased risk per 10 g of ethanol/day ((RR 1.09 (95% CI 1.07-1.12))

Postmenopausal

CUP Report 2018, Diet, nutrition, physical activity and breast cancer

• positive association in ER (+) cancer

Hormone receptor status

CUP Report 2018, Diet, nutrition, physical activity and breast cancer

Summary

• Alcohol can make breast cancer even in very small dose.

• Relative risk of breast cancer is increased with dose of alcohol

consumption

• Consumption of alcoholic drinks is

- probably a cause of premenopausal breast cancer.

- convincing cause of postmenopausal breast cancer

- probably cause of ER (-) breast cancer

- convincing cause of ER(+) breast cancer

Allison K, J Breast Cancer 2018;21(2):158-164

Alcohol and recurrence

• between 2007 and 2012, (n=1,407) , USA.

• Alcohol consumption during the 12 months preceding diagnosis

• One drink was

: one 355-mL can or a bottle of beer, one 148-mL glass of wine,

one cocktail, or one shot of liquor.

• Alcohol consumption was categorized

: as binary (none [0 drinks/month] and any [>1 drink/month])

• the number of drinks

: drinks per day (n=1,182), as never (0 drinks/week),

moderate (≤7 drinks/week), and heavy (>7 drinks/week)

Allison K, J Breast Cancer 2018;21(2):158-164

Alcohol and recurrence

Allison K, J Breast Cancer 2018;21(2):158-164

Alcohol and recurrence

Allison K, J Breast Cancer 2018;21(2):158-164

“our findings suggest better breast cancer-free survival in women

consuming alcohol, regardless of their adjuvant hormone therapy”

“The induction of enzymes in the P450 family by alcohol could accelerate

the metabolism of tamoxifen resulting in an increase in concentrations of

biologically active metabolites that inhibit the action of estrogen on

estrogen receptors potentially leading to better survival”Allison K, J Breast Cancer 2018;21(2):158-164

Alcohol and recurrence

Phanthira S., Cancer Treatment Reviews 50 (2016) 155–167

Alcohol and recurrence

assessed for alcohol intake from

16 studies (n = 35,690)

from the time of their first breast cancer

diagnosis until recurrence

Phanthira S., Cancer Treatment Reviews 50 (2016) 155–167

Phanthira S., Cancer Treatment Reviews 50 (2016) 155–167

Phanthira S., Cancer Treatment Reviews 50 (2016) 155–167

Phanthira S., Cancer Treatment Reviews 50 (2016) 155–167

Alcohol and recurrence

“The evidence for an association between alcohol and breast caner free

survival is less clear. “

“ some evidence that alcohol consumption, potentially from levels as

low as 6 g of alcohol per day, modestly increases the risk of breast cancer

recurrence”

Take Home message

• Alcohol

: makes variety of health problem

: is Group I carcinogen

• Consumption of alcoholic drinks is a probable or convincing cause of

breast cancer depending on of pre/post-menopause and ER status

• Mechanism of breast carcinogenesis

: ethanol metabolite acetaldehyde, oxidative damage

reduced folic acid, Vit B6, 12, perturbation of estrogen metabolism

• Although alcohol and breast cancer free survival is less clear, alcohol

consumption might increases the risk of breast cancer recurrence.

Thank you for your attention