Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been hypothesized to be associated with reduced risk of breast cancer; however, results of epidemiological studies have been mixed. Few studies have investigated these associations among African American women.To assess the relation of aspirin use to risk of breast cancer in African American women, we conducted a prospective analysis within the Black Women’s Health Study, an ongoing nationwide cohort study of 59,000 African American women. On baseline and follow-up questionnaires, women reported regular use of aspirin (defined as use at least 3 days per week) and years of use. During follow-up from 1995 through 2017, 1919 invasive breast cancers occurred, including 1112 ER+, 569 ER−, and 284 triple-negative (TN) tumors. We used age-stratified Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of aspirin use with risk of ER+, ER−, and TN breast cancer, adjusted for established breast cancer risk factors.Overall, the HR for current regular use of aspirin relative to non-use was 0.92 . For ER+, ER−, and TN breast cancer, corresponding HRs were 0.98 , 0.81 , and 0.70 , respectively.Our findings with regard to ER− and TN breast cancer are consistent with hypothesized inflammatory mechanisms of ER− and TN breast cancer, rather than hormone-dependent pathways. Aspirin may represent a potential opportunity for chemoprevention of ER− and TN breast cancer. Relative to US white women, African American women have a disproportionately high incidence of aggressive breast cancer subtypes, such as estrogen receptor (ER)-negative tumors –3, and hFew studies have investigated these associations among African American women. A previous Black Women’s Health Study (BWHS) analysis of aspirin use and 12-year risk of breast cancer showed a statistically significant inverse association ; howeverThe BWHS is an ongoing prospective cohort of 59,000 African American women, who were ages 21 to 69 years  at baseline in 1995. Every 2 years, follow-up questionnaires are sent to participants to update information on incident cancer diagnoses and reproductive and behavioral factors, including medication use . Noticesn = 743) or any other type of cancer (except non-melanoma skin cancer) (n = 696) before baseline in 1995, or if they did not answer the question about aspirin use on the baseline questionnaire (n = 4399); the final analytic cohort included 53,162 African American women ages 21–69 at baseline. The study protocol was approved by the Boston University Institutional Review Board (IRB) and by the IRBs of participating cancer registries as required.For this analysis, women were excluded if they had been diagnosed with breast cancer  or identified through death records or linkage to 24 cancer registries in states covering 95% of participants (5% of cases). Breast cancer diagnoses were confirmed by review of medical records, pathology reports, and cancer registry records. Data on tumor characteristics were also abstracted from these records.Among 53,126 women in the BWHS who were free from cancer and had available information on aspirin use at baseline, there were 1919 invasive breast cancers diagnosed through 2017. Information on ER status was available for 88% of these cases (569 ER− and 1112 ER+ tumors). Of the 569 ER− breast cancers, HER2 status was known for 368 (65%); 284 (77%) of these were classified as triple-negative (TN) cases.Regular medication use, defined as use at least 3 days per week, was queried on baseline and biennial follow-up questionnaires. On the baseline questionnaire, women reported current use of aspirin or acetaminophen, separately, at least 3 days per week. Current users were also asked to report the duration of use . Popular brand names  were given as a prompt. Regular use of other NSAIDs  at least 3 days per week was queried beginning in 2009. Prior to 2009, non-aspirin NSAID use was reported via open-text response and coded using the Slone Drug Dictionary ; howeverThe baseline questionnaire collected information on established and putative risk factors for breast cancer including adult height, weight, age at menarche, oral contraceptive use, parity, age at first birth, lactation, menopausal status, postmenopausal hormone use, alcohol consumption, physical activity, and breast cancer in first-degree relatives. Except for age at menarche, all data were updated on subsequent questionnaires.Women contributed person-years from the beginning of follow-up in March 1995 until diagnosis of breast or other cancer, death, or end of follow-up in March 2017, whichever occurred first . We used Cox proportional hazards regression models, stratified by age in 1-year intervals and questionnaire cycle such that age was the underlying time scale, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for use of aspirin in relation to risk of overall, ER+, ER−, and TN breast cancer, separately. Aspirin use was treated as time-varying and modeled as a categorical exposure variable ; over follow-up, current users were re-classified as past users if they no longer reported current regular use on subsequent questionnaires. In secondary analyses, we applied a 2-year lag to exposure classification, starting follow-up in 1997 and assigning aspirin use for each cycle according to that reported on the previous questionnaire. We also considered the duration of use among current users . Finally, we also evaluated possible associations with the use of acetaminophen, which is an analgesic but does not have anti-inflammatory properties.2), age at menarche , recency of oral contraceptive use , parity , age at first birth , lactation (never or ever), menopausal status , duration of estrogen plus progestin use , alcohol consumption , physical activity , and first-degree family history of breast cancer (yes or no). Additional models further adjusted for the current use of other NSAIDs . We also evaluated potential confounding by recent mammography use. Results were virtually unchanged; therefore, mammography use was not retained in the final multivariable models. Time-varying risk factors were updated at each questionnaire cycle. Missing indicator categories were used to account for missing information in covariates . To test whether associations differed by ER status, we used the contrast test method for heterogeneity by subtype ; however, the association was primarily apparent among population-based case-control studies  and hospital-based case-control studies  with no association among cohort studies  or nested case-control studies  . EpidemiThere have also been large prospective studies that reported no association or a positive association between aspirin use and breast cancer risk. Among postmenopausal women in the Nurses’ Health Study (NHS) and among premenopausal women in the NHSII, there was no association between current regular aspirin use (at least 2 tablets per week) and breast cancer risk overall or by ER status –25. ResuBesides the BWHS, the MEC is the only other prospective cohort study to report on the relation of aspirin use to breast cancer risk among African American women ; stratification by ER status was not reported . In the Aspirin and other NSAIDs could modulate breast cancer risk via their anti-proliferative, anti-angiogenic, and pro-apoptotic properties. Aspirin inhibits cyclooxygenase (COX), which is necessary for prostaglandin synthesis. Low-dose aspirin is specific for platelet COX-1, while the proposed anti-cancer effects are hypothesized to operate primarily through the COX-2 pathway . ProstagAn important limitation of this analysis is the lack of information on aspirin dose and possible misclassification of exposure based on self-report. Because we asked about regular use of aspirin defined as use at least 3 days per week, we were unable to distinguish whether more frequent use  shows stronger associations with breast cancer. Also, we did not evaluate non-aspirin NSAIDs separately because we did not consistently query the use of non-aspirin NSAIDs in the BWHS until 2009; however, adjustment for the use of non-aspirin NSAIDs reported on all questionnaires via open-text responses did not change effect estimates. Aspirin is a commonly used NSAID and may be expected to have a stronger protective effect on breast cancer because of its irreversible binding to COX-2 compared to non-aspirin NSAIDs . We lackStrengths of this study include its prospective design and more than 20 years of follow-up, including repeated assessment of aspirin use over time which allowed us to update exposure information at each questionnaire cycle. Detailed characterization of breast cancer risk factors within the BWHS enabled careful control for potential confounding factors in our analyses. Finally, this is the largest study of aspirin use and breast cancer risk among African American women to date and we had a sufficient sample size to evaluate associations for subtypes of breast cancer defined by ER and HER2 status.The results of this study support the hypothesis that regular aspirin use is associated with reduced breast cancer risk, particularly for ER− and TN breast cancer, in African American women. If findings from this study are confirmed, aspirin may represent a potential opportunity for chemoprevention of ER− and TN breast cancer.Additional file 1 : Table S1. Multivariable-adjusted hazard ratios (95% CI) for associations of lagged aspirin use in the BWHS, overall and by ER status, 1997-2017. Table S2. Multivariable-adjusted hazard ratios (95% CI) for associations of current regular aspirin use relative to non-use of any NSAIDs in the BWHS, overall and by ER status, 19952017.


During puberty, a woman’s breasts are vulnerable to environmental damage (“window of vulnerability”). Early exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods  are hypothesized to promote molecular damage that increases breast cancer risk. However, prospective human studies are difficult to perform and effective interventions to prevent these early exposures are lacking. It is difficult to prevent environmental exposures during puberty. Specifically, young women are repeatedly exposed to media messaging that promotes unhealthy foods. Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food and exposure to contaminated air, water, and soil. The purpose of this review is to gather information on potential exposures during puberty. In future directions, this information will be used to help elementary/middle-school girls to identify and quantitate environmental exposures and develop cost-effective strategies to reduce exposures. During puberty, the human breast bud undergoes major structural and cellular changes. Many human and animal studies provide evidence that during puberty, the breast is highly susceptible to damage from exposure to environmental toxins (window of susceptibility). Recent studies provide evidence that environmental exposures during puberty may increase the risk of breast cancer in adulthood. Currently, young women are exposed to unhealthy food and environmental toxins. In California, many young women live in rural, suburban, and urban neighborhoods that lead to additional exposure risks.We are all impacted by environmental exposures. The majority of rural residents lack access to the food they grow and live in food deserts . With increasing drought, water tables are dropping and there is an increasing concentration of heavy metals in both water and food. Similar to rural women, urban women have a high likelihood of living in neighborhoods that lack access to healthy food. Urban neighborhoods frequently have old plumbing, increasing the risk of heavy metal contamination. The majority of our cities are contaminated with industrial waste.There are many studies underway investigating the link between poor diet, environmental exposures, and breast cancer. Much is likely to be learned in the future. However, in the present, a generation of young women are being exposed to environmental toxins. Here, we have gathered a panel of experts to discuss some of the potential linkages between environmental exposures, diet, and breast cancer risk. It is the authors’ hope that this discussion can promote strategic interventions to reduce breast cancer risk in young women and help foster a generation of young women who are empowered to act as advocates for their health.The mature human breast is composed of milk-producing lobules, connected to the nipple by a system of branching “tree-like” ducts surrounded by adipose and connective tissue. Breast cancer is thought to develop within a terminal ductal lobular unit (TDLU), which includes the lobule and its most proximal ducts . The breAnimal and epidemiological studies provide evidence that there are windows of susceptibility: implantation, fetal growth, puberty, pregnancy, and aging, during which, the breast is thought to be particularly vulnerable to environmental exposures. Environmental exposures during windows of susceptibility are hypothesized to increase subsequent breast cancer risk. There is increasing evidence that a woman’s lifetime breast cancer risk is increased by exposures before and during puberty. Epidemiologic studies provide evidence that medications  and diseEpidemiologic and laboratory studies provide evidence that environmental exposures during puberty are associated with an increased adult risk of breast cancer. In experimental studies on rats, exposure to the carcinogen dimethylbenz [a] anthracene (DMBA) during puberty resulted in the highest number of tumors (vs. other times of life) . In tranIn 1996, the late Helene Smith proposed a model of mammary carcinogenesis, where breast cancer developed in a “high-risk epithelial field” containing genetic  damage that promoted the survival of a second genetic “hit” B [1]. ThBreast cancer is the most common malignancy diagnosed during pregnancy . Women aEpigenetics refers to heritable changes in gene expression and phenotypes without changes in the underlying DNA sequence. This is achieved by special marks added to the DNA or to proteins surrounding the DNA. Epigenetic changes can occur in response to environmental cues and alter chromatin structure and expression of genes associated with pathophysiological conditions, mediate transgenerational effects, and impact risk for cancer and diabetes ,17,18. EBRCA1 and BRCA2 significantly increase breast cancer was a landmark finding. Despite the importance of this discovery, the majority of breast cancers occur in women who lack germline mutations; increasingly, epigenetic alterations are being implicated in breast cancer initiation and progression. Study of the potential link between breast cancer and epigenetics is just beginning [The discovery that germline mutations of eginning .The epigenetic inactivation of BRCA1/2: Homologous recombination deficiency can result from epigenetic processes, leading to the silencing of homologous recombination genes, including BRCA1/2 . Early sEpigenetic mechanisms: Nuclear DNA is packed into chromatin, a histone-protein complex. The basic subunit of chromatin is the nucleosome which is composed of octameric histone protein complexes formed by dimers of core histones H2A, H2B, H3, and H4 and wrapped by 147 bp of DNA. Dynamic changes in chromatin structure determine whether gene expression is “turned on” (activation) or “turned off” (repression) in response to intracellular and extracellular cues. Changes in chromatin structure are regulated by epigenetic modifications such as DNA methylation (DNAme) and histone post-translational modifications (PTMs) ,23. In ade novo DNAme patterns during development and are maintained by DNMT1 later in life. DNA demethylases such as ten-eleven translocation enzymes (TET) catalyze the oxidation of 5-methylcytosine and dynamically regulate DNAme to generate 5’-hydroxymethylated cytosine [Epigenetic modifications are mediated by “writers” and removed by “erasers”. Epigenetic modifications are interpreted by “readers” that specifically interact with DNAme and modified or unmodified histones ,23. DNAmHistone post-translational modifications either activate or inhibit gene expression. Histone acetylation and methylation are mediated by histone acetyl transferases (HATs) and histone methyltransferases (HMTs), respectively. Their actions are opposed by histone deacetylates (HDACs) and demethylases (HDMs), respectively. HMTs and HDMs are specific in terms of the particular lysine residue and the extent of methylation. HATs and HDACs lack this specificity . These ecis and trans via interaction with key RNA binding proteins, epigenetic factors, enhancers, and chromatin. lncRNA-mediated epigenetic mechanisms regulate diverse biological processes, including X chromosome inactivation, genomic imprinting, stem cell differentiation, and inflammation; dysregulation has been reported in association with diabetes and cancer [Epigenetic mechanisms are fine-tuned by lncRNAs: >200 nucleotide-long transcripts without protein-coding potential. lncRNAs are expressed as divergent, anti-sense, and intergenic transcripts that can host genes of non-coding miRNAs and enhancer RNAs . LncRNAsd cancer .S-adenosylmethionine (SAM) (methyl group donor for DNA methylation). Environmental factors that alter early nutrition and/or SAM production alter CpG methylation at important DMRs and impact future disease risk [Genomic imprinting is an inherited form of parent-of-origin-dependent epigenetic gene regulation that renders autosomal genes functionally haploid in a species, developmental stage, and tissue dependent manner ,27. Therase risk ,36. Disease risk ,36.The epigenome represents the genome-wide interactions among all three epigenetic layers. Epigenomics refers to genome-wide profiles and consequences of these epigenetic marks. Through landmark studies such as the encyclopedia of DNA elements (ENCODE) and the National Institute of Health (NIH) Roadmap Epigenomics Project, high-throughput next-generation DNA sequencing (seq) technologies were developed to investigate the epigenome. These studies have allowed researchers to build high-resolution maps of the chromatin structure and genome-wide distribution of epigenetic modifications at regulatory elements . These tYoung women face exposures to carcinogens and potential carcinogens by drinking water, breathing air, applying cosmetics, and eating food . IncreasWater is the source of many environmental exposures . EnvironHeavy metal contamination come from a variety of sources including both point sources (mining) and nonpoint sources (lead pipes). The main causes of water contamination come from metal refineries, cigarette smoke, improper disposal of waste (electronics/batteries), industrial discharge, and leeching from processing sites ,45.Heavy metals are strongly linked to carcinogenesis and have been associated with epigenetic modifications in mice and humans ,47. LeadAir pollution is a known carcinogen, resulting from a mixture of natural substances and man-made emissions . There aSince the Clean Air Act of 1970, air quality significantly improved beginning in 2000 with a 16% decrease in unhealthy ozone levels . Althoug2.5 levels in air, and inhalation of air toxins against percent low-income and percent minority [California air pollution results from, but is not limited to, higher traffic-related emissions, frequent wildfires, an increase in oil and gas extraction, higher temperature, and topography . Low incminority . While uminority .Many studies have suggested the implications of air pollution on health via epigenetic regulation, but further investigation must be done to examine whether early life exposure to air pollution poses greater risks of breast cancer susceptibility and development. A large component of urban air pollution results from traffic-related air pollution (TRAP). TRAP is a source of particulate matter including black carbon, heavy metals, sulfur dioxides, nitrogen oxides, and polycyclic aromatic hydrocarbons (PAH) and contributes to generating ozone. Heavy metals and PAH are associated with DNA hypomethylation . Ozone cThe United States Food and Drug Administration (FDA) regulates both drugs and cosmetics. However, FDA regulation of cosmetics is significantly less stringent. Cosmetics are defined by the FDA as “articles intended to be rubbed, poured, sprinkled or sprayed on, introduced into or applied to the human body…for cleansing, beautifying, promoting attractiveness, or altering the appearance”. According to the American Cancer Society, unlike drug regulation, the FDA does not require that cosmetic companies test for product safety. Furthermore, the Federal Food, Drug and Cosmetic Act prohibits the FDA from (1) reviewing ingredients used in cosmetic products prior to marketing and (2) recalling toxic products ,56,57,58From 2004 to 2017, 10,726 adverse event cases have been reported to the FDA ; furtherThe incomplete regulation of cosmetics by the FDA and widespread availability of cosmetics containing potential endocrine disrupters and potential carcinogens is cause for concern. The FDA has made the Center for Food Safety and Applied Nutrition’s Adverse Event Reporting System (CAERS) publicly available in 2016 to increase transparency and encourage adverse event reporting from consumers related to cosmetics . AnotherHair straightening treatments are known to contain formaldehyde. The amount of formaldehyde in each product varies. Oregon’s Occupational Safety and Health Safety (OSHS) found unsafe levels of formaldehyde in a brand of Brazilian straightener . There aAluminum salts are commonly found in antiperspirants. Daily use of antiperspirants results in long-term, local exposure of the breast to aluminum salts. Chronic exposure to aluminum salts has been shown promote DNA damage in animal and human cell culture models. The concern is that chronic exposure to aluminum salts before and during puberty might have the potential to generate genomic instability in rapidly changing breast tissue .Exposure to high levels of estrogenic compounds, or EDCs, impact the interaction of endogenous estrogen and progestogen with their receptors. EDCs plays a role in regulating growth and development by binding to hormone receptors in the cell and blocking or altering downstream cell signaling. Many synthetic compounds are either known or suspected to be EDCs . Known EThere is increasing evidence that EDCs may reprogram normal progenitor cells in the breast; subsequently, these reprogramed normal cells are transformed by subsequent hormone exposures . ConsistBPA is an EDC used to soften plastics and increase its pliability. BPA has been detected in human blood, the placenta, fetal liver, and breast milk. BPA exposure is associated with early puberty and disrupts hormone signaling. In vitro, BPA upregulates AKT to increase proliferation and apoptosis-resistance. In a recent study, 27 genes commonly found to be dysregulated in ER-positive and ER-negative breast cancer interact with EDCs.Parabens are preservative that are used to extend shelf-life of commercial products. Parabens are found in body creams, antiperspirants, sunscreen, lotion, shampoos ,64. TherPhthalates are found in hair cosmetics, deodorants, nail polish, and lotions ,66. The Many studies have investigated whether diets/nutrients alter breast cancer risk. Preclinical studies provide evidence that specific dietary components may have either a protective or promoting effects . The majThe Nurses’ Health Study II (NHSII) investigated the potential association between adolescent dietary patterns and premenopausal breast cancer (614 cases) . A margiObesity was once associated with wealth; today, it is associated with poverty. Disparities in access to healthy food sources (food deserts)  and the 2 was equivalent to the incidence of type-2 diabetes at a BMI of (1) 24 kg/m2 in South-Asians, (2) 25 kg/m2 in East-Asians, and (3) 26 kg/m2 in Black/African-Americans [The relationship between BMI and obesity varies significantly between individuals of different races and ethnic groups ,76. For mericans . These sThe consumption of energy-dense foods is strongly associated with an increased risk of cardiovascular disease, diabetes, and obesity; recent studies provide a potential link with cancer. Energy-dense foods include processed foods containing high fat and/or sugar. In a case-control study with 1692 African American/Black women aged 20 and older (803 cases and 889 controls), frequent energy-dense, fast food consumption was related to increase premenopausal breast cancer risk and with ER+ breast cancers .The American Heart Association lists soft drinks as among the major sources of dietary sugar . To reduStress is a multifaceted term that can refer to a stressful stimulus , an organism’s response, either psychological or physiological, and the consequences of this response . The hypStress researchers have identified “sensitive” and “critical” phases of development; on-going studies provide evidence that early life stressors have a lifelong impact on gene expression . Early lNeighborhoods are a major determinant of health and life expectancy; individuals living just a few streets apart may have a vastly different risk of environmental exposures, diet, and disease, because of where they live ,93. In 2Since neighborhoods matter, it is important to have a detailed understanding of the environments people live and work in. Microscale environmental data are needed to evaluate how neighborhoods may be linked with disease, including street features , availability of stores and restaurants , crime, sources of pollution , and location of schools and medical facilities.A better understanding of neighborhood inequities and how they lead to increased breast cancer risk is essential for developing policy that can equitably reduce cancer risk. Environmental justice mapping studies have been particularly useful to encourage the implementation of equitable policies and empower vulnerable communities ,95,96,97Currently, there is a significant movement underway to develop interactive research tools that can support public health advocacy and environmental justice. Examples include (1) the United States Department of Agriculture (USDA) food desert locator , (2) EnvEarly exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods  are hypothesized to promote molecular damage that increases breast cancer risk; however, as outlined above, evidence for mechanistic causality is lacking. It is difficult to prevent environmental exposures during puberty; young women are repeatedly exposed to media messaging that promotes unhealthy foods.Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food (food deserts) and contaminated water and soil (neighborhood red-lining). Through our K-12 community based science technology, engineering, and math (STEM) programs, we aim to engage elementary/middle-school girls in community science. Students will measure environmental toxins in their tap water, read food labels, and identify food additives; we will work with students to develop strategies to reduce exposures . With ouReducing dietary and environmental exposures during puberty requires a step-wise, coordinated effort. Importantly, this effort must engage multiple stakeholders, neighborhoods, schools, advocacy groups, and the government. We will first test our program on a small scale, leveraging our established Los Angeles STEM programs, epigenetic science, on-going community outreach, water and soil assessment programs, and working relationship with local schools and the government. The effectiveness of our initial study will be evaluated and fine-tuned by a working group consisting of external scientific advisors, breast cancer advocates/community members, local schools, and the government.


ADH1B (rs1229984) and ALDH2 (rs671), alcohol consumption, the effect of a combination of the two polymorphisms, and breast cancer risk were studied in a population of East-Asian women. In this study, 623 breast cancer cases and 1845 controls, aged 40 or above, were included. The association between ALDH2 polymorphism and breast cancer risk was validated in 2143 breast cancer cases and 3977 controls. Alcohol consumption increased the risk of breast cancer regardless of ADH1B and ALDH2 genotypes. The rs671 polymorphism of ALDH2 was independently associated with increased breast cancer risk . The ADH1B rs1229984 polymorphism, and combined effects of the rs671 and rs1229984 polymorphisms, did not reveal any significant association with breast cancer. Stratification by menopausal status revealed that rs671 gene polymorphisms were significantly associated with breast cancer only in postmenopausal women . This is the first study to demonstrate an independent association between ALDH2 gene variants and breast cancer in Asian women. Further studies are warranted to further elucidate the etiology of breast cancer as it relates to alcohol consumption in Asian women.The associations between genetic polymorphisms in  In 2007, the International Agency for Research on Cancer (IARC) classified alcoholic beverages as group 1 carcinogens for the pharynx, larynx, esophagus, liver, colorectum, and female breast based on evidence on the toxicity of ethanol from epidemiological and animal studies2. Following alcohol intake, the enzyme alcohol dehydrogenase (ADH) oxidizes alcohol to acetaldehyde, which is highly toxic and carcinogenic to cells and tissues, and is detoxified to acetate by aldehyde dehydrogenases (ALDH)3. Thus, gene variants involved in alcohol metabolism and detoxification are also thought to affect the genetic susceptibility to alcohol-associated cancers. Among these, polymorphisms in the ADH1B and ALDH2 genes are known to play a pivotal role in cancer development in combination with alcohol consumption4. The active ADH1B allele results in approximately 40 fold higher metabolism of alcohol to acetaldehyde compared to the inactive allele5. In cases with mutant ALDH2 genes, ALDH2 enzyme activity is suppressed and acetaldehyde metabolism in the liver is impaired; subsequent toxic reactions cause symptoms including facial flushing, nausea, headache, or palpitations after alcohol intake; those with deficient variants of ALDH2 genes are likely to either consume less alcohol or be highly addicted7.Alcohol consumption is a major risk factor that adversely affects the health of people worldwide2; however, the gene variants involved in alcohol metabolism or detoxification have only been inconclusively associated with breast cancer risk9. Considering increases in both alcohol consumption in women10 and incidence of breast cancer and related mortality in Asian countries11, in combination with the higher distribution of variant genes involved in alcohol metabolism or detoxification in the Asian population12, new studies exploring the associations and interactions among alcohol consumption, related ethanol-metabolizing genes, and breast cancer are warranted.In general, epidemiological and animal studies have consistently correlated high alcohol intake with increased breast cancer risk in womenADH1B (rs1229984) and ALDH2 (rs671), alcohol consumption, and their combined effects and breast cancer risk in an East-Asian population.Thus, in the present study, we investigated the association among genetic, functionally established single nucleotide polymorphisms (SNPs) in The general characteristics of the patients with breast cancer from the National Cancer Center (NCC) and age-matched controls from the Korean Genome Epidemiology Study (KoGES) are described in Table ALDH2 rs671 polymorphism, ADH1B rs1229984 polymorphism, and breast cancer risk. Compared to the non-drinkers, the ever drinkers and those who consumed 12 g alcohol or more per day exhibited increased association with breast cancer . The rs671 genotype, although unassociated with breast cancer in an adjusted model, was significantly associated with breast cancer risk after the model was additionally adjusted for daily alcohol intake in patients with a GA or AA genotype compared with those presenting a GG homozygote  and per increment of A . The ADH1B rs1229984 polymorphism did not exhibit any significant association. The combined effects of the ALDH2 rs671 and ADH1B rs1229984 polymorphisms are presented in Appendix Table 2. No significant association was observed between the combination of the two polymorphisms and breast cancer risk.Table ALDH2/ADH1B polymorphism. In those homozygous for the GG allele of rs671, the effects of ever consuming alcohol or daily alcohol intake were associated with increased risk of breast cancer . In terms of the rs1229984 variant of the ADH1B gene, those homozygous for TT exhibited a significantly increased risk of breast cancer in both ever drinkers and those who daily consumed >12 g day alcohol ; however, in women with a TC or CC genotype, no association was observed between alcohol consumption and breast cancer. When we combined the ALDH2/ADH1B polymorphisms, those homozygous for the major allele for both rs671 and rs1229984 (GG and TT) presented increased risk of breast cancer in ever drinkers  and those who consumed 12 g alcohol or more per day .Table P-value = 0.001 for ever alcohol drinkers; OR = 1.53, 95% CI = 1.08–2.18, P-value = 0.018 for those consuming ≤12 g ethanol/day; OR = 2.87, 95% CI = 1.52–5.40, P-value = 0.001 for those consuming>12 g ethanol/day, compared with non-drinkers). Nevertheless, polymorphisms in the rs671 gene were significantly associated with breast cancer only in postmenopausal women with dominant alleles  and in the additive model , but not for premenopausal women.Stratification by menopausal status revealed that alcohol consumption was significantly associated with breast cancer in premenopausal women  and an increment in the A allele increased breast cancer risk by 1.14-fold .After investigating 2143 breast cancer cases and 3977 controls, the polymorphism in the ALDH2 gene (rs671) increase the risk of breast cancer independently, after adjusting for other covariates such as alcohol consumption, in Asian women, and in particular in postmenopausal women. In this study, both ever consuming alcohol and high dose alcohol consumption (>12 g/day) increased the risk of developing breast cancer. However, the association between alcohol consumption and breast cancer was more prominent in those with ADH1B His/His or those that were homozygous for the major allele in both ADH1B and ALDH2.This is the first study suggesting that variants of the 13. Previous studies have reported inconsistent results, wherein they evaluated whether menopausal status modifies the effect of the association between alcohol consumption and breast cancer risk14. In the present study, this association was observed only in premenopausal women. A possible explanation for the nonsignificant result in postmenopausal women could be that fewer women ever consumed alcohol or high alcohol content drinks; thus, the number was insufficient to statistically power our results. Considering that several studies suggest a modified effect of known genetic and environmental factors such as MPO gene polymorphism, family history, obesity, or alcohol use by menopausal status15, a detailed approach stratified by menopausal status with larger sample size is warranted.The association among ever consuming alcohol, high alcohol consumption (>12 g/day), and breast cancer in all women observed in the present study was in accordance with that in previous studies and reviewsADH1B and ALDH2 are the major enzymes involved in alcohol metabolism in humans. The role of the ALDH2 gene has been widely studied in East-Asian countries because of the low prevalence of its variants in European populations. It has been reported that variants of the ALDH2 gene are correlated with an increased susceptibility to numerous cancers, particularly of the upper digestive organs, such as esophageal or gastric cancer17; however, for other cancer types, the results were generally nonsignificant or inconsistent18. For breast cancer, only three studies have investigated the role of the ALDH2 gene (rs671); however, none of them reported a significant association. In all three studies, the controls were recruited from women who visited the same hospital as the patients21. Although controls did not have cancer or other systemic diseases, and the proportion of alcohol consumption was in accordance with that in our study population, their inclusion may not substitute for the general population due to Berkson’s bias, a type of selection bias22. In our study population, the controls belonged to a population-based cohort, presumably free of Berkson’s bias, thus indicating a better reflection of females in general, and even after adjusting for alcohol consumption, polymorphisms in the ALDH2 gene independently increased breast cancer risk. The association between ALDH2 gene variants and breast cancer was validated in independent cases and all sampled control populations. In addition, compared with the previous studies in which the number of breast cancer patients and controls was less than 50021, the present study has a higher number of patients and 1:3 matching was used to increase the statistical power. In combination with the possible side effects of paclitaxel, a chemotherapeutic agent, due to alcohol’s role as a solvent23 women with the GA/AA genotype of ALDH2 would be highly susceptible to not only breast cancer but also side effects of breast cancer treatment, and are therefore a population with a potentially high risk for delterious health effects.ADH1B action results in higher blood acetaldehyde levels, which can increase DNA damage and lead to cancer24. In people with ADH1B His/His, the activity of ADH1B is enhanced, followed by rapid accumulation of acetaldehyde25. In epidemiological studies, ADH1B polymorphism has been associated with tumors of the upper digestive organs4 including esophageal cancer26. In terms of breast cancer, ADH1B itself did not present any association in most previous studies 28. One study reported a marginally protective association for ADH1B IVS1 + 896 A > G with breast cancer risk; however, the same SNP considered in this study did not exhibit any association29. Another study reported an interactive effect of ADH1B and alcohol consumption on breast cancer risk27. In the present study, although we did not identify a significant association between ADH1B polymorphism and breast cancer risk, a decreasing trend was observed in those with the C allele, in particular the homozygotes of the C allele, which was consistent with previous studies29. Another study reported that the effects of the ADH1B and ALDH2 genes were mediated via alcohol consumption and decreased hepatocellular carcinoma risk30, which was not consistent with a previous meta-analysis16. In a study by Lie et al., the population included chronic hepatitis B carriers and the effect of alcohol was higher30 than seen in the present study or other studies conducted in the Korean population31. Considering the subgroup of women with possibly higher alcohol susceptibility, the effects of the ADH1B and ALDH2 genes on alcohol drinking behavior and breast cancer risk might require further investigation.ALDH2 and ADH1B polymorphism status, despite the presence of variants and alcohol intake, specifically a high dose of alcohol intake, increased the risk of breast cancer. Among the variants studied, those with a TT genotype for rs1229984 exhibited higher risk of breast cancer in ever drinkers or in those who consume more than 12 g of ethanol per day. These results are contradictory to those from a study in German women, wherein a reduction in breast cancer risk associated with 12 g or more alcohol consumption per day was observed27. The frequency of the His/Arg allele of ADH1B gene varies among populations, specifically the Asian and European populations32, and is based on diet or other lifestyle factors; moreover, other interacting genes may presumably lead to different results between studies.In the present study, the association between alcohol consumption and breast cancer risk stratified by ADH1B and ALDH2 present strong association with alcohol dependence. People with the A allele of rs671 display less alcohol dependence, possibly owing to the unpleasant effects of a higher flush response33, and those with the rs1229984 His allele also show a decreased risk of alcohol dependence, especially in Asian populations34. A genome-wide association study for alcohol consumption revealed that the rs671 A allele was associated with decreased prevalence of drinkers and number of drinks, and that the rs1229984 T allele was associated with fewer drinks but not with drinking status35. In this study population, women who carried the GG allele of rs671 consumed alcohol with >12 g ethanol/day more often compared to those with the GA/AA genotype , as in previous studies35; however, their distribution was similar regardless of rs1229984 genotype. Previous studies included both men and women 35, and sex-differences in terms of alcohol intake pattern35 and alcohol metabolism may affect inconsistencies in the results.It has been reported that both ADH1B and ALDH2 may reduce the effects of alcohol and its toxic metabolites such as acetaldehyde, the effects of alcohol drinking such as intoxication and the recovery period may result in increased alcohol exposure.Women who carried both the GG and TT genotypes for rs671 and rs1229984, respectively, presented a higher risk of breast cancer when they had ever consumed alcohol or more than 12 g ethanol per day, suggesting that for those with increased activity of the enzymes involved in alcohol metabolism and detoxification, the effects of alcohol consumption on breast cancer risk are increased. In these populations, alcohol would be eliminated faster than in other populations. Although highly active ALDH2 gene and breast cancer in postmenopausal women and no association in premenopausal women20, our results reveal an increased association between the Lys (A) allele of rs671 and breast cancer in postmenopausal women. The previous study included few premenopausal women, only 226 cases and 209 controls and only 60 cases of postmenopausal women carrying the Lys allele20; this may explain the lack of association. Regarding the ADH1B gene, other studies have demonstrated no significant association with breast cancer in postmenopausal women36 and those aged 5027, and these observations were consistent with our results.Although a study conducted in Korea revealed marginally decreased association between the Lys allele of the ALDH2 and ADH1B genes is comparable with that in the general population37. Second, recall-bias could affect the results for measurements of alcohol consumption and other covariates. Some patients were recruited while receiving treatment, which may also affect the results. Third, the effects of other genes related to alcohol metabolism, such as Cytochrome P450 2E1, were not considered. Fourth, although this study included a larger sample size compared with previous studies on the association between ALDH2, ADH1B, alcohol consumption, and breast cancer, the statistical power may still be limited for elucidating gene–gene and gene–alcohol consumption interactions, and stratified analysis. In addition, some of the non-significant results from our subgroup analysis could be attributed to the low power of this study. Fifth, some variables that may affect both alcohol intake and breast cancer such as diet and exercise, were not considered because of limited available information and may have been incompletely adjusted for.This study has certain limitations. First, the existence of selection bias should be considered. To increase comparability, cases and controls were individually matched by age. Although external validity may be limited, the prevalence of variants in ALDH2 gene and breast cancer in Asian women with results validated from a large number of cases and controls. Alcohol consumption increased breast cancer risk, but for cases homozygous for the major alleles of ADH1B or/and ALDH2 polymorphisms, the increment was more prominent, suggesting that this was a high-risk population for breast cancers associated with alcohol consumption. Further studies with a larger sample size could help confirm the association between alcohol intake and gene interaction and breast cancer risk.This study is the first to reveal an independent association between variants of the in situ breast cancer, as confirmed by histology, at the NCC in Korea between February 2013 and October 2016. Healthy controls were selected from the KoGES, a population-based cohort constructed by the National Research Institute of Health (NIH), and the Centers for Disease Control and Prevention of Korea. Full details of the KoGES are described elsewhere38. Female control participants with a history of cancer were excluded, and 3986 women were considered for the study. Among these, 3977 controls provided information on alcohol consumption. All participants were from Korea, and written informed consent was obtained before enrolment. This study was approved by the National Cancer Center Institutional Review Board (IRB No. NCC 2015-0177). All procedures were performed in accordance with the Declaration of Helsinki.In total, we selected 750 women recently diagnosed with either invasive or All cases and controls were asked to complete a set of interviewer-assisted questionnaires on demographics, medical history, reproductive factors, and lifestyle . The subjects were questioned about alcohol consumption, their present drinking status, as well as the total duration of alcohol consumption for both present drinkers and those with a history of alcohol intake. In addition, the type of alcoholic beverage, weekly intake frequency, amount of alcohol consumed on each occasion, and serving sizes were evaluated. The subjects were classified according to drinking status (never and ever). Among ever drinkers, subjects were further classified according to alcohol intake: ≤12 g pure alcohol/day and >12 g pure alcohol/day based on the amount of ethanol in a standard drink.40. Of the 750 breast cancer cases and 3977 controls, 5 cases were excluded owing to a low call rate of <97% (n = 1) and family relationships (n = 4); after quality control, 745 cases and 3977 controls were evaluated. SNPs were excluded for low quality based on SNPolisher analysis , low call rate <95% in either the cases or controls (n = 371), deviation from Hardy–Weinberg equilibrium  in the controls (n = 713), and monomorphic characteristics in our population . In total, 688,196 markers were evaluated for quality control.Genomic DNA was extracted from peripheral blood leukocytes and genotyped using the Korea Biobank Array with 833,000 SNPs. The Korea Biobank Array is a chip optimized for genetic studies in the Korean population. Full details on Korea Biobank Array are described elsewhereALDH2 and ADH1B genes, respectively, were analyzed. The cases and controls were individually matched by age at a 1:3 ratio, and ultimately 623 breast cancer cases and 1845 controls aged 40 or above were included in the final analysis. Discrepancies between the evaluated cases and controls were 0% and 0% for rs671 and 0% and 0.6% for rs1229984, with a P-value of 0.922. These SNPs had minor allelic frequencies of 15.5% and 25.2% and met the Hardy–Weinberg equilibrium in the control samples.The SNPs rs671 and rs1229984, in the ALDH2 polymorphism and breast cancer. Demographic and lifestyle information, including on alcohol intake, was unavailable for these patients. Peripheral blood DNA was genotyped using an Affymetrix Genome-wide Human SNP Array 6.0 . As ALDH2 (rs671) was not included in the array, genotype imputation for rs671 was performed. The SHAPEIT (v2.r837) was used for prephasing, and imputation was performed using IMPUTE2 (2.3.2). Data from the 1000 Genome Project phase 3 East-Asian Ancestry sample (n = 504) were applied as a reference panel. The quality control process and imputation was conducted as follows: among all subjects, those with a sex mismatch (n = 3) were excluded. No subjects showed a low call rate or family relationships. SNPs were excluded in cases of low call rate <95% , deviation from Hardy–Weinberg equilibrium  in the controls (n = 897), or monomorphic traits in the population (n = 1710). In total, 513,738 markers were subjected to quality control. After imputation, the quality score was R2 = 0.57. The age distribution of the 2143 breast cancer patients and 3977 controls is presented in Appendix Table Data from 2143 breast cancer patients who were recruited as part of the KoGES were evaluated according to their sex, age, and genotype to validate the association between The relationship between alcohol consumption and breast cancer risk was assessed with a simple logistic regression and a multiple logistic regression adjusted for age at menarche, age at first full term pregnancy, age at menopause, body mass index, smoking status, and rs671/rs1229984 genotype. The relationship between rs671 genotype, rs1229984 genotype, and breast cancer risk was additionally assessed with a simple and a multiple logistic regression adjusted for age at menarche, age at first full term pregnancy, age at menopause, body mass index, smoking status, and alcohol consumption. To assess the association between each SNP and breast cancer, the codominant, dominant, and additive models were considered. In addition, the combined effects of rs671 and rs1229984 genotype on breast cancer were assessed.ALDH2 and ADH1B genotypes and alcohol intake status were collectively studied to evaluate their combined effect on breast cancer risk. Stratified by ALDH2, ADH1B, and a combination of ALDH2/ADH1B genotypes, the association among alcohol consumption itself, daily alcohol intake, and breast cancer was evaluated with odds ratio (OR) and P-value. In addition, after stratification by menopausal status, the relationship among alcohol consumption, rs671, and/or rs1229984 genotypes and breast cancer risk was assessed.The ALDH2 polymorphism and breast cancer risk, the OR and P-values were presented, and adjusted for age between 2143 breast cancer cases and 3977 controls  from KoGES. These analyses were performed with PLINK v.1.0741 and R statistical software version 3.2.2 .To validate the association between Informed consent was collected for all cases and controls. This study was approved by the National Cancer Center Institutional Review Board (IRB No. NCC 2015-0177).Supplementary Table 1-3.


Ovarian cancer screening is unavailable on the NHS. There are screening tools, such as the Risk of Ovarian Cancer Algorithm (ROCA), which have been developed for early diagnosis of ovarian cancer. The ROCA was evaluated in low risk women in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS),2 and in high risk women in the UK Familial Ovarian Cancer Screening Study (UKFOCSS).3 In both studies a high proportion of women with earlier stage disease were detected. However, long term follow-up data from UKCTOCS did not show a delayed mortality benefit and hence, screening is not currently recommended in general population women.5Ovarian cancer is the commonest cause of death among gynaecological cancers.BRCA1/BRCA2 carriers,4 RRSO has been found to be effective in significantly reducing ovarian cancer risk and mortality , poorer sexual function10 and detrimental impact on bone health.12 Data from low risk general population women show a negative impact on cardiac13 and neurological health from oophorectomy, but corresponding data from high risk women are lacking.15 These consequences predominantly occur in women who do not take HRT. Potentially lower survival has been reported in low risk women under 50 years of age who underwent premenopausal oophorectomy and did not use HRT.17 HRT is indicated to relieve symptoms and prevent/minimise any complications and adverse impact on long-term health.In the absence of robust screening tools, preventative surgery is the key strategy to reduce the risk of ovarian cancer. In women at increased risk of ovarian cancer , risk-reortality . A 2–4% 2BRCA1/BRCA2 carriers18 and in women with Lynch syndrome .19 A concomitant hysterectomy is undertaken in those with Lynch syndrome as they also have a 40–60% lifetime risk of endometrial cancer.20 In the UK, given the historic restricted access to genetic testing, RRSO has been offered to women from high risk families with an estimated 10% or more lifetime ovarian cancer risk who were unable to access gene testing.21 However, there has been significant variation in the family history based criteria used, with some identifying women in the intermediate risk category (around 7–10%) for RRSO.RRSO has been traditionally offered and shown to be both clinically effective and cost-effective in 23 RRSO can therefore also be offered to women with moderate risk gene mutations including RAD51C, RAD51D, and BRIP1 (5–13% lifetime ovarian cancer risk),26 as well as selected women with a significant family history of ovarian cancer (e.g. one or two first-degree relatives with ovarian cancer)28 who are at intermediate risk (5-10% lifetime risk).30PALB2 has been confirmed as a moderate risk ovarian cancer gene, with some now supporting RRSO in these women, while others cite the limited evidence for this. RRSO can be considered for women with PALB2 mutations following a non-directive counselling process taking into account additional risk and protective factors, and preferably carried out near/after menopause  for PALB2 carriers. In BRIP1 carriers and mutation-negative, intermediate risk women (5–10% lifetime ovarian cancer risk) with a strong family history, it may be delayed until 45–50 years  requiring HRT. Clearly the issue of risk and age of surgery needs to be individualised and there must be informed discussion with women regarding the consequences of iatrogenic surgical menopause, benefits of HRT, and its risks and limitations so they can make informed decisions , taking into account clinical factors and personal preference. RRSO is usually offered once a family is complete. There are occasional exceptions when women undergo IVF and have embryos stored prior to RRSO in order to complete their family later. In women with early onset cancers in the family it may also be undertaken from up to 5 years before the earliest recorded age of onset of ovarian cancer in the family. It is typically offered from 35–40 years for 50 years .29,30 A ecisions . Women a420 It may be appropriate in a small number of other women for independent gynaecological indications, such as fibroids and adenomyosis.Routine concomitant hysterectomy is justified only in women with Lynch syndrome because of an increased risk of endometrial cancer.BRCA1 carriers.32 This comprises a small proportion (approximately 7%) of endometrial cancers,33 with the overall population-based lifetime risk for endometrial cancers being 2.4% in the UK and 2.9% in the USA. Moreover, the number of reported serous endometrial cancer cases are small, confidence intervals wide, and the absolute lifetime risk is low (around 3%), and total endometrial cancer risk is not increased in BRCA1 carriers. Endometrial cancer risk is not increased in BRCA2 carriers. Therefore, more corroborating data and precision around endometrial cancer risk are needed before hysterectomy in BRCA1 or BRCA2 carriers can be routinely advocated.Few studies have reported an increased risk of serous (subtype) endometrial cancer in 59 HRT use ameliorates all these symptoms. Despite HRT, the reported symptoms, particularly for sexual dysfunction, remain above those who have not undergone premenopausal oophorectomy.10 Specifically, sexual dysfunction following RRSO is reported in up to 74% of women compared with general population levels of 40–45%.34Iatrogenic menopause owing to RRSO can be associated with vasomotor symptoms, mood changes, sleep disturbance, reduced libido, vaginal dryness, dyspareunia (painful intercourse) and poorer sexual functioning compared with women who retain their ovaries.13 and up to 3% absolute increase in mortality from heart disease in low risk women who have had early surgical menopause and did not take HRT.13 An increased risk of stroke has also been reported in low risk women,35 however, these data were not statistically significant. Other reported potential negative consequences in low risk women include increased incidence of neurocognitive impairment, dementia and parkinsonism.17 Detrimental consequences have predominantly occurred in women who do not take HRT. Adequate comparable data on cardiac and neurological consequences are lacking for high risk women.15 RRSO is associated with elevated bone turnover markers, an increased risk of osteopenia and osteoporosis,12 however, data on excess fracture risk are limited.36 The impact of estrogen deficiency is related to the duration of lack of estrogen and therefore earlier age at RRSO carries greater risk; this should be a factor in decision making  is associated with an increased risk of heart disease,n making .10 There is evidence that HRT reduces the detrimental impact on bone health (osteoporosis)37 and significantly improves quality-of-life38 in high risk women.39 In low risk women it has been found to reduce ischaemic heart disease and associated cardiovascular disease mortality,13 and neurological consequences following oophorectomy. A summary of benefits and risks is given in HRT is indicated for symptom relief and to ameliorate the adverse long-term consequences of premature menopause following RRSO.5.1BRCA carriers)  . HRT is 5.241Estrogen-only HRT (E-HRT) should be used in women undergoing hysterectomy in addition to RRSO. For those with an intact uterus, estrogen is combined with a progestogen (E+P-HRT) to protect against endometrial hyperplasia/cancer. Progestogens can be given cyclically to induce regular withdrawal bleeds, or continuously in a bleed-free formulation. Several systemic HRT preparations are available with different combinations, strengths and routes of administration. In some women additional topical estrogen may be required to treat urogenital atrophy.42 Vaginal estrogen is not associated with an increased risk of endometrial hyperplasia.43Estrogens can be delivered orally or transdermally (subcutaneous implants are no longer distributed in the UK). Transdermal estrogens have a lower risk of venous thromboembolism (VTE), stroke and myocardial infarction than oral preparations.44 Oral micronised progesterone may have a better risk profile than synthetic progestogens.43Progestogens can be delivered orally, transdermally, or directly in the uterus (progestogen-releasing intrauterine system). The latter is associated with fewer adverse effects than systemic progestogen .44 Oral 45Tibolone is a synthetic steroid with estrogenic, progestogenic and androgenic activity. It can be used as continuous combined HRT to treat vasomotor, psychological and libido symptoms following surgical menopause, while conserving bone mass and reducing the risk of vertebral fractures.5.346 Transdermal testosterone improves sexual activity, orgasms, desire, and positively impacts Personal Distress Scale scores in women affected by hypoactive sexual dysfunction following natural/surgical premature menopause, irrespective of E+P-HRT.47 Short-term data confirm safety of transdermal testosterone, although some androgenic adverse effects (acne and hair growth) are reported.47 However, data specific to high risk women are lacking and impact on breast cancer risk is unknown. There are no licensed preparations for women in the UK, so treatment should be in specialist care settings, with access to hormone assays and monitoring of adverse effects. Off-license preparations of testosterone include gels and subcutaneous implants; use should be evaluated after 3–6 months and usually limited to 24 months.48Premenopausal oophorectomy reduces free androgen index levels by 50%. Testosterone replacement may benefit women experiencing low energy levels and reduced libido despite adequate estrogen replacement.5.4Adverse effects are listed in 5.5BRCA1/BRCA2 carriers after premenopausal RRSO. The mean duration of use reported varies from 3.6–7.6 years (range 0.6–24.4 years in the largest study). Short-term HRT following RRSO in BRCA1/BRCA2 carriers has not been shown to increase breast cancer risk or negate any potential protective effect on subsequent breast cancer risk , but additional long-term data and larger well-designed studies addressing this issue are needed to corroborate this.49 In low risk women E-HRT has a better risk profile than E+P-HRT. More data in high risk BRCA women are needed. Although specific data on natural progesterone are lacking in BRCA1/BRCA2 high risk women, a favourable risk profile is reported in low risk general population women.56 Safety data to continue HRT beyond the age of 51 years in high risk women are lacking and its use is not currently routinely recommended. Any decision to continue HRT should be based on a clinical discussion of pros and cons involving the woman and a menopause specialist or gynaecologist experienced in caring for high risk women. However, some women at increased risk of ovarian cancer may not be at increased risk of breast cancer, such as BRIP1 carriers or women with Lynch syndrome. HRT use in women over 5I years of age may be governed by the same principles as women at population-based risk.A number of observational studies have evaluated HRT use in cer risk .15,38,49BRCA1-associated breast cancers and 65–79% of BRCA2-associated breast cancers are estrogen receptor-positive.57 In women with triple-negative breast cancer, HRT can be considered for short-term use on an individual basis, particularly in those with good prognosis. It can also be considered in long term survivors who have undergone bilateral mastectomy, as may happen in some BRCA carriers who develop breast cancer. Any decision about HRT use should be multidiscliplinary involving the woman, a breast oncologist and a menopause specialist or gynaecologist experienced in caring for high risk women. For breast cancer patients with vaginal/urogenital symptomatology alone, non-hormonal approaches, such as lubricants and moisturisers, are the first line options. Ospemifene, a newer selective estrogen receptor modulator with an estrogen-like effect in the vagina may potentially be beneficial for symptomatic vulvar and vaginal atrophy (VVA). However, adequate data in women with breast cancer are lacking, with use in one small study58 restricted to women with a history of breast cancer 10 years and more prior to enrolment. Consequently, it is not recommended for use in this group of women presently. Intravaginal administration of dehydroepiandrosterone (DHEA) has also been shown to be clinically effective for the symptoms of VVA; however, its use is not yet recommended in women with past history of breast cancer because of insufficient safety data. If non-hormonal options are not effective and symptoms are debilitating, short-term topical estrogen at the lowest effective vaginal dose may be considered following specialist advice (including for estrogen receptorpositive breast cancer with a good prognosis).60 Professional bodies have suggested that vaginal estrogen should be given with tamoxifen and not aromatase inhibitors.62 The effect of any systemic estrogen absorption may be counteracted by tamoxifen’s mode of action at the receptor level in breast tissue. The evidence base for this is limited. If switching adjuvant therapy is considered, this should involve the breast oncologist with a menopause specialist to consider potential differences in breast cancer recurrence rates as well as symptom control. HRT should be used/prescribed following clinical discussion with the woman, so they are clear about the recommendations and circumstances under which use of HRT is or is not possible.For women with a personal history of breast cancer, HRT is usually contraindicated because of estrogen receptor-positive status. About 24–30% of 5.65.6.1BRCA carriers or women at high risk of ovarian cancer are lacking. However, good quality data are available from low risk women.63 Consistent with advice for those at low risk, only combined regimens should be used in women with a uterus. In healthy postmenopausal women, continuous combined HRT is associated with a slightly lower risk of endometrial hyperplasia/carcinoma than cyclical regimens.43Although overall risk of endometrial cancer is not increased post RRSO, specific data on endometrial cancer risk with HRT use in 5.6.264 Transdermal HRT should be considered instead of oral preparations for women at increased risk of VTE, including those with a body mass index over 30 kg/m2. Women may be commenced on transdermal HRT immediately postoperatively and do not require anticoagulation unless there are additional risk factors for VTE. In low risk women with premature ovarian insufficiency, the absolute risk of stroke is low,43 and nor is it significantly increased following surgical menopause.35 Data specific to high risk women undergoing RRSO are lacking.Oral HRT is associated with increased VTE risk, especially during the first year of treatment, and appears to be higher with E+P-HRT than E-HRT. The VTE risk with standard therapeutic doses of transdermal HRT is similar to baseline population risk.5.7There are few contraindications aside from history of breast cancer and personal history of VTE/thrombophilia. However, the latter can be considered for transdermal HRT after discussion of the benefits versus risks and input from haematology specialists on a case-by-case basis. HRT should not be offered if there is undiagnosed abnormal vaginal bleeding, suspected or active endometrial cancer.5.843 Women with known osteoporosis, a strong family history, or those at increased risk due to the use of aromatase inhibitors for breast cancer should have initial and periodic (every 2–5 years) DEXA scans.65 It is not necessary to routinely monitor endometrial thickness while using topical or systemic HRT.After starting HRT, it is advisable to review therapy after 3 months and annually thereafter. While routine tests may not be necessary, investigations should be prompted by specific symptoms or concerns, for example unexpected bleeding. Serum hormone levels are generally not helpful in making treatment decisions. It is important to evaluate and advise on cardiovascular risk factors. Assessment of osteoporosis risk should be carried out. Dual energy X-ray absorptiometry (DEXA) scanning for bone mineral density (BMD) should be considered 1–2 years after RRSO, especially if there are additional risk factors for poor bone health. If BMD is normal and HRT has been prescribed, the value of a repeat DEXA scan is low.BRCA carriers in some studies,49 with higher uptake rates of approximately 74% reported in women cared for in specialist centres.66 Good communication with the general practitioner, and informing women regarding the benefits and risks of HRT is essential to help to maintain compliance.Maintaining HRT compliance is necessary to minimise the detrimental consequences of premature menopause. Poor compliance rates varying from 25–60% have been reported following RRSO in 6Women with contraindications to HRT and those who decline HRT may consider alternative pharmacological, non-pharmacological and complementary treatments for symptoms of menopause. However, overall evidence for such treatments is limited and they do not address long-term health risks after RRSO.67 and following treatment for breast cancer.69 Vasomotor symptoms were rendered more tolerable and less intrusive. Both CBT and exercise were effective in diminishing endocrine and urinary symptoms, but only CBT reduced the burden of hot flushes and night sweats, and led to an increase in sexual activity.68 CBT may also alleviate low mood or anxiety associated with surgical menopause.66 CBT delivered as group therapy70 or self-administered are equally effective,69 with data supporting an internet-based approach.71 While specific trials in RRSO populations are absent, the parallel with cancer-induced menopause makes it reasonable to apply this modality to surgically-induced menopause on clinical grounds and symptom similarity.Three RCTs have demonstrated that cognitive behavioural therapy (CBT) is helpful after natural menopause72Although RRSO-specific data are limited, psychosexual interventions post gynaecological cancer have been effective using CBT, psychoeducation and mindfulness. A small study of similarly structured interventions in 39 women following RRSO showed significant improvements in sexual desire, arousal and satisfaction.73Most pharmacological trials are small studies of short duration. Pharmacological options include selective serotonin reuptake inhibitors (SSRIs), selective noradrenaline reuptake inhibitors (SNRIs), clonidine, gabapentin and betablockers. There is little evidence regarding efficacy and safety of these medications for treatment of menopausal symptoms in young women with surgically-induced menopause. Overall, studies have demonstrated that venlafaxine 37.5 mg titrated up to 150 mg/day, paroxetine 10 mg/day or citalopram 10-30 mg/day are the most effective agents. Clonidine 100 micrograms/day provided significant reduction in the numbers of hot flushes and improved quality-of-life compared with placebo in women with breast cancer, but may have unacceptable adverse effects.74 Some evidence suggests phytoestrogens  may relieve vasomotor symptoms, but data on safety and survival benefits in breast cancer patients are inconsistent. Phytoestrogens are not recommended for breast cancer survivors.Vaginal lubricants and moisturisers can relieve vaginal dryness during intercourse but do not have systemic effects.72). Exercise may achieve clinically important preservation of bone health among premenopausal women with early breast cancer.76 Dietary calcium and vitamin D3 supplementation may be required, particularly in women with inadequate vitamin D status and/or calcium intake. Supplementation to achieve a total intake of 1200 mg/day of calcium and 600-1000 IU/day of vitamin D3 has been recommended.60 Bisphosphonates are effective in treating osteoporosis, but should only be considered with advice from an osteoporosis specialist.65To address the risk of bone demineralisation and improve cardiovascular health following RRSO, women are advised to maintain a healthy lifestyle, undertake weight-bearing exercise, avoid smoking and excessive alcohol intake, and maintain normal body weight ,77 lose weight if applicable, and ensure adequate sleep to improve subjective cognitive symptoms. Other general lifestyle advice includes wearing lighter clothing, sleeping in a cooler room, and avoiding possible symptom triggers such as spicy foods, caffeine, smoking and alcohol.78Women who are more active have fewer menopausal symptoms.8In the UK, RRSO has previously been offered to women with a high estimated lifetime risk (10% or more) of ovarian cancer. RRSO is the most effective method of preventing ovarian cancer, and is cost-effective in women at 4–5% or greater lifetime ovarian cancer risk. With increasing genetic testing, identification of moderate risk gene mutations, and ability to estimate risk based on family history and other risk factors, there is now an emerging and expanding role for RRSO in women at intermediate risk (5–10% lifetime risk) of ovarian cancer.With increasing uptake of RRSO for prevention of ovarian cancer, more women will be exposed to the longterm consequences of premature surgical menopause.If not contraindicated, it is important following premenopausal oophorectomy that HRT is offered until the age of natural menopause.It is essential that women receive evidence-based information and multidisciplinary input, with advice on HRT, symptom management, specialist counselling and sustained support to deal with various physical, emotional and long-term health consequences.Family history should be incorporated into the individualised risk assessment process for all women.In cases where ovarian cancer risk assessment appears complex or difficult, it is important to seek advice from a specialist such as a clinical geneticist or gynaecologist/gynaecological oncologist with expertise in genetic risk assessment or hereditary cancer risk management.Further research is required to guide the most appropriate form of HRT in high risk young women.Appendix