This paper states that although numerous new drugs are available for breast cancer, no population benefit is shown from the year 2000 on. It urges the oncological community to revise the “drug approach strategy” in daily practice and pay more attention to early detection and prevention.Background: Breast cancer treatment has seen tremendous progress since the early 1980s, with the first findings of new chemotherapy and hormone therapies. Screening started in the same period. Methods: A review of population data (SEER and the literature) shows an increase in recurrence-free survival until 2000 and it stagnates afterwards. Results: Over the period 1980-2000, the 15% survival gain was presented by pharma as a contribution of new molecules. The contribution of screening during that same period was not implemented by them, although screening has been accepted as a routine procedure in the States since the 1980s and everywhere else since 2000. Conclusions: Interpretation of breast cancer outcome has largely focused on drugs, whereas other factors, such as screening, prevention, biologics, and genetics, were largely neglected. More attention should now be paid to examining the strategy based on realistic global data. Clinicians and researchers alike raise the question: what is the impact of current treatments on cancer outcome? The most frequent tumor overall 67.2/100.000), and more specifically in women of all races (126.0/100.000), is breast cancer 00.000, a SEER datPrevention is beneficial for the health of the population, but it comes with a price. The number of cancer patients, subject to further evaluation and treatment, is expected to increase between 2012 and 2025 by 37%. Prevention could target pathobiological mechanisms of cancer-related conditions including obesity and diabetes, bearing a higher metabolic cancer risk; the immune system putatively interfering with the progression of precancerous conditions; and possible protumoral side effects of preventive agents shifting balances in the tumor ecosystem.p = 0.001), respectively [Body mass index (BMI) reveals that overweight and obesity are associated with worse outcomes in breast cancer patients. For all cancers combined, a BMI of 40 was associated with a 52% (for men) and 62% (for women) increase in mortality as compared to normal weight. For breast cancer, BMIs of 18.5–24.9, 25.0–29.9, 30.0–34.9, 35.0–39.9 and ≥40.0 have relative cancer risks of 1.00, 1.34, 1.63, 1.70, and 2.12  and there was a trend towards improved overall survival [Focusing on prevention to reduce breast cancer incidence will likely require both a population-based approach to reducing exposure to modifiable risk factors and a precision prevention approach to identifying women at increased risk and targeting them for specific interventions, such as risk-reducing medication. The inclusion of newer factors, such as polygenic risk and mammographic density, can give an idea about individual women’s breast cancer risk. A widespread implementation of evidence-based risk medications is available, but overall implementation remains a challenge . An examsurvival . The reaSocioeconomic conditions that contribute to higher cancer rates in specific populations warrant the analysis of different environmental exposures and the development of policies that might limit these exposures and identify interventions to prevent cancer in people at higher risk. For breast cancer survivors, return to work (RTW) is important from an economic, societal, and personal perspective. One year post surgery, 57% of survivors worked the same and 22% worked reduced working time compared to pre-diagnosis. Impaired RTW was associated with depressive symptoms, arm morbidity, persisting physical fatigue, lower education, and younger age. Cessation of work after breast cancer is associated with worse QoL  .p < 0.01) in the lowest, second, and third quartile, respectively [Racial factors linked or not to socio-economic circumstances play a role in breast cancer outcome. Five-year survival was worse for Black compared to White women in each socioeconomic quartile with 5-year survival hazard ratios of 1.33, 1.23, and 1.20 (ectively .p = 0.002). After discontinuation of hormonal contraception, the risk of breast cancer remained higher (1.0 to 1.6) after use for 5 years or more [Current users of hormone replacement therapy (HRT) have a twice higher risk of developing breast cancer than never users . For women taking HRT for more than 5 years, the risk is almost three times higher  . Compare or more .Prevention by medication is exemplified by tamoxifen, reducing breast cancer incidence by more than 30%. In a recent paper, Rowan and colleagues report that across three tamoxifen placebo-controlled prevention trials , started almost 30 years ago, although there were 226 fewer breast cancer cases, there were nine more deaths from breast cancer in the tamoxifen groups . As endop > 0.10 for a test of no difference after 835 events had occurred), suggesting the noninferiority of endocrine therapy compared with endocrine therapy plus chemotherapy. In this population, the 9-year invasive DFS rate was 83.3% for endocrine therapy alone and 84.3% for endocrine therapy plus chemotherapy  [Whether or not ER- positive patients benefit from adjuvant chemotherapy is an open question. In the TAILORx trial, 6907 women were randomly assigned to endocrine therapy alone or endocrine therapy plus chemotherapy with 3399 and 3312 women available for an analysis according to the randomized treatment assignments in both arms, respectively. After a median follow-up of 90 months, the difference in invasive DFS—the main study end point—met the prespecified noninferiority criterion ( = 0.26) .At the St Gallen expert consensus in 2007, three categories were recognized: highly endocrine responsive, partially endocrine responsive, and endocrine nonresponsive. The panel accepted HER2 positivity to assign trastuzumab but noted that adjuvant trastuzumab has only been evaluated in conjunction with chemotherapy. Chemotherapy is typically given with or before trastuzumab in patients with HER2-positive disease, and it may be used in patients with endocrine-responsive disease when endocrine therapy alone is insufficient .Metastasis is the major cause of poor outcomes. Cancer cells escape from the primary tumor, invade the blood vessels, and home in on distant organs such as the lung, liver, and bone ; there, The overall survival of breast cancer might be sufficiently explained by earlier stage and less evidence of any major impact of systemic treatment There is no doubt that screening has an impact on breast cancer outcome as it detects smaller tumors. However, mammography and echography show no benefit over physical examination ; they raMapping the genes responsible for inherited breast cancer may allow the identification of early lesions that are critical for the development of breast cancer in the general population. Chromosome 17q21 harbors a gene for inherited susceptibility to breast cancer in families with early onset disease . AdjuvanThe statement that the increase in the 5-year relative survival for breast cancer from 76.3% to 90.2% between 1980 and 2000  is due tSimilar questions emerge from Belgian data, where survival increased between 2004 and 2017 by 6% up to 91% with mainly eight drug combinations. At the same time, screening was nationally introduced, resulting in 6% smaller tumors . In the cancer.org 25 refer to breast cancer. Looking to the SEER Interactive Antineoplastic Drugs Database (seer.cancer.gov), for breast drugs, which have at least some indication of referring to breast cancer, we find 248 single drugs and 393 regimens available.More recent studies implicating new drugs have been designed on the basis of novel molecular technology. The cost effectiveness of this strategy is more difficult to evaluate than established care because of high initial pricing, limited data on efficacy or long-term effects, and potential for bias in the methods and findings as a result of industry-related conflicts of interest. So far, the number coded for these new molecules as Biological/ Immunology is 47, and on the website of If the latter drugs were effective, we should at least see better outcomes within the first 1 to 4 years. A recent analysis of 124 FDA drugs approved for cancer between 2003 and 2021 showed only a small benefit of 2.8 months  for overall survival (OS) and 3.30 months  for progression-free survival (PFS) [It is often unclear how long and at what dose an antitumor drug should be administered for an optimal effect at minimal toxicity. It is usually not known how the drug is best combined with surgery, radiotherapy, and other pharmacological agents. These uncertainties complicate the decision making of doctors and their patients. The European Medical Agency (EMA) and the European Organization of Research and Treatment of Cancer (EORTC) collaborating in the Cancer Medical Forum (CMF) plans to tackle this problem . Now, thThe explosion of new molecules with different approaches and running trials (N = 706) tested in the USA on breast cancer , most ofAs a conclusion, we can only say that when interpreting breast cancer relative survival, we should look at the entire population rather than individual cases or treatment populations, and consider the impact of stage migration, which influences outcome. Prevention is undoubtedly important, and education in the young population should be prioritized.


APOBEC3B gene belongs to a cluster of DNA-editing enzymes on chromosome 22 and encodes an activation-induced cytidine deaminase. A large deletion of APOBEC3B was associated with increased breast cancer risk, but the evidence is inconclusive. To investigate whether or not APOBEC3B is a breast cancer susceptibility gene, we sequenced this gene in 617 Polish patients with hereditary breast cancer. We detected a single recurrent truncating mutation  in four of the 617 (0.65%) hereditary cases by sequencing. We then genotyped an additional 12,484 women with unselected breast cancer and 3740 cancer-free women for the c.783delG mutation. The APOBEC3B c.783delG allele was detected in 60 (0.48%) unselected cases and 19 (0.51%) controls . The allele was present in 8 of 1968 (0.41%) familial breast cancer patients from unselected cases . Clinical characteristics of breast tumors in carriers of the APOBEC3B mutation and non-carriers were similar. No cancer type was more frequent in the relatives of mutation carriers than in those of non-carriers. We conclude the APOBEC3B deleterious mutation p.Val262Phefs does not confer breast cancer risk. These data do not support the hypothesis that APOBEC3B is a breast cancer susceptibility gene. The  Breast cancer is the most common malignancy among women. Annually, it is diagnosed in over two million women worldwide, including about 20,000 cases in Poland. The lifetime risk of breast cancer in the Polish population is approximately 8% . HoweverBRCA1, BRCA2, PALB2, and CHEK2 CTTCTTGGACCTGGTTC[BHQ1] and APO-wt [6FAM] CTTCTTGGACCTGTTCC[BHQ1] and primers APO-delG-F AAGAATCTTCTCTGTGGCTTTTTAC and APO-delG-R CGGGTCCAACTGCAAAGAA. All mutations were confirmed by Sanger sequencing. Sequencing reactions were performed using a BigDye Terminator v3.1 Cycle Sequencing Kit (Thermo Fisher Scientific) according to the manufacturer’s protocol using primers GGCTAAGAATCTTCTCTGTG and CAGGAGATGAACCAAGTGAC. Sequencing products were analyzed on an ABI Prism 3100 Genetic Analyzer (Thermo Fisher Scientific).We genotyped 12,484 women with breast cancer and 3740 controls for the APOBEC3B c.783delG  allele was estimated in 12,484 breast cancer cases and 3740 cancer-free women. Odds ratios were generated from two-by-two tables. Women with breast cancer, with and without an APOBEC3B mutation, were compared for age at diagnosis and clinical features of the breast cancers. Statistical significance was assessed using Fisher exact test or Chi-squared test where appropriate. Means were compared using the t-test. To estimate the survival of women with and without the mutation, we followed the breast cancer patients from the date of diagnosis until the date of death or July 2014. We compared the survival between mutation carriers and non-carriers by log-rank test. An age-adjusted hazard ratio was calculated using Cox regression analysis.The prevalence of the APOBEC3B gene. All four patients had the c.783delG  truncating mutation.We identified a truncating mutation in four of 617 women (0.61%) with hereditary breast cancer by sequencing the entire p = 0.94). The mutation was detected in 8 of 1968 patients (0.41%) with familial breast cancer within the unselected cases . The mutation frequency was identical (0.48%) in women diagnosed at the age of 50 years or below (28 of 5778) and in patients diagnosed above the age of 50 years (32 of 6706). The mutation frequency by age and family history of breast cancer is shown in The c.783delG  variant was genotyped in 12,484 women with unselected breast cancer and 3740 cancer-free controls. It was found in 60 (0.48%) unselected cases and in 19 (0.51%) controls  and 2044 deaths in 12,294 non-carrier patients (16.6%) . The 10-year survival was 78% for the carriers compared to 76% for non-carriers. The age-adjusted HR for mortality given the APOBEC3B mutation was 1.00 .Survival data were available for 12,353 breast cancer cases. After a mean follow-up of 64 months, there were 10 deaths in 59 carriers of the APOBEC3B mutation to see whether or not there is an excess of different cancers in first- and second-degree relatives. No particular cancer was seen in excess in the relatives of the APOBEC3B mutation carriers, compared to those of non-carriers, including cancers of the breast, prostate, colon, kidney, lung, larynx, pancreas, stomach, cervix, endometrium, ovary, leukemia and lymphoma  of the breast, preventive mastectomy, prophylactic oophorectomy, and women with breast or ovarian cancer and a BRCA1/2 mutation benefit from individualized chemotherapy using platins and PARP1 inhibitors [CHEK2 mutations confer about a 3- to 5-fold increased risk of breast cancer in a woman depending on her family history of breast cancer. CHEK2 mutation-associated breast tumors are more likely to be estrogen receptor (ER)-positive than sporadic breast cancers, and patients with breast cancer who carry a CHEK2 mutation respond well to tamoxifen [CHEK2 mutation by about 15% and should be considered in the treatment of CHEK2 mutation-associated breast cancers. The effect of oophorectomy was strongest in women with early-onset breast cancer (50 years or below) and those with adverse prognostic factors [PALB2 mutations confer about a 5-fold increase in the risk of breast cancer and about a 3-fold increase in the risk of ovarian cancer [PALB2 founder mutations (c.509_510delGA and c.172_175delTTGT) were associated with a 4.5-fold increased risk of breast cancer [PALB2 mutation to be poor. For PALB2 mutation carriers breast MRI is recommended and preventive mastectomy and oophorectomy should be discussed [To date, over twenty genes have been associated with a genetic predisposition to breast cancer, but based on the mutation frequencies, the magnitude of cancer risk, and the influence on clinical management with mutation carriers, we consider that the most important breast cancer susceptibility gene to be  decades . It is ehibitors ,48,49,50amoxifen ,52,53,54n cancer ,56. In oiscussed ,58.BRCA1, BRCA2, CHEK2, and PALB2 in about half of 1018 Polish families with hereditary breast cancer, and we have observed that 18 founder mutations are responsible for about 80% of all the mutations detected in these genes [BRCA1, BRCA2, CHEK2, and PALB2 as an initial screening tool for all patients with breast cancer and unaffected individuals with a positive family history of breast cancer. The advantages of testing for founder mutations include quick turnaround time and low cost. In patients who are found not to carry a founder mutation, we perform full sequencing using gene panels including BRCA1, BRCA2, CHEK2, and PALB2 in breast cancer cases with familial clustering of this cancer and/or in patients with early onset disease (diagnosed at age 45 or below). In addition, we offer TP53 sequencing for women with breast cancer diagnosed at the age of 30 or below, as it was reported that about 5% of these women carry a TP53 mutation, and radiotherapy is contraindicated for TP53 mutation positive cases [Poland is a genetically homogenous country, and this is expressed by the high frequency of founder mutations. Previously, we have identified pathogenic mutations of se genes . Based ove cases . Such a ve cases . HoweverAPOBEC3B mutations are present in Poland and whether they predispose to breast cancer. The APOBEC3B gene encodes an activation-induced cytidine deaminase (AICDA/AID), which is involved in the immune response against viruses, regulation of DNA methylation, and inducing DNA damage and apoptosis [APOBEC3B has been described as a driver of breast cancer [APOBEC3B expression is regulated by estrogen [APOBEC3B gene have been detected in breast cancer tumor tissue [APOBEC3B deletion of ~30 kb, which extends between the last exon of APOBEC3A and the eighth exon of APOBEC3B and removes the entire APOBEC3B protein-coding region, was associated with increased breast cancer risk in Asian populations [To optimize genetic testing it is necessary to describe the full spectrum of breast cancer predisposing mutations in different populations, and to identify all breast cancer susceptibility genes. In the current study, we asked whether or not poptosis ,32. APOBt cancer . APOBEC3estrogen , a hormor tissue . In addiulations . APOBEC3B mutations predispose women to breast cancer in several ways, including the sequencing of the entire APOBEC3B gene in familial cases, and conducted a large case–control study and a pedigree analysis. We also investigated whether or not breast cancers in women with APOBEC3B mutations are associated with specific clinical characteristics and survival among patients. In none of these analyses was there evidence of cancer predisposition for carriers of an APOBEC3B truncating mutation.In this study, we approached the question if APOBEC3B gene by sequencing 617 hereditary cases . In a large case–control study, we showed that the c.783delG founder mutation was not associated with an increased risk of breast cancer in Polish women . The mutation frequency was the same (0.48%) in 5778 women diagnosed at the age of 50 years or below and in 6706 patients diagnosed above the age of 50. These results contrast with those reported by Radmanesh et al., who published that the same c.783delG mutation of the APOBEC3B gene confers an increased risk of unselected breast cancer by 2.3 fold  and early onset breast cancer risk (below age of 50) by 3.2 fold  in Belarus, Russia, Germany, and Iran [APOBEC3B p.Val262Phefs mutation was analyzed in both studies. In our study, we identified a total of 83 mutation carriers, compared to 33 in the previous study. Based on our study there is insufficient evidence that the APOBEC3B p.Val262Phefs truncating mutation predisposes to breast cancer.Notably, we identified a single truncating mutation of the The c.783delG mutation results in a frameshift within exon 6 and creates premature termination of the protein 42 codons downstream . It is located adjacent to the active site at Glu255 and eliminates the metal-binding sites of APOBAC3B, and therefore is predicted to lead to a loss of enzymatic function. In our study, the mutation was detected with an allele frequency of approximately 0.3% in Poland. The mutation has been reported by the Exome Aggregation Consortium (ExAC) at an overall MAF of 0.8%, with the highest prevalence in the African/African American population (5%), and much lower frequencies in European populations (0.3%), Ashkenazi Jews (0.3%) and the South Asian population (0.8%). Our study does not exclude a modest increase in breast cancer risk associated with the c.783delG allele and further studies in other ethnic groups are needed.BRCA1, CHEK2, NBN, RECQL and ATRIP) is similar in different regions of Poland [Our study is large and benefits from the genetic homogeneity of the Polish population which is populated by ethnic Slavs. The Polish population is well suited for association studies and false results due to admixture have not been reported. Our cases of breast cancer were not selected for family history. We have previously shown that the frequency of Polish founder alleles . This data does not support the hypothesis that APOBEC3B is a cancer susceptibility gene.In summary, our results suggest that the pulation . It is u


BRCA1 which increases a woman’s risk for breast cancer (70%) and ovarian cancer (40%). The prevalence of BRCA1 gene mutations has been studied widely and in many countries, mostly in women affected with cancer. In many settings testing is offered routinely to women with serous ovarian cancer or early-onset or triple-negative breast cancer. It is preferable to identify a mutation in a healthy women prior to the diagnosis of cancer. The basic strategies for prevention include surgical prevention, chemoprevention and screening (early detection). Much progress has been made in the past two decades evaluating the benefits of these three approaches. In this commentary I provide my personal views regarding these various interventions in the context of counselling a newly diagnosed health woman with a BRCA1 mutation.With widespread testing for susceptibility genes, increasing numbers of women are being identified to carry a mutation in one of many genes which renders them susceptible to cancer. The first gene to be identified (in 1994) was  BRCA1 gene faces a lifetime risk of breast cancer of approximately 70% and a risk of ovarian cancer of about 40% .These numbers center our focus on the salpingo-oophorectomy. We estimate that for every three salpingo-oophorectomies performed we save one life. [This leads to an interesting paradox. The Bahamas is the country in the world with the highest prevalence of utations . On a reBRCA1 carriers  [Our patient goes for a bilateral salpingo-oophorectomy and hysterectomy  No cancer or precancerous lesion is found. She is prescribed estrogen only hormone therapy which has been shown to be safe for  cancer)  and estrBRCA1 mutation developed breast cancer after a bilateral mastectomy and one died [BRCA1 carriers after a preventive mastectomy remained about twice as high as the population norm [Now she faces a critical choice. Does she continue with the annual MRI examinations or opt for preventive mastectomy? After the BSO her risk of breast cancer remains high, but her risk of dying of breast cancer is lowered – perhaps to 5% to age 75. If she follows up with a bilateral mastectomy the risk falls further - to 1% or so. In a study from the Netherlands, eight of 722 women with a one died . In a Swion norm .BRCA carrier undergoing MRI screening to be about twice that of the Ontario population. We estimated the probability of not dying of breast cancer at 20 years from the first MRI was 98.2%. A second Dutch group found that of approximately 400 BRCA1 carriers followed by MRI, 33 developed breast cancer and five developed metastatic breast cancer [in combination if we are to propose an alternative to preventive mastectomy. And we need to follow the cohorts from age 35 to age 75. At present, I believe the combination of MRI and BSO offers the best alternative for patients who wish to avoid bilateral mastectomy and this needs to be discussed with the patient who chooses screening. They must know the numbers. The issue is goes beyond counting deaths, there other considerations as well, such as the operation itself, relief of anxiety and fear of cancer, the need for annual screening until age 70 . Surgical options and type of reconstruction must be discussed. In general, women who opt for preventive surgery are happy with their decision and are relieved to know they have done everything they can to prevent cancer and can now avoid screening. Of course, many other women wish to retain their breasts. They must be aware that if they choose screening there is a high chance they will be eventually treated for breast cancer with chemotherapy and bilateral mastectomy.How does this compare to MRI? In Ontario, we enrolled 489 women in an MRI prospective screening study, 91 developed breast cancer and four died of breast cancer . We estit cancer . It is cBRCA1 carriers use it [In 1995, I had hoped that by 2022 preventive surgery would be replaced by a safe and effective means of chemoprevention. We are not there yet. Tamoxifen use is supported as part of chemoprevention recommendations , 29 but s use it , 31, buts use it .BRCA1 carriers has switched from tamoxifen to denosumab. This drug targets the progesterone pathway rather than the estrogen pathway through blockage of the RANKL/RANK signaling pathway [The frontrunning candidate for cancer prevention in  pathway –36. We h pathway . It has  pathway  and denoBRCA1 testing if there is nothing I can do about it if I test positive?” A lot has changed since then and testing has become integrated in clinical oncology practice. The tools we have discussed above  have changed the landscape dramatically. Now our challenge is to get the tools in the right hands and to be available for as many women as possible. We need to widen our clinical criteria and increase our uptake of testing in order to identify unaffected carriers at a young age (preferably before age 40). If we rely on testing women with cancer first, we need to put more effort into getting their unaffected sisters and daughters involved. We need to overcome the barrier where the relative is not invited to be tested through the testing center, but is first contacted by the family member as direct contact has been shown to improve uptake [Not too many years ago, patients would ask me “Why should I go for e uptake . In Canae uptake . We also


Estrous cycles are recurring changes in therian mammals induced by estrogen, progesterone, and other hormones culminating in endometrial proliferation, ovulation, and implantation if fertilization occurred. In women, the estrous cycle is the menstrual cycle; but, unlike most mammals, the end of an infertile cycle is marked by endometrial sloughing and the start of another without an anestrous phase. Women stop cycling at menopause, while in most mammals, cycles continue until death. Epidemiologic studies identified menarche, menopause, births, lactation, and oral contraceptive (OC) use as key risk factors for ovarian, breast, and endometrial cancers. A composite variable was created to estimate the number of cycles not interrupted by events that stop ovulation. Captured by the phrase “incessant ovulation”, repetitive cycles were first postulated to affect ovarian cancer risk and later extended to breast and endometrial cancers. These associations could be explained by cumulative effects of repetitive tissue changes within reproductive organs, immune consequences of repetitive ovulation through the glycoprotein mucin 1, and residual effects of past ovulations that enhance ovarian production of testosterone. The latter two pathways could affect the risk for cancers in other organs not considered “reproductive”. Estrous cycles are recurring events in placenta-forming mammals induced by estrogen, progesterone, and other hormones that culminate in changes to the uterine lining, ovulation, and support for an implanted zygote if fertilization occurred. Nutritional, environmental, and genetic factors determine the onset of sexual maturity, which occurs relatively later in animals with greater longevity and requires a certain body size to be achieved on an allometric scale. Estrous cycles vary in duration, frequency, and seasonality and, in most mammals, repeat until death . In womeThe variable, ovulatory  years, is estimated by subtracting the age at menarche from the age at menopause  from which time pregnant, nursing, or using oral contraceptives (or other hormones stopping ovulation) are subtracted. Lifetime ovulatory  cycles are estimated by multiplying ovulatory years by cycles per year, approximately 13, for a cycle length of 28 days. More ovulatory cycles and greater cancer risk were first linked to ovarian cancer and later extended to breast and endometrial cancers. Here, we review the strength of the epidemiologic evidence for ovulatory years as a risk factor for these cancers, discuss mechanisms by which they might increase risk, and briefly examine how these mechanisms could link ovulatory cycles to cancers in organs not considered “reproductive”.Globally, in 2020, it was estimated that breast, endometrial, and ovarian cancers totaled approximately 3 million new cases and a million deaths ; there iLater age at menarche reduces the risk for all three cancers –11, but Not included in While epidemiologic studies of reproductive cancers have mostly focused on the effects of individual reproductive events, interest in a composite variable that combines these events has emerged. Before discussing the evidence linking ovulatory years and cancer risk, we consider issues related to constructing the algorithm to estimate them. Yang et al. evaluated 14 algorithms in relation to ovarian and endometrial cancers . They idAnother issue relates to co-variates that should be adjusted for in estimating the risk for cancers that might be associated with the length of ovulatory years (LOY). We think it is unnecessary to adjust for the component variables used in calculating ovulatory years since these are already part of the variable. Adjusting for variables that are components of LOY weakens estimates of LOY’s effect on disease risk (and vice versa) . In addiCiting a study in which ovarian adenocarcinomas developed in hens housed to maximize egg production, Fathalla  first liSince ovulatory years are not fully “set” until menopause, this might suggest that the association with ovarian cancer will be more apparent after menopause. In fact, the association is stronger in premenopausal women . This isThere are numerous data that breast cancer risk is increased by an earlier age at menarche and a later age at menopause , and subAlthough PCOS clearly increases endometrial cancer risk , there iThus, LOY is a risk factor common to ovarian, breast, and endometrial cancers. Mechanisms that could explain these associations could either be organ-specific or based on common pathways.−7 mutations per gene per cell division (9 cells/g) of proliferating tissue  promotes a cohort of developing follicles to secrete estrogen and the endometrium proliferates; ovulation, where the dominant follicle releases its oocyte associated with a spike in FSH and luteinizing hormone (LH); a luteal phase, where the granulosa-thecal layer from the dominant follicle is converted to a progesterone-secreting corpus luteum and the endometrium is converted to a secretory type; and menstrual phase, where the endometrium is shed and a new cohort of follicles selected, if fertilization did not occur . The supdivision , suggestg tissue . Sporadig tissue . While mg tissue , 83.The breast also undergoes cyclic changes, especially involving the terminal ductal lobular units thought to be the source of both lobular and ductal breast cancer . SimilarProliferative changes in the ovary during a cycle primarily involve stromal, granulosa, and thecal cells that surround immature oocytes and promote them to develop into mature oocytes. However, cancers arising from granulosa, thecal, or germ cells are relatively rare in adult women in whom the predominant types are epithelial tumors. The surface epithelium of the ovary was thought to be the origin of these tumors, and repeated disruption and repair of this layer with each ovulation might lead to p53 mutations, predisposing to epithelial ovarian cancer where defective p53 is a hallmark feature . HoweverIn vitro studies demonstrated that exposure of tubal cells in culture to FF led to the proliferation of FTSEC and P53 accumulation  end of the fallopian tubes (FTSEC) began to receive attention as the source of high-grade serous ovarian cancers, the most common and lethal type . A case mulation , suggestmulation  and for mulation . This paIn addition to the cumulative effects of ovulatory cycles on tissues specific to the breast, endometrium, and ovaries, there are mechanisms that offer more general explanations for LOY as a risk factor for reproductive cancers and, perhaps, other cancers. These include an immune-based model and a hormonal model.An immune-based model involves human mucin 1 (MUC1), a transmembrane-glycoprotein expressed at the apical cell surfaces of normal glandular epithelium of many organs including breast, salivary glands, gastrointestinal tract, pancreas, bladder, prostate, fallopian tubes, endometrium, and some hematopoietic cells . In cancAssays to measure anti-MUC1 antibodies have also been developed using various MUC1 epitopes associated with tumor-like MUC1 . IgM andNatural antibodies against MUC1 have also been found in healthy individuals, raising important questions. What events are associated with the appearance of anti-MUC1 antibodies, and do these antibodies contribute to successful immunosurveillance of MUC1+ cancers? Anti-MUC1 antibodies generated in the absence of cancer appear to be promoted by inflammatory events involving tissues that normally produce MUC1. These events may include childhood mumps, puerperal mastitis, and tubal ligation—each shown to raise anti-MUC1 antibodies and each shown to lower the risk for ovarian cancer in case–control studies –109. ImpPointing out that the presence of anti-MUC1 antibodies leads to reduced risk for ovarian cancer, the corollary follows that their absence may increase the risk for cancer. We have shown that a greater number of ovulatory cycles are associated with lower anti-MUC1 antibody levels in three different populations using two different assays to measure anti-MUC1 antibodies , 111. WeProspective studies found that the combination of elevated serum testosterone and estradiol in postmenopausal women predicts future risk for endometrial, breast, and ovarian cancers –115. RelThe answer to the first question comes from studies in which ovarian veins were cannulated in postmenopausal women at the time of hysterectomy and/or oophorectomy and levels of sex hormones coming directly from the ovaries compared with levels in the peripheral blood –118. TheBiological events during an ovulatory cycle that might change the ovary’s potential for androgen production likely involve the ovary’s germ cell reserve, the process of follicle maturation, and the fate of follicles recruited during a cycle but not selected for ovulation , 125. PrPossibly relevant to the fate of thecal remnants are two related conditions called ovarian stromal hyperplasia (OSH) and hyperthecosis (OHT). OSH refers to the nodular or diffuse proliferation of the stromal cells of the ovary, while OHT is distinguished by the presence of round to polyhedral theca-lutein-like cells occurring singly or within nests within a stroma that is itself proliferative . For decGiven this background, is there evidence that LOY influences postmenopausal hormone levels? Two studies in the current literature address this with conflicting results , 133. ThWe pointed out that the model involving a link between LOY and mucin immunity may pertain to cancers in “non-reproductive” organs. The same may apply to the model involving LOY and sex hormones. Melanoma may be such a cancer. A large prospective study of melanoma in French women looked at ovulatory age and found that postmenopausal women with LOI <33 years had half the risk for melanoma compared to women with LOI >39 years, RR , equating with greater risk for more ovulatory years . DetailsA somewhat unique feature of estrous cycles in women compared to other mammals includes the sloughing of the endometrial lining at the end of a cycle in which an oocyte was not fertilized. This allows estimates of the onset of sexual maturity, end of reproductive potential, and, in between, the frequency of presumed ovulatory cycles that were not interrupted by pregnancies, breastfeeding, or OC use. There are substantial epidemiologic data that support the premise that more estimated ovulatory cycles (captured by the phrase “incessant ovulation”) increase risks for ovarian, breast, and endometrial cancers. One pathway through which these effects may occur includes cumulative effects of repetitive tissue changes within reproductive organs with each ovulatory cycle. In the terminal ductal lobular units of the breast, proliferative activity is increased during the luteal phase of the cycle, which could be a key factor in both lobular and ductal breast cancer. In the endometrium, repetitive shedding and regrowth of the endometrium may lead to the accumulation of mutations in the tumor suppressor, PTEN, a marker for endometrial cancer. In ovaries, the secretory epithelium of the tubal fimbria, with each ovulation, is exposed to follicular fluid whose inflammatory properties may induce the proliferation of cells with defective p53 leading to high-grade serous cancers. Although the vagina and cervix also undergo cyclic changes, cancer involving these organs appears to be dominated by infectious agents. However, it is possible that tissue changes in other organs could be affected by repetitive cycles; ovulatory years should be examined for any cancer in which there are male–female differences in occurrence.A second pathway might involve immune events related to human mucin 1, a transmembrane glycoprotein, expressed at the apical cell surfaces of normal glandular epithelium of many organs including the breast, fallopian tubes, and endometrium. In cancers arising from these tissues, MUC1 becomes overexpressed on the entire cell surface favoring metastases through several mechanisms and associated with poor prognosis. Conversely, some patients with MUC1-positive cancers have anti-MUC1 antibodies; their presence is associated with better prognosis. Anti-MUC1 antibodies have also been identified in healthy individuals without cancer, and there is some evidence to suggest these antibodies may lower the risk of ovarian cancer. Repetitive ovulation enters the story based on the observation that more ovulatory cycles are associated with lower anti-MUC1 antibodies, which are associated with increased risk for ovarian cancer. It is not clear, however, whether lower anti-MUC1 antibodies seen with more ovulatory cycles reflect immune downregulation from the cyclic elevation of MUC1 released during ovulation or menstruation or simply reflect fewer events like pregnancy and breastfeeding known to produce anti-MUC1 antibodies. This pathway could apply to cancer in which immune-based treatments involving MUC1 have shown some success including colon and small cell lung cancers. The role of ovulatory years in the epidemiology of these cancers should be investigated; the possibility that immune reactions are related to other mucins such as MUC16 (CA125) should be considered.A third pathway involves residual effects of past ovulations that enhance the postmenopausal ovary’s production of testosterone, which can then be converted to estradiol in peripheral tissue, especially in women with greater BMI. This effect may result from the accumulation of residual stromal and thecal cells recruited during ovulatory cycles that display greater resistance to apoptosis than granulosa cells. Two observations support the relevance of this pathway to explain why more ovulations increase the risk for breast, endometrial, and ovarian cancers. First is the observation that a pattern of elevated testosterone and estradiol in healthy postmenopausal women is associated with a greater risk for these cancers. Second, the ovaries of women with breast and endometrial cancers display patterns described as OSH and OHT. Like the possible pathway involving the immune effect related to mucins, this pathway could support a credible link between more ovulations and cancer in non-reproductive organs including melanoma in which testosterone may play a role.In conclusion, the estimation of ovulatory cycles deserves much greater attention as a factor in the epidemiology of cancer in women.The author confirms being the sole contributor of this work and has approved it for publication.


Breast and thyroid cancer are increasingly prevalent, but it remains unclear whether the observed associations are due to heightened medical surveillance or intrinsic etiological factors. Observational studies are vulnerable to residual confounding, reverse causality, and bias, which can compromise causal inference. In this study, we employed a two-sample Mendelian randomization (MR) analysis to establish a causal link between breast cancer and heightened thyroid cancer risk.We obtained the single nucleotide polymorphisms (SNPs) associated with breast cancer from a genome-wide association study (GWAS) conducted by the Breast Cancer Association Consortium (BCAC). The FinnGen consortium’s latest and largest accessible GWAS thyroid cancer data at the summary level. We performed four MR analyses, including the inverse-variance-weighted (IVW), weighted median, MR-Egger regression, and weighted mode, to evaluate the potential causal connection between genetically predicted breast cancer and higher risk for thyroid cancer. Sensitivity analysis, heterogeneity and pleiotropy tests were used to ensure the reliability of our findings.P = 0.038). However, there was no causal association between genetically predicted triple-negative breast cancer and thyroid cancer . There was no directional pleiotropy or horizontal pleiotropy in the present study.Our study revealed causal relationship between genetically predicted breast cancer and thyroid cancer  = 1.135, 95% confidence interval (CI): 1.006 to 1.279, This two-sample MR study supports a causal link between ER-positive breast cancer and heightened the risk of thyroid cancer. Our analysis did not reveal a direct correlation between triple-negative breast cancer and thyroid cancer. According to the American Cancer Society, breast cancer had the highest incidence 30%) of new cases and the second highest mortality rate 15%) among female deaths in the United States in 2020  program cancer registries, another investigation was conducted into the potential association between breast cancer and thyroid cancer . HoweverAn important aspect of conducting MR analysis is to investigate the causal effects of genetic variants that are strongly associated with potential risk factors on exposure and outcomes, as evident from previous studies –24. MR aWhile prior clinical observations and relevant published studies suggest that thyroid cancer and breast cancer are associated , 8, no MP<5×10−8). Secondly, the independence assumption was ensured by verifying that the genetic variants were not associated with any other potential factors linked with breast cancer and thyroid cancer. Lastly, the exclusion-restriction assumption was met by setting a significance threshold at genome-wide (P > 5 × 10−5) and stipulating that the genetic variants were not related to thyroid cancer other than through breast cancer. A study frame diagram was provided in In our study, a two-sample Mendelian randomization (MR) design was employed to examine the causal relationship between breast cancer and thyroid cancer. To minimize bias resulting from data overlap, aggregated genetic data for breast cancer and thyroid cancer were obtained from the Breast Cancer Association Consortium (BCAC)  and the The study obtained GWAS summary statistics from the Breast Cancer Association Consortium (BCAC) for a total of 133,384 cases with breast cancer and 113,789 breast cancer-free controls . The res2 of at least 0.7.In this study, we conducted an analysis of the Genome-Wide Association Study (GWAS) summary statistics from the Breast Cancer Association Consortium (BCAC) . The datFinnGen research project is a public-private partnership endeavor that integrates genotype data from Finnish biobanks and digital health record data from the Finnish health registry. In this study, we conducted an analysis employing the data on malignant neoplasm of the thyroid gland with the exception of all cancers, encompassing a sample size of 1,525 cases and 259,583 controls,. It is noteworthy that this data was obtained from the FinnGen consortium’s latest release in December 2022 .P < 5 × 10−8). Then, we used linkage disequilibrium (LD) to assess the presence of gene linkage in these SNPS, and r2 value of 0.001 and 10,000 kb window. Secondly, to meet the independence assumption, we further screened Phenoscanner (http://www.phenoscanner.medschl.cam.ac.uk/) to determine the potential pleiotropic confounders. Then, those exposure-related SNPs were deleted from the GWAS of thyroid cancer. Third, to meet the third assumptions (genetic variants solely-influence the outcome through the risk-factor), we excluded those SNPs that directly related with the thyroid cancer by setting a threshold at genome-wide significance (P > 5 × 10-5). Additionally, we computed F-statistics (2 = 2×(1-MAF)×MAF×β2)], and weak IVs (F < 10) were deleted.The breast cancer GWAS data were obtained from BCAC  at genomatistics   were applied to determine the potential influence of variation heterogeneity and pleiotropy . As a prP-value (two-sided).All analyses were performed based on TwoSampleMR (version 0.5.6) and R software (version 4.2.1). The level of significance for the test was established at 0.05 for the P < 5 × 10−8), following the matching with the GWAS of thyroid cancer, only 65 SNPs remained. Furthermore, after assessing the SNP dataset using in PhenoScanner . After matching with the GWAS of thyroid cancer, only 25 SNPs remained. Among these, 4 SNPs  were discarded due to their palindromic and ambiguous structure. Ultimately, 19 SNPs were selected for assessing the genetic risk of thyroid cancer in patients with TN breast cancer, and all F-statistics ranged from 250.29 to 1122.63, indicating the presence of strong instruments , whereas MR-Egger, weighted median method, and weighted mode produced more conservative estimates that did not attain statistical significance  (P = 0.177)  =1.135, 95% CI: 1.006 to 1.279, = 0.566) Figure 2P = 0.883). Additionally, the leave-one-out or single SNP analysis showed no evidence of significant disproportionate effect for any given SNP on the causal estimates (P = 0.545). The funnel plot also indicated the absence of horizontal pleiotropy, as the causal effect of variables corresponded to their precision . Nonetheless, there was no significant directional pleiotropy in the overall breast cancer population , and the leave-one-out analysis indicated no significant disproportionate effect for any given SNP on the causal estimates  to arrive at a causal effect estimate. While our findings do not provide proof of a particular mechanism for carcinogenesis, they highlight possible pathways that require further investigation.However, our study has several limitations. We used summary-level data and subgroup analyses by ER status, but we could not stratify breast cancer analyses by other cancer risk variables . MR can only draw conclusions regarding trait connections in the populations from which the GWAS are obtained. Finally, although our study group is of European descent, the European community is ethnically diverse, and our study cohort may not be fully representative.The results of this MR analysis provide evidence in support of a causal link between an elevated ER-positive breast cancer risk and an increased risk of thyroid cancer. Further investigations into this relationship are warranted in the future. However, our data did not reveal a direct association between TN breast cancer and thyroid cancer, indicating that the preventative and control measures employed to address post-thyroid changes may not confer benefits for individuals with TN breast cancer. This study highlights the effectiveness of this analytical technique in identifying causal relationships, which may facilitate the identification of additional cancer-related links in the future.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The studies involving human participants were reviewed and approved by FinnGen research project. The patients/participants provided their written informed consent to participate in this study.HT and ZT conducted analyses and wrote the first draft of the paper. ZT and HT acquired the funding. FH and SW contributed to data verification. All authors contributed to the article and approved the submitted version.


Breast cancer and its treatments may increase the risk of type 2 diabetes (T2D). We conducted a systematic review and meta-analysis to investigate the association between breast cancer and the incidence of T2D overall, and according to breast cancer treatments.We searched PubMed, Embase and references of relevant papers for studies on breast cancer, breast cancer treatment, and subsequent T2D risk. Using random-effects models, we calculated effect estimates and associated 95% confidence intervals of the association between breast cancer, adjuvant breast cancer treatments  and chemotherapy), and subsequent T2D. We used funnel plots to assess publication bias.Among 15 eligible studies, 10 reported on T2D risk after breast cancer, chemotherapy, or endocrine therapy; five studies investigated more than one association. Compared with patients without breast cancer, those with breast cancer and those who received any endocrine therapy had elevated risk of incident T2D . Among breast cancer patients only, the risk of T2D was higher for those who received tamoxifen compared with those who did not receive tamoxifen . Due to few studies, analyses investigating T2D risk after treatment with aromatase inhibitors or chemotherapy were inconclusive.Our findings suggest an elevated risk of T2D in breast cancer survivors, particularly after tamoxifen therapy. Further research is needed to determine the impact of aromatase inhibitors, and chemotherapy on the incidence of T2D after breast cancer.The online version contains supplementary material available at 10.1007/s10549-023-07043-6. Breast cancer is the most frequently diagnosed malignancy in women. In 2023, ~ 2.3 million incident breast cancers will be diagnosed worldwide. Due to improvements in breast cancer diagnostics and treatment, the population of breast cancer survivors has increased. In 2020, there were about 7.8 million 5-year survivors of breast cancer globally . This nuObservational studies point towards increased risk of T2D in breast cancer survivors –7. BreasA meta-analysis by Ye et al. aimed to investigate the incidence of T2D after breast cancer and endocrine therapy, suggesting elevated risk of T2D in breast cancer survivors . Still, We therefore conducted a systematic review and meta-analysis to collate evidence on the association between breast cancer and subsequent risk of T2D. We also evaluated this association according to the receipt of breast cancer treatments.We conducted this study in accordance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  and the We performed a search for all eligible studies in MEDLINE (PubMed) and EMBASE from inception through May 2022. See Online Resource 1 for search terms. We also searched the reference lists of eligible articles.We included all observational studies where (i) breast cancer or breast cancer treatment [chemotherapy or endocrine treatment (tamoxifen or aromatase inhibitors)] among breast cancer patients was included as an exposure and (ii) the outcome was incident T2D. We restricted to published papers written in English, Danish, Norwegian or Swedish.Two investigators  independently screened all articles by title and abstract to remove irrelevant studies. The results from all searches were inserted into Covidence  and duplicates were removed. The same two investigators performed independent unblinded eligibility assessment of the retrieved publications and evaluated their eligibility for inclusion based on the afore-mentioned eligibility criteria.The two investigators used a predefined data extraction form to extract the following data from the eligible studies: author, title, journal, publication year, study design, study period, study size, length of follow-up, inclusion criteria, exclusion criteria, data source, methods, age and sex distribution, exposure (treatment), comparator group, outcome(s), risk estimate used, main results, and potential confounders adjusted for. When effect estimates (EEs) were not available, the investigators extracted the raw data. We also retrieved 95% confidence intervals (CI) as measures of precision.Diabetes mellitus in the studies was ascertained via diagnostic codes, prescriptions for antidiabetic medication, and/or blood glucose testing. For studies that did not specify which type of diabetes mellitus was examined, we assumed it was T2D if the women were diagnosed with diabetes mellitus as adults (at age 18 years or older).Since there is no consensus regarding how to assess study quality and risk of bias, we followed the COSMOS-E guidelines . Consequ2 statistics.EEs for each outcome were pooled using a random-effects model with the Restricted Maximum Likelihood (REML) method and illustrated using forest plots. Statistical heterogeneity was assessed using IMeasures of relative risk  were considered equivalent. As the outcome is rare, and the studies investigated the same exposure and outcome, we considered it reasonable to compare the ratios . In studThe estimates for breast cancer and risk of developing T2D were pooled in one analysis, while the effects of endocrine therapy overall, tamoxifen and aromatase inhibitors were examined in separate analyses. For each of these treatments, breast cancer patients were compared to breast cancer patients who did not use the treatment and/or non-cancer referents, depending on the data available from the articles.Last, we used funnel plots to visually assess publication bias across studies.Statistical analyses were performed using R Statistical Software .Our systematic search in PubMed and EMBASE yielded 2699 studies, of which 756 were duplicates and 1900 were excluded based on title or abstract alone. The full text of the remaining 43 studies was examined. Of these, 28 studies did not meet the eligibility criteria and were thus discarded . There was evidence of statistical heterogeneity, as indicated by an overall INine studies reported on the association between endocrine therapy and subsequent T2D among breast cancer patients –26, 28. Mean follow-up time in all but one study by Santorelli et al. , ranged Except for one study, which included propensity score-matched controls , the stu2 statistic of 0%. Our findings on the incidence of T2D associated with the receipt of the various endocrine therapies are summarized in Figs. Four studies evaluated the association between chemotherapy and subsequent risk of T2D: all were cohort studies , 24, 27.Overall, the three studies with a comparison cohort showed an increased risk of T2D after chemotherapy, regardless of whether the controls were breast cancer patients or non-cancer referents. The study by Accordino et al. showed an adjusted OR of 1.19 (95% CI: 1.08–1.31) after at least two years follow-up ; in LipsOur findings suggest that breast cancer survivors have increased risk of developing T2D compared with women without cancer. The elevated risk of T2D was particularly evident in the first few years after chemotherapy, dissipating in some studies with longer follow-up. Breast cancer patients who received tamoxifen therapy had higher risk of developing T2D compared with those who did not receive tamoxifen and compared with non-cancer referents.Our study builds on the previous evidence presented in the meta-analysis by Ye et al. . Yet, thOur observed elevated risk of T2D associated with chemotherapy may be partly attributable to the afore-mentioned glucocorticoid-associated transient hyperglycemia . We noteThe increased risk of T2D in breast cancer survivors who received tamoxifen may be attributable to several factors. Tamoxifen has been associated with lower insulin sensitivity in premenopausal women with overweight, rendering them susceptible to developing T2D . Mouse mSeveral issues warrant consideration when interpreting our findings. Most studies had small sample size, which impacted the sub-analyses investigating specific treatments. This is reflected in the wide confidence intervals in the forest plots illustrating the association of tamoxifen and aromatase inhibitor use with the risk of T2D. Another issue is the use of databases to obtain information on diabetes mellitus. Preclinical diabetes can remain undiagnosed for years; thus, the likelihood of testing and diagnosing T2D in a population of cancer survivors may be higher compared with their non-cancer counterparts. This would yield differential misclassification since breast cancer survivors may have more frequent health care contact and therefore be more likely to go to a hospital or primary care physician given their pre-existing condition. This may have inflated our observed risk of developing T2D in cancer survivors compared with their non-cancer counterparts. Another limitation is the lack of information on diabetes type which we assumed to be type 2 if not stated otherwise. We therefore set the age limit to 18 years, but some individuals aged above 18 years might still have been diagnosed with type 1 diabetes. Still, we expect this to be few women and to have negligible impact on our findings.None of the included studies differentiated between breast cancer in pre- and postmenopausal women. This is important given the distinct disease courses and endocrine therapies recommended for pre- and postmenopausal women with breast cancer. Use of aromatase inhibitors became standard treatment for postmenopausal women in 2004 . Yet, noAlthough some of the studies adjusted for patient weight at baseline, no studies incorporated information on weight changes during follow-up. Breast cancer treatment leads to weight gain, which in turn, can also increase the risk of T2D . BecauseOverall, our findings highlight the limited data on the association between breast cancer and subsequent risk of T2D. The statistical power varied across the studies and our meta-analyses. Moreover, we observed considerable heterogeneity across all our meta-analyses, precluding definitive conclusions.Still, our findings provide insights into the potential impact of breast cancer and its treatments on the subsequent risk of T2D. Additional research is needed to fully understand these associations, particularly, the risk of T2D among premenopausal women with breast cancer, and the risk of T2D according to type of endocrine therapy—i.e., tamoxifen therapy or aromatase inhibitors. Our study highlights that more research is needed on the effects of radiation and anti-human epidermal growth factor receptor-2 (anti-HER2) therapies, which were not a focus in our study. We note that a single study suggested that left-sided radiation therapy was associated with increased risk of T2D, hypothesizing that the elevated risk was due to the proximity of the pancreas to the radiation field . Anti-HEIn conclusion, this systematic review supports an association between breast cancer and an increased risk of T2D. Nonetheless, our review was limited by the low number of published studies and the potential for surveillance bias regarding T2D status in breast cancer survivors compared with their non-cancer counterparts. Furthermore, few studies reported data on the risk of T2D associated with specific breast cancer treatments, and no studies explicitly investigated the risk of T2D in premenopausal breast cancer patients. Still, the evidence points to increased risk of T2D in breast cancer survivors. Clinicians and those working in cancer survivorship care should consider the benefit of routine blood glucose testing in breast cancer survivors.Online resource 1 (PDF 101.9 kb)Below is the link to the electronic supplementary material.


The role of cigarette smoking on breast cancer risk remains controversial, due to its dual carcinogenic-antiestrogenic action.In the population-based multi-case-control study (MCC-Spain), we collected epidemiological and clinical information for 1733 breast cancer cases and 1903 controls, including smoking exposure. The association with breast cancer, overall, by pathological subtype and menopausal status, was assessed using logistic and multinomial regression models.Smokers had higher risk of premenopausal breast cancer, particularly if they had smoked ≥30 years , although most estimates did not achieve statistical significance. In contrast, among postmenopausal women, smoking was associated with lower risk of breast cancer, mainly in overweight and obese women. The strongest risk reductions were observed among postmenopausal women who had stopped smoking ≥10 years before cancer diagnosis, particularly for HER2+ tumors ; p for heterogeneity = 0.040). Also, those who had smoked <10 pack-years  or 10–25 pack-years  during their lifetime were at a reduced risk of all breast cancer subtypes ; however, women who had smoked more than 25 pack-years showed no reduced risk.Menopausal status plays a key role in the relationship between tobacco and breast cancer for all cancer subtypes. While smoking seems to increase the risk in premenopausal woman, it might be associated to lower risk of breast cancer among postmenopausal women with excess weight. During the last decades, a number of epidemiological studies have evaluated the effects of tobacco smoking on breast cancer, but this relationship remains unclear. While some studies have found an increased risk among women who have smoked heavily or during long periods3, others suggest this association may be limited to women who have smoked between puberty and the first full-term pregnancy5, and others fail to observe any increased risk7. Difficulties disentangling this association possibly derive from its complexity. On the one hand, the timing of exposure may play a relevant role due to the breastrelated windows of susceptibility8; on the other hand, smoking combines the presence of carcinogens – which have been shown to induce mammary tumors in rodents10 – with the antiestrogenic properties of tobacco11.Despite advances in diagnostic methods and treatments, breast cancer remains currently the most common cancer in women and a major cause of disease burden across the world13. Further, some studies suggest that the effect of smoking might differ by pathological subtype, especially considering that the differences between prognostic as well as molecular and cellular characteristics seem to indicate unique etiologies for each subtype15.Additionally, due to the heightened relevance of adipose tissue as estrogenic producer after menopause, it has been proposed that obesity may modify this relationshipIn spite of proposed hypotheses explaining the effects of tobacco on the breast, controversies over cancer subtypes and the importance of the dual carcinogenic-antiestrogenic effect continue to arise. In this study, we examine the relationship between active cigarette smoking and invasive breast cancer risk, focusing on the differences according to menopausal status, body mass index (BMI) and tumor subtype.16.The multi-case-control (MCC-Spain) study is a population-based case-control study conducted between 2008 and 2013 in 12 Spanish provinces to identify environmental, lifestyle and genetic factors related to 5 tumors: breast, prostate, colorectal, gastric, and chronic lymphocytic leukemia. It used a single set of population-based controls, frequency matched by age and sex, with the overall distribution of cases for each province. The study design has been described elsewhere17. Participants had to be aged 20–85 years, to have lived within the recruitment area at least 6 months prior to inclusion in the study, to be able to answer the epidemiological questionnaire, and not to have had a previous history of the disease, breast cancer in this case. The Ethics Committee of the participant institutions approved the study protocol. All participants were informed about the study objectives and provided written informed consent. For the present study, a subset of 1733 histologically confirmed incident breast cancer cases and 1903 population controls was included . Response rates were 69% for breast cancer cases and 63% for controls. Cases were classified according to pathological subtype into three groups: 1) Estrogen or progesterone receptor positive (ER/PR) without overexpression of the human epidermal growth factor receptor 2 (HER2) (HR+); 2) HER2 positive (HER2+), and 3) triple-negative (TN), i.e. ER-, PR- and HER2-.The cases were recruited in 22 collaborating hospitals and identified as soon as possible after diagnosis through active search and periodical visits to the collaborating hospital departments. Population-based controls, randomly selected from the general practitioner lists of the catchment area of each collaborating hospital, were invited to participate by phoneMCC-Spain participants were administered an epidemiological questionnaire by trained personnel in a face-to-face interview, filled a food frequency questionnaire and donated biological samples. The epidemiological questionnaire registered sociodemographic and self-reported anthropometric data (height and weight one year before the interview), and collected information on personal and family history of cancer, pre-existing medical conditions, residential and occupational history, tobacco use and physical activity previous to diagnosis. Detailed information was also collected on gynecological and obstetric variables including age at menarche, parity, age at first birth, menopausal status, age at menopause, history of benign breast disease, family history of breast cancer, oral contraceptive and postmenopausal hormone therapy use.Tobacco smoking variables including age at initiation, duration and intensity were truncated to take into account a minimum latency period of one year before cancer diagnosis. Women who reported having smoked <100 cigarettes during their lifetime were classified as never smokers. Former smokers were classified according to the time since cessation (<10 or ≥10 years). Additionally, former and current smokers were classified according to the age at smoking initiation, duration , and intensity of consumption . Duration and intensity of tobacco consumption were combined to generate a measurement variable for cumulative exposure . Finally, taking into account the information on reproductive history, parous women were classified according to the time (<10 or ≥10 years) and the number of cigarettes (<15 or ≥15 cigarettes/day) they smoked before their first birth.Sociodemographic and smoking characteristics are described with mean and standard deviation values , or frequencies and percentages . Differences between cases and controls were assessed using Student’s t-test and chi-squared test, respectively, assuming equal variances. The association between breast cancer risk and each smoking variable was examined using unconditional logistic regression models which included the matching variables (age at recruitment and province of residence) and education level, as cases and controls were unbalanced for this factor. Multivariable models were further adjusted for known breast cancer risk factors: age at first birth, number of children, menopausal status, previous breast biopsies, family history of breast cancer, and alcohol consumption.2) in post-menopausal women, and effect modification was tested with likelihood ratio tests that compared models with and without interaction terms.Stratified analyses were conducted by menopausal status  and by body mass index  in the adjusting models. Results are expressed as adjusted odds ratio (AOR) or relative risk ratio (RRR), with 95% confidence interval (95% CI). All analyses were performed with the statistical package Stata 15/IC .The MCC-Spain study was approved by the Ethics Committee of each collaborating institution, in conformity with the principles of the Declaration of Helsinki. Participants were informed about the objectives and signed an informed consent. Personal identifiers are removed from the datasets in order to secure the confidentiality of the subjects. Researchers were asked to sign a confidentiality agreement. The database was recorded in the Spanish Agency for Data Protection (Number: 2102672171).A total of 1733 breast cancer cases and 1903 controls were included in the analysis. 2.Results of post-menopausal women stratified by BMI  found that the protective effects of tobacco were restricted to overweight and obese women . Among nPathological tumor subtype information was available for 1578 (91.1%) cases. Only 300 cases were HER2+ and 134 were TN, limiting our statistical power to detect differences among these subgroups. Our results suggest that the association of cigarette smoking and breast cancer risk is modulated by menopausal status. Thus, we observed an increase of risk limited to pre-menopausal women, which was more apparent among long-term smokers, among women who started smoking after the age of 18 years, and for HR+ tumor subtype. In contrast, post-menopausal women who smoked had lower risk of breast cancer than non-smokers, especially among long-term smokers and for HER2+ tumor subtype; this decrease was, however, restricted to overweight and obese women.22. Similarly, several studies where analyses were conducted separately according to menopausal status, frequently reported no risk increase for breast cancer, or even protective effects, among post-menopausal women with a smoking history24, although some recent cohorts with a large number of incident cases found an increase in breast cancer risk among both pre- and post-menopausal women25. The increase, nevertheless, has been consistently reported to be greater before menopause22. We cannot rule out that the discrepancies with our results might be due to residual confounding, or related to the low number of cases in certain subgroup analyses; another possible explanation may lie in the differences in tobacco use among the studied population, as the prevalence, duration and intensity of smoking have been historically higher in American and Nordic cohorts25, compared to Spanish cohorts – especially older women26.These findings are partly in accordance with our expectations. Over recent decades, evidence surrounding the role of tobacco in breast cancer has been inconsistent and inconclusive. However, in the past years, large sample cohort studies and meta analyses have consistently reported a small increase in the risk of breast cancer associated with cigarette smoking, in agreement with our results12. In contrast, we have not found any risk increase among women who smoked heavily before their first full-term pregnancy, even though this association has been consistently described in the literature22.The combined effects of obesity and tobacco smoking, on the other hand, have received less attention, but our findings are concordant with previous studies11. The joint outcome might present itself either as a balanced risk between carcinogenic stimulus and hormonal blockade, or as a risk decrease due to a higher relevance of antiestrogenic effects24. This ‘dual’ effect of tobacco may explain our different results among pre- and post-menopausal women, as well as the lack of a consistent association between smoking and breast cancer reported by some studies, especially those which did not assess pre- and post-menopausal women separately28. The seemingly opposite effects of smoking according to menopausal status reported here have been also found in other studies29. In the EPIC Study, a large European cohort including 25343 Spanish women29, the authors found an increase of risk in women smoking before menopause, reporting a dose-response effect for cigarette consumption between menarche and first birth; however, after menopause, an increase of pack-years was associated with a decrease in risk. A study by van den Brandt24 found the highest breast cancer risk among women smoking a high number of pack-years before menopause and no cigarette consumption afterwards; in contrast, the risk was significantly decreased among women who were light smokers before menopause and became heavy smokers thereafter.According to our results, menopause plays a relevant role in the relationship between breast cancer risk and tobacco exposure. Tobacco has both carcinogenic and antiestrogenic activity. During pre-menopause, the carcinogenic stimulus of tobacco may outweigh its antiestrogenic effects, which can be insufficient to counteract the high estrogen levels, altogether increasing the risk of breast cancer. After menopause, in spite of tobacco retaining its carcinogenic potential, mammary cells become less susceptible to stimuli, and estrogen levels are further reduced due to the antiestrogenic activity of tobacco, as nicotine and other tobacco compounds interfere with aromatase, a key enzyme in the metabolic pathway of estrone32. Before menopause, the ovaries are the main source of estrogens. After ovarian decline and menopause, adipose tissue becomes the main producer of estrogens in the form of estrone. While pre-menopausal obesity has little to no effect in contributing to the high levels of estrogens produced by the ovaries, high amounts of adipose tissue after menopause will significantly increase those levels, stimulating the growth of estrogen-sensitive breast tumours13. Similarly, this dual effect might help to explain why, in our data, the highest risk reduction among post-menopausal women is not found among heavy smokers, but rather among those with a moderate tobacco use, especially women exposed to a low-moderate intensity sustained over a long period of time. Perhaps, above certain doses, the carcinogenic effects might exceed the antiestrogenic effects of tobacco even in this subgroup of women.Another interesting result of our study, also related to this dual effect, is the possible role of obesity as modulator of the relationship between tobacco use and breast cancer among post-menopausal women. Our data hint at differences in breast cancer risk according to BMI. Obesity has been recognized as a risk factor for post-menopausal breast cancer, but not for pre-menopausal cases20 reported an increased risk among smokers for both, ER+ and ER- breast cancer, yet the effect was stronger and more consistent for ER+ tumors. Also, in the EPIC Study29, smoking appeared to be a risk factor for ER+, but not for ER- tumors (including ER-/PR+), although the authors, again, did not provide risk estimators by menopausal status. Nevertheless, there are a few studies that have evaluated pre-menopausal cases – a cohort33 and a population-based case-control34 study which reported an increased risk of breast cancer with smoking in ER+ –, or, in post-menopausal women, two case-control studies35 which found no association between smoking and ER+ breast cancer, and a Norwegian nested case-control15, including women aged 50–69 years, that found an increase of risk for ER+ and ER-/PR+ tumors. To our knowledge, no previous studies have reported an association between decreased post-menopausal HER2+ breast cancer risk and cigarette smoking. However, researchers studying subtypes usually focus on estrogen and progesterone receptor status to establish tumor subtype; it is also relatively usual to combine pre- and post-menopausal women35. Therefore, any specific association could have been overlooked, especially due to the low frequency of HER2+ tumors, compared to ER+ tumors. Only one nested case-control study15 researching the impact of alcohol, physical activity and smoking explicitly reported no association between these factors and HER2+ tumors.Regarding the relationship with tobacco by tumor types, we have not found differences among them in pre-menopausal cancers, probably due to the low number of cases of HER2+ and TN tumors, as the HR+ subtype constitutes >70% of all tumors in this group. On the other hand, for post-menopausal women, TN seemed to have the lowest risks, although in most cases the tests for heterogeneity suggest that there might not be differences by subgroup. In the literature, several studies have reported a stronger association between cigarette smoking and ER+ breast cancer. Without considering differences by menopausal status, a pooled analysis of 14 cohort studies of nearly one million participants3. The wide age range of participants allowed the separate study of pre- and post-menopausal women, and the availability of clinical data allowed the possibility of evaluating the relationship between cigarette smoking and specific tumor subtypes by menopausal status. Also, we have explored the possible role of BMI as modulating factor in postmenopausal women, adding new information to this complex picture.Our study has several strengths. The comprehensive evaluation of smoking history has enabled us to classify participants according to smoking status, age at initiation, duration and intensity, both overall and in relation to reproductive milestones, and to provide a global view of the relationship between breast cancer and tobacco use. Also, the MCC-Spain study, which is the largest case-control cancer study done in Spanish population, has the advantage of counting with randomly selected general population controls, as well as with incident cases. This last factor reduces the risk of survivorship bias, which could be a problem if tobacco smoking played any role in tumor progression, with higher rates of breast cancer proliferation, recurrence, and mortality26. To prevent a possible confounding effect, education level was included as an adjusting variable in all our analyses. Lastly, the generalizability of our findings might be limited, as our study was conducted within the Spanish population, which may differ from other countries in both genetic traits and lifestyle habits.On the other hand, our work presents certain limitations. First, as stated above, smoking prevalence was low among older women, which, combined with the low number of cases in certain subgroups, limited our capacity to explore the association among them. Thus, we cannot rule out the possibility that our findings may be partly due to chance, and that they might not reflect any actual effects of tobacco use on breast cancer risk. However, current evidence suggests otherwise, and, in our study, both the risk increase in pre-menopausal and the decrease in post-menopausal women were consistent across smoking variables. Likewise, even though we tried to address the risk of confounding with our comprehensive inclusion of well-established risk factors of breast cancer, they may be still residual confounding. Second, given our case-control design, the risk of having certain recall bias is unavoidable, and we cannot know whether it is differential or non-differential. Nevertheless, we tried to minimize this risk by administering a common and comprehensive questionnaire about tobacco use by a trained interviewer. Also, most women do not consider tobacco as risk factor for breast cancer, which would favor a non-differential bias. Third, response bias was a concern for our study, as women with a higher education level seemed more prone to participate. In this sense, the pattern of female tobacco use in Spain has evolved: among older women, smoking was uncommon except for university-educated women; during the last decades, smoking has become widespread in society and is currently more frequent among women of low economic and education levelThe role of tobacco as a breast cancer risk factor appears to be modified by menopausal status and obesity. The effect of cigarette smoke might depend on breast differentiation and estrogen metabolism in each specific life period. In our study, pre-menopausal women show a modest increase of breast cancer risk, suggesting that the carcinogenic properties of tobacco prevail among young women, whereas the decreased risk among post-menopausal women is consistent with the antiestrogenic effects of tobacco. The harmful effects of tobacco on other organs and its role as a risk factor for other types of cancer, however, largely exceed this observed protective influence. Therefore, our findings support the development of early smoking prevention programs.Click here for additional data file.


This study used a Mendelian randomization (MR) approach to investigate the causal relationship between genetically predicted endometriosis (EMS) and breast cancer risk. A total of 122,977 cases and 105,974 controls were included in the analysis, with gene-level summary data obtained from the Breast Cancer Association Consortium (BCAC). An inverse variance-weighting approach was applied to assess the causal relationship between EMS and breast cancer risk, and weighted median and MR-Egger regression methods were used to evaluate pleiotropy. Results showed a causal relationship between EMS and a decreased risk of overall breast cancer . Furthermore, EMS was associated with a lower risk for estrogen receptor (ER)-positive breast cancer in a subgroup analysis based on immunohistochemistry type . However, there was no causal association between ER-negative breast cancer and survival . Pleiotropy was not observed. These findings provide evidence of a relationship between EMS and reduced breast cancer risk in invasive breast cancer overall and specific tissue types, and support the results of a previous observational study. Further research is needed to elucidate the mechanisms underlying this association. Depending on a woman’s advanced menopausal state and the status of the tumor receptors, breast cancer is a heterogeneous disease. The development of breast cancer is the result of a combination of internal and external factors. Some studies have identified certain risk factors for breast cancer, including age, family history, history of benign breast disease, history of estrogen use, lifestyle, obesity, and fertility2.In 2020, there were approximately 2.3 million new breast cancer cases worldwide, accounting for 11.7% of all new cancer cases. Women have a high mortality rate due to breast cancer 3. Numerous epidemiological and clinical studies have shown that EMS is estrogen-dependent. Estradiol (E2) has been shown to promote adhesion, invasion, proliferation, apoptosis inhibition, and inflammatory response maintenance in ectopic lesions. Elevated estrogen levels in ectopic lesions in patients with EMS suggest that local estrogen metabolism plays an important role in EMS development4. Additionally, extensive epidemiological data indicate that chronic estrogen exposure increases the likelihood of breast cancer5. Therefore, whether there is an association between EMS and breast cancer is a question of interest. Previous observational studies have yielded inconsistent results in EMS and breast cancer risk examination, with most showing implied increased risk 6. However, in the most recent largest study, international collaboration on breast cancer research reported a recommendation for a reduced risk of invasive breast cancer in women who self-report EMS7. The relationship between EMS and breast cancer has not been systematically studied because of potential biases such as confounding factors or reverse causality. Therefore, there is no conclusive evidence that EMS contributes to breast cancer progression. Additional investigations are needed to draw definitive conclusions regarding the causality and biology of these associations.Endometriosis (EMS) is one of the most prevalent diseases in women of childbearing age, with a prevalence of 5–10%8, suggesting that MR may provide a way to examine the EMS-breast cancer relationship. Therefore, we sought to examine this association using information from recent genome-wide association studies (GWAS) on EMS and breast cancer.Mendelian randomization (MR) was used to overcome these limitations. This analytical method uses random genetic classification from parents to progeny to evaluate the association between EMS and breast cancer risk. When specific assumptions are met, this approach is largely independent of biases inherent in standard observational studies. A previous study has shown that EMS has a significant genetic componentThis study aimed to investigate genetically predicted EMS with the risk of overall breast cancer and cancer by estrogen receptor status (estrogen receptor-positive [ER+] and estrogen receptor-negative [ER−]) using MR methodology.10. Firstly, we selected Instrumental variables (IVs) significant relationship with EMS  at the genome-wide level. Secondly, to satisfy the independence of genetic variation and confounders, we searched in Catalog and PhenoScanner databases to ensure that each IV included was unrelated to known confounders. Finally, we calculated the F statistic to avoid the bias of weak IVs and confirmed that these results were not affected by weak IVs. The design concept of this study are shown in Fig. In this study, we used MR to explore the relationship between exposure and outcome. Among them, the inclusion of instrumental variables mainly follows the three principles of MR9. For the Breast Cancer Association Consortium dataset (BCAC), we recommend that the reader refer to the main GWAS manuscript and its Supplementary Material for more information on the consent protocols for the respective cohorts.EMS data were obtained from the FinnGen project (FinnGen), including 2953 EMS cases and 68,969 control participants. The samples of participants in our study for genetic analysis were obtained from the BCAC; a total of 122,977 cases and 105,974 controls were utilized, containing 38,197 ER+ cases and 21,468 ER− casesMendelian randomization (MR) methods were employed in this study. And three different analytical methods were used in the MR analysis to prevent this. Each analysis was based on a different horizontal multiplicity model. The benefit of comparing these three results is that the consistency of the three methods makes the results more credible. The main analysis was performed using an inverse variance-weighting (IVW) approach, which provided the most accurate estimates but assumed that all SNPs were valid IVs. MR-Egger approach is based on the assumption of InSIDE in order to perform a weighted linear regression of exposure results, but it is susceptible to IVs. Weighted median approach could significantly improve the detection ability of causal effects as well as reduce type I errors. MR-PRESSO is a variant of IVW that eliminates IVs and its causal estimates differ significantly from other IVs. It provides accurate analysis if horizontal pleiotropy occurs in less than 50% of IVs.12. Cochran Q statistics and MR-Egger regression were used to explain this study's heterogeneity and pleiotropy. Then, MRPRESSO, the leave-one-out analysis, and funnel plot were also used as additional multiplicity controls to global, outlier, and distortion tests.We used different methods for assessing potential effects to ensure the third MR hypothesis that the IVs were independent of the outcome except for exposureAll data were obtained from published studies approved by the institutional review boards, and informed consent was obtained from the participants of the original study. Therefore, no further sanctions were required. And all analyses were carried out using two-Sample MR and MRPRESSO packages in R software . The OR value is mainly converted through beta exp(β). Significance levels were set at 0.05.The GWAS data used in this study were public de-identified data. The ethics committee approved these data; therefore, there was no need for additional ethical approval.Informed consent was obtained from all individual participants included in the study.Authors are responsible for correctness of the statements provided in the manuscript. See also Authorship Principles. The Editor-in-Chief reserves the right to reject submissions that do not meet the guidelines described in this section.It was confirmed that all protocols were approved by the Lihuili Hospital Committee of Ningbo University. Confirm that all methods are implemented in accordance with relevant guidelines and regulations.−8, F > 10). Thus, none of the SNPs was susceptible to IVs. The causal effects of each genetic variant on breast cancer are shown in Figs. The SNPs’ signatures of the EMS are shown in Table We evaluated the causal relationship between EMS levels and breast cancer using IVW, MR-Egger, and weighted median regression. Our findings suggest a reduced risk of breast cancer in patients with EMS . Subgroup analysis based on the type of immunohistochemistry showed a higher risk of ER+ breast cancer in patients with EMS , whereas no significant correlation was observed between EMS and ER– breast cancer  , further indicating that pleiotropy did not bias the causal effect. Furthermore, in the published GWAS, there was no evidence that the included EMS-associated SNPs were significantly associated with any phenotype except EMS, which indicates that the assumptions of the third MR were not violated.This study evaluated the causal relationship between EMS and breast cancer using a Mendelian randomization approach. We found that each SD increase in EMS predicted a 5.0% decrease in breast cancer risk. The inference still held in the subtype analysis; in patients with ER + breast cancer, each SD increase in EMS predicted a decrease in the risk of breast cancer by 8.1%; however, no causal relationship was observed in ER– patients. In addition, to exclude the possibility that this causal inference received confounding factors, potential confounding factors, such as obesity and smoking, were analyzed. Consequently, we considered that confounding factors did not confound the causal inference.13. Many studies have investigated the relationship between EMS and breast cancer; however, no consistent conclusion has been reached. Some studies have confirmed that EMS increases the risk of breast cancer16. Few studies considered EMS protective against breast cancer18. Other studies have argued that there is no relationship between EMS and breast cancer20. The possible selection and detection biases in these studies could significantly hamper the data assessment. For example, the selection of women undergoing endometrial surgery in some studies has led to potential selection bias. Additionally, the choice to use a discharge diagnosis of EMS contributed to detection bias, as only severe cases were included in the study. Selection and detection bias excluded many patients with cancer from the study, which might have led to an inaccurate assessment of EMS developing into breast cancer. Simultaneously, some studies used a self-reported format , which may have led to recall bias.Despite being benign, EMS also has the characteristics of a malignant tumor21. Inflammatory responses due to overproduction of reactive oxygen species are also present in breast cancer patients22. One study reported that women who underwent bilateral oophorectomy with hysterectomy because of EMS experienced a 58% decrease in breast cancer risk. This might be owing to an early interruption of the inflammatory process that could lead to breast cancer risk23.The fundamental pathological change in EMS is not proliferation of epithelial cells, but an increase in inflammation and cell survival resulting from apoptosis or diminished differentiation25. Reduced methylation of CpG islands in the ERβ gene promoter leads to increased expression levels in endometrial stromal cells, whereas hypermethylation silences ERβ expression. ERβ in endometrial stromal cells dominated the ERα promoter and deregulated its activity, which facilitated the suppression of ERα levels, leading to an altered ERβ:ERα ratio in tissues26. It was shown that in breast cancer, the expression of ERβ was decreased compared to that in normal tissues, suggesting a protective effect of ERβ against ERα-induced overproliferation27. Women diagnosed with EMS in the postmenopausal period have an increased risk of breast cancer. It is possible that a higher Erβ level in women with EMS leads to a better prognosis. Our study also found a protective effect of EMS against ER+ breast cancer but not against ER– breast cancer.The function of estrogen is mediated by two estrogen receptors (ERα and ERβ). Studies on EMS have shown increased levels of ERβ and decreased levels of ERα in endometriotic tissue compared to that in the normal endometrium29. Women younger than 40 years of age had a reduced risk of developing breast cancer when diagnosed with EMS compared with women older than 40 years. The reduced risk among younger women may be because of their exposure to anti-estrogenic drugs. The increased risk in menopausal women may be owing to a common risk factor between postmenopausal EMS and breast cancer15. Thus, the use of anti-estrogen drugs in patients with EMS might reduce the risk of breast cancer.The consensus among clinicians and researchers is that estrogen increases the risk of laparoscopically visible EMS and associated pelvic pain, and that targeting cyclooxygenase-2 in the estrogen biosynthesis pathway and the prostaglandin pathway decreases or eliminates laparoscopically visible EMS and pelvic pain17.It has been shown that when comparing DNA repair capacity (DRC) in both EMS and breast cancer, women with EMS were 10% less likely to have low DRC compared to women without EMS, and those diagnosed with EMS at 38 years of age were 40% less likely to have low DRC. A low DRC is an important risk factor for breast cancer, as reported in the literature and in the same group of women. The mechanisms associated with the protection of breast cancer by EMS and the positive association between EMS and DRC remain largely unknown. Some drugs may also alter DRC, indirectly affecting the risk of breast cancer. As more is known about the molecular similarities between EMS and breast cancer, this knowledge should provide more effective strategies to prevent and treat both conditions30.The standardized incidence of in situ breast cancer increased in the 40- to 59-year-old age group; however, patients with EMS aged 40 years or older might undergo breast imaging more frequently than the general population, which could potentially increase the detection and prompt treatment of in situ cancer and thus reduce breast cancer riskThis study has several strengths. The MR analysis was used for the first time to evaluate the causal association between EMS and breast cancer. Since genetic mutations are inherited from the parental generation, they do not receive external environmental influences and are therefore not subject to reverse causality, which is often present in observational studies. Additionally, we excluded the influence of potential confounding factors. Moreover, we derived these data from published GWAS data. The GWAS data contained 2,953 cases and 68,969 controls, which is a large sample size that made our study more convincing.This study also has some limitations. First, our study indicated that EMS reduced the risk of breast cancer and provided more insight into the clinical disease. However, this has limitations in clinical application since one cannot make people with a high risk of breast cancer develop EMS, which would be difficult to achieve and unethical. Second, only a weak protective effect was observed. Third, our study population was limited to European ancestors, and further studies are needed to determine whether this is feasible in other populations.In conclusion, these findings provide evidence of an association between EMS and reduced breast cancer risk, with the strongest correlation observed in ER+ breast cancer. These results are in agreement with those of our previous analysis of a large pooled epidemiological study. Further studies are needed to understand the mechanisms underlying this association.