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TRANSCRIPT
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