Although several studies have evaluated the risk of gynecological cancers in women with polycystic ovary syndrome (PCOS), there are controversies regarding it.This study aimed to investigate the association of PCOS with endometrial, ovarian, and breast cancers.PubMed, Scopus, Web of Science, and Google Scholar databases based on MESH terms using the combination of the appropriate keywords were searched to retrieve observational studies on endometrial, ovarian, and breast cancers in PCOS women, published from inception to April 2020. This meta-analysis was performed to determine the pooled odds ratio (OR) of these cancers in women with PCOS. Publication bias was assessed by using Begg's test.Of 1347 records retrieved by searching the databases, a total of 14 articles were included in the study. Overall, the pooled OR of the composite outcome, including endometrial, ovarian, and breast cancers in women with PCOS was higher than that of women with no PCOS . The pooled OR of endometrial  and ovarian  cancers in women with PCOS was higher than the control group, whereas the pooled OR of breast cancer was not significantly higher than that of the control group.This meta-analysis indicated an increased risk of endometrial and ovarian cancers in women with PCOS. Polycystic ovary syndrome (PCOS), one of the common abnormalities in reproductive age women (1), is defined by ovulation abnormalities, high levels of androgens, and polycystic ovaries in ultrasonography (2). PCOS is also associated with several conditions, such as glucose intolerance, diabetes, hypertension, central obesity, metabolic syndrome, and cardiovascular diseases (3-7).The high prevalence of endometrial hyperplasia and carcinoma due to chronic anovulation, associated with prolonged exposure to unopposed estrogen has been long recognized. Moreover, PCOS complications, such as obesity, nulliparity, diabetes, and hypertension, are risk factors for endometrial carcinoma (8-10). In this regard, a population-based cohort study reported a 17-fold increase in the risk of endometrial cancer among women with PCOS, compared to those without PCOS (11). Several hypotheses have been proposed for the increased risk of ovarian cancer in PCOS women, such as anovulation, increased androgen exposure, and lack of progesterone (12). Another study found that the risk of ovarian cancer was 2.5 times higher in women with PCOS compared to healthy women (13). It is possible that the sustained elevation of serum estrogen levels may lead to the growth of hormone-sensitive tumors, such as breast cancer (14); therefore, anovulation can be considered as a critical risk factor in women with PCOS. Several studies have investigated the risk of breast cancer in women with PCOS; however, the actual risk remains unclear . Although some studies have assessed the risk of endometrial, ovarian, and breast cancers in women with PCOS, their results are often conflicting, and the risk of these cancers in women with PCOS is still debated .Hence, this study aims to conduct a meta-analysis of observational studies to investigate the association of PCOS with endometrial, ovarian, and breast cancers. Since the severity of PCOS manifestations can distort the results, we adjusted the results for PCOS diagnostic criteria in a meta-regression analysis.This meta-analysis was designed according to the guidelines for the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to assess the pooled odds ratio of endometrial cancer in women with PCOS, compared to healthy controls (19).Data was searched using PubMed, Scopus, Web of Science, and Google Scholar for retrieving studies published up to April 2020 investigating gynecological cancers in women with PCOS.Two reviewers (M.A. and A.F.) performed searches separately. Search on PubMed was performed initially, based on MESH terms using the following keywords:  AND .Search limitations were humans and English language publications. There was no time limitation. The same search strategy was applied for all databases, based on the titles, abstracts, and keywords. We applied a `pearl growing' strategy. First, we obtained the full text of the studies, then the reference list of the studies was reviewed to prevent missing related articles.All types of observational studies, including case-control, cross-sectional, and cohort designs were eligible to be included in the meta-analysis. Studies needed to report raw data of events, odds ratio (OR), and relative risk to provide sufficient information to allow calculation. Any PCOS diagnosis criteria were eligible to be included, for example, Rotterdam, National Institute of Health, Androgen Excess Society, International Classification of Diseases, and also a self-reported questionnaire.The exclusion criteria included studies 1) assessing conditions, for example, polycystic ovary, androgen excess disease instead of PCOS, 2) without control groups, 3) with unreliable and incomplete results, and 4) assessing hyperplasia rather than cancer.All relevant studies assessing at least one of the cancers of endometrial, ovarian, and breast in women with PCOS were included in this meta-analysis.Search results were screened based on the predefined eligibility criteria. All references were entered into EndNote software. The initial selection was based on article titles, and then a second selection based on abstracts was done and duplicates were deleted by one reviewer (A.F). Finally, the full text of selected articles was reviewed for data extraction. Disagreements were resolved by 2 other reviewers (M. A. and F.R.T.).Two reviewers (M.A. and A.F.) extracted data from the full text of selected articles and checked twice to lessen errors. For each study, information such as author's name, publications year, article title, design of the study, study population, number of outcomes, and unadjusted or adjusted OR, relative risk, or HR of the outcomes were extracted.M.A. and A.F. assessed the quality of the included studies and F.R.T. resolved any disagreements. Newcastle-Ottawa scale was applied for the quality assessment (20).The high quality was defined when a study got Cochrane collaboration's tools were applied to assess the risk of bias in each study (21).In this meta-analysis, outcomes of interest were endometrial cancer, ovarian cancer, and breast cancer.This meta-analysis was conducted to obtain a pooled OR of endometrial, ovarian, and breast cancer in PCOS women. Heterogeneity was assessed via I-squared statistics and in the case of values with upper limits 50% random effect method was applied, otherwise the fixed-effect method.To assess publication bias, Begg's test was used (22); it was found significant for p In case of publication bias, forest plot corrected via trim and fill method was drawn. To estimate pooled ORs, we applied the `Meta-prop' random effect method (25). The 95% prediction interval (95% PI) was estimated to evaluate clinical significance as compared to statistical significance for the pooled OR. Moreover, the random effect meta-regression model was fitted to assess the effects of PCOS diagnosis criteria and age on the results. We also run a sensitivity analysis to detect probable influential studies with a high risk of bias. Statistical analysis was conducted using STATA software .Figure 1 presents the flow diagram of the search strategy and study selection. Of 1347 records retrieved by searching the databases, a total of 14 studies, including 4 cohorts  and 10 case-control  studies, were selected for the final analysis. Nine studies  were classified as high-quality, and 5  as moderate-quality (Table I-II).Two studies  based on the international classification of diseases, 2  used the Rotterdam criteria, 1 (26) used the laparoscopic criteria, and 9  reported no criteria. In addition, 7  reported breast cancer, 6  reported ovarian cancer, and 6  reported endometrial cancer.2 (95% CI: 26.3-26.7), respectively. Table III presents the results of the meta-analysis and meta-regression.In this meta-analysis, 12,955 women with PCOS and 118,481 controls were included. The pooled mean (95% CI) of age and body mass index of all study populations were 27.8 yr (95% CI: 27.8-27.9) and 26.5 kg/mFigures 2-5 present the forest plots of the pooled ORs for the composite outcome  as well as separate outcomes, including endometrial, ovarian, and breast cancers in women with PCOS vs. the control group. The pooled OR of the composite outcome in women with PCOS was higher than that of women with no PCOS . The results also indicated that the pooled OR of endometrial and ovarian cancers in women with PCOS was higher than that of their counterparts , whereas the pooled OR of breast cancer in women with PCOS was not significantly higher than controls.Moreover, the 95% PIs for the odds of endometrial cancer, ovarian cancer, breast cancer, and all cancer types were estimated in women with PCOS vs. their counterparts . The results of meta-regression analysis revealed that the diagnostic criteria of PCOS and age had no significant effects on the heterogeneity of the outcomes .The results of Begg's test showed a significant publication bias for endometrial cancer in both PCOS and non-PCOS groups and breast cancer in the PCOS group, which was adjusted by the trim and fill method .Figures 8-9 represent the risk of bias in the included studies. Most case-control studies had a low risk of bias in domains of sample selection and the primary outcome in the case and control groups, despite a high risk of bias in the assessment of exposure and control of the prognostic variable. In cohort studies, there was a low risk of bias in the adequacy of follow-ups, assessment of outcomes, selection of exposed and non-exposed cohorts, and presence of the outcome of interest at the onset of the study. Moreover, we found a high risk of bias in controlling for prognostic variables, assessment of exposure, and assessment of the presence or absence of prognostic factors. The sensitivity analysis of endometrial cancer, ovarian cancer, breast cancer, and all cancers showed that no study caused heterogeneity among the results .This meta-analysis was carried out to assess the association of PCOS with endometrial, ovarian, and breast cancers. The results revealed that PCOS was associated with an increased risk of endometrial and ovarian cancers, but not breast cancer.It is known that in women with PCOS who have anovulatory menstrual cycles, progesterone, a key hormone in the endometrium against estrogen-driven growth, does not play a regulatory role. This can result in the development of endometrial hyperplasia and adenocarcinoma, mainly due to constant unopposed estrogen activity in the endometrium (35). In other words, an estrogen/progesterone imbalance may lead to endometrial hyperplasia increasing the risk of endometrial cancer in the long run (36). Also, the endometrium of women with PCOS, who received ovulation induction showed the downregulation of progesterone-regulated genes in the secretory phase, leading to progesterone resistance (37). Overall, hyperandrogenism is a clinical feature of PCOS (2). Besides, secretion of ovarian steroids, such as testosterone, is higher in women with endometrial cancer, compared to the healthy population (38). It is well documented that women with PCOS have increased levels of endometrial androgen receptors, compared to the fertile controls (39). Hypersecretion of luteinizing hormone is another feature of PCOS (40). This finding is important since the expression of luteinizing hormone receptors increase in women with anovulatory cycles and endometrial hyperplasia, and it may be associated with endometrial carcinogenesis (41). Insulin resistance is another common feature in many women with PCOS, which leads to compensatory hyperinsulinemia and a 4-fold increase in the prevalence of type II diabetes . Hyperinsulinemia, caused by insulin resistance, promotes endometrial cell proliferation and increases the risk of endometrial cancer (14). Also, evidence suggests that the risk of endometrial cancer is higher in women with diabetes compared to those without diabetes (43). Other risk factors for endometrial cancer, such as obesity, nulliparity, and hypertension, are also associated with PCOS (14).Our results showed that the risk of endometrial cancer was 2.2 times higher in women with PCOS than the controls. In agreement with our findings, a meta-analysis of 4 studies suggested that women with PCOS were 3 times more likely to develop endometrial cancer, compared to those without PCOS (14). Likewise, another meta-analysis of 5 studies showed a 3-fold increase in the risk of endometrial cancer in PCOS women compared to the general population (44). Similarly, a meta-analysis of 11 studies demonstrated that the risk of endometrial cancer was nearly 3 times higher in PCOS women compared to their counterparts (45).It is well-documented that ovulation is an etiological cause of ovarian cancer; however, it cannot be the only contributor to the pathogenesis of this cancer (12). Although the risk of ovarian cancer in women with PCOS is expected to be low due to anovulation, it is higher than that of healthy women (6). Hormonal mechanisms are hypothesized to be involved in the etiology of ovarian cancer (46). Increased androgen exposure in women with PCOS has been hypothesized to be associated with an increased risk of ovarian cancer (12). This association could be explained by evidence regarding the presence of androgen receptors on healthy ovarian cells, as well as benign and borderline tumors (12). Moreover, it has been shown that higher androgen levels during pregnancy were associated with an increased risk of borderline serous and mucinous tumors . Hyperinsulinemia and the resulting increase in insulin-like growth factor-1, which plays an important role in tumorigenesis, have also been suggested as the main mechanism (49).The present study indicates that the risk of ovarian cancer is 1.3 times higher in PCOS women than their counterparts. In line with our results, a meta-analysis conducted in 2009 (14) reported that women with PCOS are twice more likely to develop ovarian cancer, compared to those without PCOS. Our results are also consistent with the findings reported by another meta-analysis, which showed a 2.5-fold increase in the risk of ovarian cancer in women with PCOS aged There is a complex relationship between PCOS and breast cancer, as the consequences of PCOS have been associated with both the increased and decreased risk of breast cancer (18). The anovulatory cycle and infertility are among the characteristics of PCOS, suggested to decrease the risk of breast cancer (50). However, obesity is a major risk factor for breast cancer in both post and premenopausal women, and as mentioned previously, it is also a common finding in PCOS women (51). This reduction in the risk of breast cancer among women with ovulatory disorders is because of luteal phase deficiency in the menstrual cycle; therefore, the levels of estrogen and progesterone do not increase. Also, it is well-documented that breast cancer cell proliferation is higher during the luteal phase . Moreover, hyperinsulinemia has been suggested as an independent risk factor for breast cancer (53). The correlation between androgen excess and the pathogenesis of PCOS is still controversial; however, androgens seem to trigger the development of estrogen-receptor (ER)-negative breast cancer . Advanced maternal age during the first pregnancy and nulliparity are also important risk factors for breast cancer (56).Despite the mentioned mechanisms, we found no significant association between PCOS and breast cancer. Similar to our results, a meta-analysis showed that women with PCOS were not exposed to a higher risk of breast cancer, compared to those without PCOS (14). Likewise, another meta-analysis of 8 studies found no significant association between PCOS and breast cancer (57). Similarly, a recent meta-analysis reported no significant association between PCOS and breast cancer (45). However, more comprehensive prospective cohort studies are needed to examine the association between PCOS and breast cancer and to identify the involved mechanisms.In our meta-analysis, the risk of bias assessment revealed the high risk of bias for some included studies, especially case-control studies, which might influence our results. To detect these possible effects, we performed a sensitivity analysis. However, no significant studies were found, which could cause heterogeneity.The most important strength of our study was including a larger number of studies, especially cohort studies. Unlike previous meta-analyses, we did not include studies investigating women with polycystic ovarian morphology, who were not diagnosed with PCOS (58-60); this may increase the accuracy of our findings.On the other hand, the main limitation of this meta-analysis was that a large number of studies did not report the mean age and details of diagnostic criteria for PCOS. However, after considering the PCOS diagnostic criteria and the mean age through meta-regression, we found that these variables were not significant sources of heterogeneity. Also, in most previous studies, cases of self-reported PCOS have effects on the exactness and validity of the results. Even though in this meta-analysis we tried to lessen all possible biases, it should be considered that there was significant heterogeneity in most of the outcomes. Since this heterogeneity could be due to variations in PCOS phenotypes and diagnostic criteria, we considered the results for PCOS diagnostic criteria via meta-regression. However, our findings showed that the diagnostic criteria of PCOS exerted no significant effects on the heterogeneity of the outcomes.Moreover, a large number of studies, identified through our database search, did not have any control groups, which could limit the number of studies eligible for our analysis. While some potential confounders, such as body mass index, might affect the results, we could not consider these variables due to the paucity of data. Although pooling fully adjusted ORs can provide more real effect sizes, we considered unadjusted ORs, since included studies had not adjusted the same confounders that may lead to further bias for summary effect size in meta-analyses, especially for weak or medium associations so that the direction of causal inference would be even reversed (61). Also, we could not consider family history, lifestyle, medication use , and many other conditions, which can play important roles in the development of cancer. Ovarian cancer consists of distinct histotypes; however, we combined them due to the paucity of data. Moreover, considering the borderline statistical significance of the results, we estimated the clinical significance by measuring PIs, which showed no clinical significance, possibly due to the limited number of included studies. All of these limitations should be considered in interpreting the results.This study indicated the increased risk of endometrial and ovarian cancers in women with PCOS. Therefore, screening programs for early detection of these cancers, especially in women with PCOS, can be considered an important strategy for improving their survival.The authors have no conflict of interest to declare.


Chemoprevention with anti-estrogens, such as tamoxifen, raloxifene or aromatase inhibitors, have been shown to reduce breast cancer risk in randomized controlled trials; however, uptake among women at high-risk for developing breast cancer remains low. The aim of this study is to identify provider-related barriers to shared decision-making (SDM) for chemoprevention in the primary care setting.Primary care providers (PCPs) and high-risk women eligible for chemoprevention were enrolled in a pilot study and a randomized clinical trial of web-based decision support tools to increase chemoprevention uptake. PCPs included internists, family practitioners, and gynecologists, whereas patients were high-risk women, age 35–75 years, who had a 5-year invasive breast cancer risk ≥ 1.67%, according to the Gail model. Seven clinical encounters of high-risk women and their PCPs who were given access to these decision support tools were included in this study. Audio-recordings of the clinical encounters were transcribed verbatim and analyzed using grounded theory methodology.Six primary care providers, of which four were males (mean age 36 [SD 6.5]) and two were females  and seven racially/ethnically diverse high-risk female patients participated in this study. Qualitative analysis revealed three themes: (1) Competing demands during clinical encounters; (2) lack of knowledge among providers about chemoprevention; and (3) limited risk communication during clinical encounters.Critical barriers to SDM about chemoprevention were identified among PCPs. Providers need education and resources through decision support tools to engage in risk communication and SDM with their high-risk patients, and to gain confidence in prescribing chemoprevention in the primary care setting.The online version contains supplementary material available at 10.1186/s12911-022-01954-y. Breast cancer is the most common cancer and the second leading cause of cancer-related death among women in the U.S, making it an important public health priority . The U.SShared decision-making (SDM) is a collaborative process by which healthcare providers partner with patients to achieve informed health decisions , 9. ThroRealRisks for patients and BNAV (Breast cancer risk NAVigation) for primary care providers (PCPs), which were both used in this current study. Results from an initial single-arm pilot study with 50 high-risk women showed that exposure to RealRisks led to improved accuracy of breast cancer risk perceptions and increased chemoprevention knowledge [In order to address barriers to SDM in relation to breast cancer chemoprevention in the primary care setting, our team developed two web-based decision support tools: nowledge . In thisnowledge , 16,we aOur study design is a qualitative study with clinical encounters of providers and their high-risk patients. The clinical encounter data was captured from providers enrolled in a pilot study that was conducted prior to implementing the RCT , the samBNAV tool and patients in the intervention arm were randomized to RealRisks. All audio-recordings of providers and their high-risk female patients were transcribed verbatim to capture the conversations occurring in the clinical encounters. Several of the encounters included Spanish-speaking patients and their interpreters. These encounters were transcribed in Spanish and then translated to English by bilingual members of the research team. The transcripts were then verified and de-identified by T.S. and T.J. Written informed consent was obtained from all enrolled patients and healthcare providers. These studies were approved by the institutional review board at CUIMC in New York, NY.For this qualitative study, a subset of patients and providers enrolled in the pilot study and RCT were consented to have their routinely scheduled clinical encounters audio-recorded at CUIMC , 15. AllRealRisks, a patient-centered decision aid (DA) that is available in English and Spanish. RealRisks includes interactive modules designed to improve a high-risk woman’s accuracy of her personalized breast cancer risk and increase her self-efficacy when engaging in dialogue about breast cancer risk and chemoprevention options with her healthcare provider. Through the RealRisks DA, patients inputted information on breast cancer risk factors to calculate their personalized 5-year invasive breast cancer risk according to the Gail model, learned about the risks and benefits of chemoprevention, and indicated their intention to take or not take chemoprevention and factors that influenced their decision-making. RealRisks then generated an action plan for patients summarizing their interactions with the DA. Healthcare providers had access to an intervention called BNAV. The BNAV tool is a repository of information and resources on breast cancer risk assessment and risks and benefits of chemoprevention, as well as a dashboard of personalized breast cancer risk reports for their enrolled patients [BNAV includes educational modules on breast cancer risk, chemoprevention, screening, genetic testing, and risk communication. The patient and provider tools relate to each other as the patient inputs her information into RealRisks and the BNAV tool includes a summary of the patient’s personalized breast cancer risk profile and the patients’ personal preferences about chemoprevention, which are both made available to the provider through the BNAV tool. The efficacy of both tools is currently being tested in two randomized controlled trials [Patients in the intervention group of the RCT were randomized to patients , 15, 17.d trials , 16, 18.To generate a table of patients and provider characteristics, we conducted descriptive analyses to generate frequencies for categorical variables and means for continuous variables. For the qualitative analysis, seven audio-recorded clinical encounters between PCPs and their patients in the primary care setting were included. An investigator (TJ) trained in qualitative data analysis organized and coded the data using grounded theory methodology –21. CodiTable Based on our analysis and interpretation of the clinical encounter data, we identified three themes: (a) competing demands during clinical encounters; (b) lack of knowledge about chemoprevention; and (c) limited risk communication during clinical encounters.In our study, we found that a key barrier to implementing SDM during the clinical encounter is that PCPs frequently addressed multiple health problems occurring with their patients and made many referrals for primary care health issues Table ; therefoLack of knowledge about chemoprevention is a barrier that emerged from the clinical encounter data. One provider stated that s/he was not aware of a pill for chemoprevention. Another provider strongly discouraged his/her patient from taking a chemoprevention pill, indicating that it was not needed, thereby displaying a lack of knowledge of the benefits of chemoprevention for breast cancer risk reduction. In another clinical encounter, a provider did not discuss the benefits or harms of chemoprevention and reassures the patient that her mammograms have been normal in the past. Most providers were strong advocates of screening mammography for their high-risk patients without discussing chemoprevention as an option for breast cancer risk-reduction. The excerpts  for chemoprevention in the primary care setting. First, we found that there are numerous competing demands occurring during a primary care visit that often forces providers to establish priorities based on their patients’ needs. Therefore, SDM for breast cancer chemoprevention seldomly occurred between PCPs and their high-risk patients during clinical encounters. There were a multitude of discussions around other primary care health topics that were occurring in the clinical encounters, yielding little time for discussion about breast cancer risk and risk-reducing options, particularly chemoprevention. Since SDM can be time-consuming, providers could benefit from using resources such as our decision support tool BNAV to help facilitate risk communication and chemoprevention discussions in a timelier and more succinct manner. Since the average age of our participants is 73 years, future considerations should include targeting younger women at higher-risk for developing breast cancer who have fewer comorbidities and are more open to taking chemoprevention medications. These younger women with a higher risk–benefit profile are more likely to benefit from taking chemoprevention in comparison to older women with lower risk. The lack of SDM that occurred in these encounters is consistent with previous studies that have focused on cancer-related care , 22. HofBNAV Tool.Another finding of this study is that providers lacked knowledge about chemoprevention, which may have prevented them from having meaningful discussions with their patients to assess interest in taking chemoprevention. In our study, providers did not feel comfortable prescribing risk-reducing chemoprevention medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who were at high risk for developing breast cancer. Previous studies have found that insufficient knowledge among providers about anti-estrogen therapy is a major barrier to uptake of chemoprevention , 24. A sThere is also a need to change the culture of prescribing chemoprevention in the primary care setting. Previous studies have found that exposure to direct-to-consumer advertisements of statin drugs increased the odds of patients both being diagnosed with high cholesterol and using statins by 16–20% . These pAdditionally, we found that providers seldomly engaged in risk communication with their patients. Several options exist for breast cancer risk-reduction . HoweverBNAV intervention used in this study. BNAV addresses provider-related barriers to chemoprevention by educating and preparing providers to assess and manage their patient’s risk of breast cancer by providing clinicians with a personalized risk profile of their patient along with educational resources on breast cancer prevention options, such as chemoprevention. Despite providers having access to BNAV, we found that providers were not skilled or comfortable having SDM discussions with their patients and lacked knowledge of chemoprevention. Perhaps the earlier version of BNAV was not well utilized by providers because it was not integrated into the clinic workflow and instead was a free-flowing website; therefore, it wasn’t widely adopted by providers initially. Since this study has been conducted, the senior investigators of the research team have integrated BNAV into the ambulatory medicine dashboard of the EHR to improve access to the tool for providers. Our findings underscore the need for a more practical application of decision support tools and hands on demonstration of the tool to educate and support providers and their patients in the primary care setting to reduce barriers to SDM for chemoprevention.There is a need to implement evidenced based guidelines into clinical care to promote greater patient-provider communication about breast cancer risk management approaches, such as chemoprevention drugs. Presently, very few women receive a prescription for chemoprevention by PCPs, despite national guidelines, which recommend that clinicians offer to prescribe risk-reducing chemoprevention medications to women who are at high-risk for developing invasive breast cancer . Since cRecordings of clinical encounters allowed us to gain insight into provider-patient communication. The study also has limitations. First, we recorded single clinical encounters and did not follow these encounters over time. In addition, our study included a small number of clinical encounters that occurred at an urban academic medical center in New York City; therefore, our findings may not be generalizable to other clinical settings.In this study, we identified provider-related barriers to SDM for chemoprevention uptake among high-risk women that have important implications for future improvements. Providers need education, decision support, and resources to conduct risk assessments, engage in risk communication and SDM with their high-risk patients, and to gain confidence in prescribing chemoprevention in the primary setting.Additional file 1. BOXES 1- 7. Excerpts from audio-recordings of clinical encounter data to demonstrate qualitative themes.


The aim of the present work was to systematically review and meta-analysis the available evidence regarding the effects of oral contraceptives using on breast cancer risk in BRCA germline mutations. The included studies were published between 2002 and 2021. Data were pooled from nine case–control studies, comprising a total of 33,162 woman. The association between oral contraceptive use and risk of breast cancer may differ in breast cancer defined by BRCA mutation status. This meta-analysis showed a diverse effect of oral contraceptive use against breast cancer in BRCA carrier mutations. However, futher case control studies are necessary to examine breast cancer risk.p = 0.1594. However, increased breast cancer risk was associated with age at first use of OCs ≥20 years: OR = 1.21, 95% CI:1.07 to 1.36, p = 0.002. Multivariable meta-regression with covariates of age of first OC use , duration of OC use , and time since last OC use  did not have a significant effect on the breast cancer risk. This meta-analysis suggests a diverse effect of oral contraceptive use against breast cancer in BRCA carrier mutation. The association between OC use and breast and ovarian cancers needs more investigation.Oral contraceptive use is one of the major modifiable risk factors for breast cancer. To investigate the effect of oral contraceptive taking on breast cancer risk by BRCA 1 and BRCA 2 mutation status, we conducted a systematic review and meta-analysis of case-controlled studies. Therefore, English language articles were retrieved by searching MEDLINE (PubMed), EMBASE and the Cochrane Library up to August 2021. Data were pooled from none case–control studies, comprising a total of 33,162 subjects, including 23,453 who had never used oral contraceptives. Overall meta-analysis indicated a statistically insignificant risk reduction: OR = 0.86, 95% CI: 0.70 to 1.06,  Breast cancer genetic, heterogeneous diseases are characterized by high variability by ethnicity and race in terms of incidence, clinical features, and prognosis. In the general population, breast cancer is the leading cancer type in females, comprising 11,7% of all new cancer cases and causing 6.9% of all cancer-related deaths worldwide in 2020 . Most frThe genes with high penetrance include the following genes: TP53, CDH1, PTEN, and STK11; the rare genes with medium penetrance are CHEK2, ATM PALB2, and BRIP1 .Genes of BRCA1 and BRCA2 are localized on chromosomes 17q21 and 13q12, respectively . Both BRThe complete loss of function of both proteins leads to an increase in genomic instability. Germline mutations in these genes increase the risk of many malignancies over the course of life, especially breast cancer. The risk of developing breast cancer in women with BRCA mutations ranges from 45% to 75%. Among BRCA1 mutation carriers, the estimated lifetime risk of developing breast cancer ranges from 40% to 85%. In the case of the BRCA2 mutation, carriers have more or less the same risk of developing breast cancer ,12,13. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related breast cancer patients vary depending on the population . BRCA paAmong BRCA carriers, data are limited on the influence of modifying factors on breast cancer risk. In both BRCA mutations, early onset menarche increases breast cancer risk; first birth after age 30 y reduces breast cancer risk in BRCA1 but generates increased risk in BRCA2, while breastfeeding decreases breast cancer risk in both BRCA1 and BRCA2 mutation carriers ,16,17In addition to the genetic risk factors, as well as the mentioned risk modifying factors, endocrine interventions should be mentioned. Among these, one of the most common is oral contraception (OC) . In the The aim of the present work was to systematically review and meta-analysis the available evidence regarding the effects of oral contraceptives using on breast cancer risk in BRCA germline mutations.This systematic review with meta-analysis was designed according to PRISMA  guidelines to identify case–control studies examining the effect of oral contraceptive use on breast cancer risk in mutation carriers in BRCA1 and BRCA2 .We reviewed the contents of the electronic bibliographic databases: PubMed (MEDLINE), EMBASE, and the Cochrane Library for articles compatible with the assumptions of our work. The search was limited to papers published in English and was conducted up to August 2021. In the computer search, we used the following keywords in various combinations: (‘breast cancer’) AND (‘BRCA1′ OR ‘BRCA2′) AND . To provide a complete overview of the available relevant publications, for this purpose, we additionally scrutinized references to previously published review articles, meta-analyses, and other works not retrieved in our electronic search.Studies were considered eligible for inclusion if they met the following criteria: the study describes outcomes among BRCA1/2 mutation carriers; of case–control design; it provides data on the quantitative association between OC use and risk of breast cancer; healthy mutation carriers were the control group; data included in the articles were sufficient to calculate the odds ratio (OR) and 95% confidence interval (CI); and the articles were written in English. The exclusion criteria were as follows: no control group; the control group was not mutation carriers; lack of sufficient information; results were reported as graphics or percent changes; duplicated reports; and articles were published in languages other than English. Inclusion/exclusion decisions were made after independent and duplicate examination of the full manuscripts.Data were extracted from all eligible studies by the lead author and subsequently reviewed by the co-author for accuracy. The information consisted of the first author’s name, year of publication, region of the study, study design, number of cancer cases, number of controls, and characteristics of the studied populations.We assessed and scored the methodological quality of included studies based on three aspects according to the Newcastle–Ottawa Scale (NOS), that is, study design (including the selection of study population), data comparability, and outcome assessment . On a sc2 and Cochrane Q to evaluate heterogeneity, by the following criteria: high heterogeneity, I2 >75%; moderate heterogeneity, I2 = 50% to 75%; and low heterogeneity, I2 < 50% [The meta-analysis of summary statistics from individual studies was carried out using the STATISTICA 13.3 program  by way of employing the Medical Package program. Based on the data obtained from each study, we calculated the odds ratio (OR) and the 95% confidence interval, a cross-classification of OC users and breast cancer type. A meta-analysis was carried out combining OR from various studies using the DerSimonian–Laird random effects model . In addiI2 < 50% . The risk of publication bias was assessed by applying Egger’s linear regression test  and BeggA detailed review of selection procedures is shown in The included studies were published between 2002 and 2021. Data were pooled from nine case–control studies, comprising a total of 33,162 subjects, including 23,453 (70.7%) who had never used oral contraceptives (OCs). Characteristics of the included clinical trials are shown in The quality of the analyzed studies as assessed on the basis of the Newcastle–Ottawa Scale ranged between 5 and 8, and the average score was 6.22 for included studies.p = 0.1594. The major problem of this analysis was the high heterogeneity rate (I2 = 91.08%). The Egger’s test , however, indicated no evidence of publication bias, while Begg’s test  suggested possible publication bias. In the subgroup analysis, only age at first use of OCs ≥20 years revealed a significant increase in breast cancer risk . Eight comparisons of data ,36,38,39p = 0.3767), duration of OC use , and time since last OC use  did not have a significant effect on the breast cancer risk.Multivariable meta-regression with covariates of age of first OC use . Publication bias was not evident according to the Begg’s test  and Egger’s test . The meta-analysis of all the included studies noted insignificant reduction in breast cancer risk: OR = 0.91, 95% CI: 0.74 to 1.12, = 0.3716  and relap = 0.88, while intake of OCs ≥ 20 years led to a statistically significant increase in the risk of breast cancer: OR = 1.28, p = 0.02. There was also a statistically significant reduction in the risk of breast cancer in BRCA1 mutation carriers based on the variable comparing of starting intake of OC at the age below vs. above 20 years; OR = 0.78, p = 0.0002 , duration use of OCs , time since last use  showed these covariates had non-significant impact on breast cancer risk.Multivariable meta-regression with covariates of age first use of OCs  did not show evidence of publication bias , duration of OC use , and time since last OC use  did not have a significant effect on the risk of breast cancer.Based on data from three citations ,38, an a = 0.00% . We founp = 0.1594. In the subgroup analysis, only age at first use of OCs ≥20 years revealed a significant increase in breast cancer risk . The meta-analysis in BRCA1 mutation carriers noted insignificant reduction in breast cancer risk: OR = 0.91, 95% CI: 0.74 to 1.12, p = 0.3716. Intake of OCs ≥20 years led to a statistically significant increase in the risk: OR = 1.28, p = 0.02. The relationship between the risk of breast cancer in BRCA mutation carriers and the covariate <10 years vs. ≥10 years was a statistically significant reduction: OR = 0.83, p = 0.002. The random-effects meta-analysis in BRCA2 mutation carriers showed a slight, non-significant reduction in the risk of breast cancer: OR = 0.98, 95% CI: 0.62 to1.55, p = 0,9243. Starting OC use ≥20 years resulted in a statistically significant increased risk: OR = 1.42, p = 0.03. In turn, in the analysis of covariate <10 years vs. ≥10 years, a statistically significant reduced risk of breast cancer was noted: OR = 0.65, p = 0.000.Overall meta-analysis for BRCA1/2 indicated an in-significant risk reduction: OR = 0.86, 95% CI: 0.70 to 1.06, In this systematic review and meta-analysis, we incorporated evidence gathered in recent studies that taking oral contraceptives may influence the risk of breast cancer in BRCA mutation carriers. Although the results show no statistical significance, our meta-analysis suggested the need for prospective, controlled studies on extensive material of BRCA mutation carriers regarding the use of modern oral contraceptives. Whether exogenous estrogens, such as oral contraceptives, modify the breast cancer risk in BRCA1 and BRCA2 mutation carriers is actually a controversial topic. Some studies suggest that oral contraceptives may increase the breast cancer risk among BRCA mutation carriers ,36,38,39There are several limitations that should be considered when interpreting the data. The results of the meta-analysis are based on a relatively limited number of available studies, as well as on different numbers of participants and variable observation time in individual samples, which may result in insufficient statistical power and limit the drawing of final conclusions. Moreover, the different periods of research carried out are associated with the use of different doses of contraceptive preparations and different ingredients. Furthermore, the characteristics of the women participating in the studies may also have an impact with regard to various comorbidities, as well as inter-individual differences in the metabolism and bioavailability of OC. Overall, data on the risk of OC use in BRCA mutation carriers are limited. Almost all of the available studies are retrospective, and especially for BRCA2 mutation carriers, study populations were often small. We are aware that one of the limitations of our meta-analysis is the use of repeated data, to a varying degree, from different research periods provided by the co-authors of these studies in individual multicenter studies.Women at moderate risk of breast cancer have several options to reduce their risk, including lifestyle options, i.e., physical activity, BMI control, and no alcohol consumption . High BMHowever, for women who have an increased risk of developing breast cancer, there are additional factors that can change and reduce the risk of breast cancer, including surgery and medication ,48. TamoThe association between oral contraceptive use and risk of breast cancer may differ in breast cancer defined by BRCA mutation status. This meta-analysis showed a diverse effect of oral contraceptive use against breast cancer in BRCA carrier mutations. However, this association needs more investigation.


This case–control study assesses the independent roles of reproductive history, postmenopausal hormonal therapy (HT), socioeconomic status (SES), and occupational physical activity on the risk of breast cancer (BC).Odds ratios (OR) were estimated from conditional logistic multivariate regression model in a data set of 19,253 Finnish women diagnosed with BC between 1994 and 2013 and 96,265 age-matched population controls.Both pre- and postmenopausal white-collar workers had significantly increased risk of ductal and lobular BC as compared to manual workers. Moderate occupational physical activity reduced risk of lobular BC by 14%. There was a transient increase in the risk of BC observed after each birth followed by a protective effect starting some years after the delivery. As the number of children increased, the short-term excess risk was lower and protective effect was observed earlier. Continuous estrogen-progestin therapy (EPT) significantly increased the risk of both ductal and lobular BC and the magnitude of risk was directly proportional to duration of use . Monthly EPT for 5+ years increased the risk . Users of estradiol plus levonorgestrel intrauterine system devices showed ORs of 1.56 (95% CI 1.45–1.69) and 2.18 (95% CI 1.81–2.64) for ductal and lobular BC, respectively.This study concludes that pregnancy has a dual effect on BC risk, with a transient increase in risk followed by a long-term protective effect. The SES and HT have a large effect on BC risk while occupational physical activity has only a small independent effect.The online version contains supplementary material available at 10.1007/s10549-022-06571-x. Breast cancer is the most common malignancy worldwide, with around 2.26 million new diagnosis among female estimated in the year 2020  In FinlaReproductive factors such as low parity and high age at first birth, lack of breastfeeding, early menarche and late menopause are well established risk factors for breast cancer in epidemiological and clinical studies –5. The hRecently there has been increasing interest to associations of work environment and breast cancer risk. Physical inactivity has shown to be associated with breast cancer, but the results concerning the occupational physical activity are inconsistent –18. In aThe risk of breast cancer is determined by complex mechanisms involving individual’s genetic, physiological, reproductive, lifestyle and environmental factors. Numerous epidemiologic studies have examined the relation between breast cancer and single risk factors individually but there are not many publications on the independent roles of multiple factors in same study. Although it has been acknowledged that the breast cancer is not a single disease with a uniform etiology, the etiological differences in risk according to age at diagnosis and other characteristics of tumor such as histology are not adequately studied , 24. TheThis is a retrospective case–control study, which includes all Finnish women who were diagnosed with their first breast cancer (ICD-10 code C50) between 1st January 1994 and 31st December 2013. Altogether 19,253 cases were identified in the national population-based Finnish Cancer Registry. The cancers recorded by the Cancer Registry have been notified by hospitals, pathological and hematological laboratories, physicians, and dentists, and from death certificates [For each case of breast cancer, five female controls were randomly selected from the Finnish National Population Registry matched by the year of birth. The controls had to live in Finland at the time of cancer diagnosis of the case (index date). The Population Registry also provided information on the dates of birth of biological children of the cases and controls.Information about SES, education, and occupational history of all the study subjects was obtained from Statistics Finland. SES in our study is classified according to Statistics Finland’s classification of socioeconomic groups 1989, which is based on the classification of the United Nations Economic Commission for Europe (Appendix 1). The classification is formed by several criteria considering persons stage in life , occupational status, and nature of occupation . For theFor all study participants, information on occupational history was obtained from Statistics Finland. Finland's national classification of occupations is based on the international classification of occupations 2010 (ISCO-08) of the International Labour Organization (ILO). The national classification of occupation has been revised in 1987, 2001 and 2010. We used a conversion key for converting the occupational codes to the 311 categories of the longitudinal occupational classification used in the NOCCA Job Exposure Matrix . In theInformation on postmenopausal HT was obtained from the nationwide Prescription Registry of the Social Insurance Institution of Finland. The registry includes data on systemic HT purchases in Finland since 1994. Systemic HTs are available in Finland only with doctor’s prescription and automatically registered. In our study, purchases of HT at the age of ≥ 50 years for a minimum duration of 6 months was considered as postmenopausal HT.Only estradiol (E) was used as the estrogen component during the study period. Systemic HT in our study was categories as E only, E combined with progestin therapy (EPT) and E  plus levonorgestrel-releasing intrauterine system (E+LNG-IUS). EPT was defined as continuous when oral or transdermal E was combined with daily progestin, as monthly when progestin was given for 10–14 days every month and once-in-3-months progestin when progestin was given for 10–14 days every 3 month. Information on the removal date of intrauterine devices is not available and therefore, the duration of LNG-IUS exposure was defined assuming that a woman who purchased one device used it for five years, which is the average duration of LNG-IUS use in Finland .A conditional logistic regression model was used for matched cases and controls for both univariate and multivariate analyses. Odds ratio (OR) with 95% confidence intervals (95% CI) was used to evaluate the association between study variables and breast cancer. We tested for the correlation between SES, education and occupational physical activity as well as fitted several alternate models with the combination of these variables. We dropped education variable from our final analysis because educational information was correlated with SES and was unknown for a large proportion of study participants.Reproductive variables in our study are parity ; number of children ; age at first birth ; age at last birth . Duration of use of each type of HT was categorized into < 1 year, 1–< 5 years, 5+ years; except for E+LNG-IUS which is categorized as number of devices purchased (1 and 2+ purchase). The analyses were stratified according to age at breast cancer diagnosis , and by histology .To estimate the dual effect of pregnancy on breast cancer risk, a conditional logistic regression was run with parity, time since delivery and interaction between these two variables included in the model. The model was adjusted for SES. The fitted results of this model were plotted for the breast cancer risk by parity and time since the delivery. All analyses were performed using R statistical software, version 1.2.1335.Out of the 19,253 breast cancer cases, 82% were diagnosed at the age 50+ years, and 78% were of ductal and 16% of lobular subtype Below is the link to the electronic supplementary material.


Available data on cancer secondary to ionizing radiation consistently show an excess (2-fold amount) of radiation-attributable solid tumors in women relative to men. This excess risk varies by organ and age, with the largest sex differences (6- to more than 10-fold) found in female thyroid and breasts exposed between birth until menopause (~50 years old) relative to age-matched males. Studies in humans and animals also show large changes in cell proliferation rates, radiotracer accumulation and target density in female reproductive organs, breast, thyroid and brain in conjunction with physiological changes in gonadal hormones during the menstrual cycle, puberty, lactation and menopause. These sex differences and hormonal effects present challenges as well as opportunities to personalize radiation-based treatment and diagnostic paradigms so as to optimize the risk/benefit ratios in radiation-based cancer therapy and diagnosis. Specifically, Targeted Radionuclide Therapy (TRT) is a fast-expanding cancer treatment modality utilizing radiopharmaceuticals with high avidity to specific molecular tumor markers, many of which are influenced by sex and gonadal hormone status. However, past and present dosimetry studies of TRT agents do not stratify results by sex and hormonal environment. We conclude that cancer management using ionizing radiation should be personalized and informed by the patient sex, age and hormonal status. Exposure to external ionizing radiation in the context of war, nuclear accidents and medical procedures poses well-known health risks, including acute radiation sickness (tissue reaction or deterministic effects), which may result in death, as well as an increase in the risk of cancer in the years following exposure (stochastic effects) ,2. The rCompared to external radiation risks, literature on sex differences in secondary cancer risks due to internal radiation exposure following ingestion of contaminated foods or diagnostic/therapeutic injection of radioactive compounds is sparser and sometimes contradictory ,16,17,18Following the atomic bombing of Hiroshima and Nagasaki in 1945, survivors have been surveilled for decades for cancer and other health consequences of the exposure to radiation. Noting the location of the survivors relative to the epicenter, the radiation dose absorbed by individuals could be calculated. This information helped create the largest extant database on health risks from exposure to ionizing radiation, describing the rates of radiation-attributable cancers in males and females as a function of age at exposure ,22,23,24In Perusal of As can also be seen in This pattern appears to be unique to breast and thyroid, and likely explains the female-specific shift in the likelihood (rank order) of various cancers as a function of age/hormonal status. Although female radiation-attributable lung cancer rates are higher than those of males, the ratio of female to male remains constant and independent of age at exposure . This sex difference disappears only in extreme old age, suggesting that, unlike breast and thyroid, the risk of radiation-induced lung cancer is modulated by age and sex, but not by hormonal status. Notably, the sex difference in the risk of lung cancer cannot be fully explained by differential effects of smoking, since the gender-averaged excess relative risk per Gy of lung cancer (at age 70 after radiation exposure at 30) was estimated as 0.59 for non-smokers, with a female–male ratio of 3.1 . A smallAnother observation suggesting a relationship between radiation-induced cancer and female gonadal status can be found when examining the relative susceptibility to various cancers as a function of age. Thus, the four most susceptible organs in young females (<50 years old at exposure) are (in descending order) breast, lung, thyroid and colon, while the rank order in older females is lung, bladder, colon and blood (leukemia), much more similar to the rank order in males , which does not change appreciably with age at exposure between birth and old age . A direcImportantly, not all tumors are more susceptible to radiation in females: The risk of radiation-induced bladder cancer is identical in males and females regardless of the age at exposure , bottom.The best source of information on the effects of therapeutic radiation on secondary cancer risk derive from survivors of Hodgkin’s Lymphoma (HL) treated with radiation, who have been observed in a number of studies designed to monitor the rate of secondary cancers in this population over an extended time period ,36,37,38Notably, radiation treatment of childhood cancer appears to be associated with significant increases in breast cancer risk, comparable to those reported in females with a BRCA gene mutation ,40: bothThe higher vulnerability of females to radiation-induced thyroid cancer, noted above for atomic bomb survivors, is also seen in the medical context. In a relatively large cohort of subjects given radiation therapy for a variety of childhood cancers, including HL, leukemia, central nervous system cancer and soft tissue sarcoma , relativA more recent analyses of this population ,45 confiRegarding treatment of non-pediatric patients, studies of secondary cancers associated with radiation treatment of breast cancer consistently reveal a statistically significant increase in the risk of subsequent cancer in the contralateral breast . Which wRadiation treatment of breast cancer is also associated statistically significant increase in the risk of lung and other cancers ,48,49,50Finally, the use of external ionizing radiation for therapy is not limited to cancer ,53,54,55p < 0.001). Notably, the majority of patients in this study were elderly males, and the menopausal status of the women or the specific organ/site of the cancer  were not mentioned. Comparing radiation dose and cancer risk associated with whole body PET/CT scanning in the U.S. and Hong Kong, Huang et al.  Vorozole, which reported direct measurements of ovarian exposure at different phases of the menstrual cycle [Another case in point is the guidelines for human dosimetry of  in 2012 . The autal cycle  found thal cycle . The maxal cycle ; it is cal cycle ,126,127.al cycle . As for


This narrative review provides new insights, and it reports the current state of knowledge on occupational cancers among women based on previously published research, particularly in three female working categories: beauticians and hairdressers, farmers, and healthcare workers. Finally, a focus on breast cancer is presented among female workers.The facts that occupational cancer in women is under-investigated, with few in-depth analyses are well known. In recent decades the workforce has changed, with an increasing number of women employed. Therefore, the inclusion of women in occupational cancer studies has become more urgent and feasible than in the past decades. The difficulties to evaluate occupational causes of female gynecologic tumors in most past cohorts and the potential variation in outcome responses between men and women must be taken into consideration. This narrative review discusses women’s occupational cancer as a current area of research, focusing on three groups of workers characterized by peculiar exposure to occupational carcinogens and where women are often employed: beauticians and hairdressers; farmers; and healthcare workers. We discuss the most relevant cancers in each working category, with a particular focus on female breast cancer. In the three industries reviewed in detail, there are some risk factors which may affect primarily women, inducing breast cancer and cervical cancer, as well as risk factors that are carcinogenic in both genders, but whose effects are less well known in women. For several decades, the available data on occupational cancers in women have been scarce, and researchers have shown that studies on work-related cancer need to expand their focus on women. In fact, occupational cancer studies focused mainly on men despite employment patterns for women changing dramatically, and so should lead to reversing this trend . Since tWhile it is reasonable to assume that substances that cause cancer among men are carcinogens also in women, Blair  noted a We conducted a narrative review on occupational cancer in women. We reviewed estimates of the burden of occupational cancer in women, evidence on cancer risk in three occupational groups with high prevalence of female workers—namely hairdressers, nurses and agriculture workers—and the evidence on occupational risk factors of breast cancer, the main female cancer. We did not conduct systematic searches of the literature, but we included previous reviews and large-scale studies identified via searches in the PubMed database for the years 2000–2022, and from the personal archives of one of the authors (PB).Some reviews assessed the inclusion of women in studies of occupational cancer. Zahm et al. reviewed eight journals from 1971 to 1990, reporting that only 35% of articles included examined white women, and 10% non-white women . One of the largest studies on occupational cancer is the Nordic Occupation Cancer Study (NOCCA) , which aGiven the growing number of women in the workforce, resulting in an increasing proportion of women exposed to occupational risk factors, this narrative review aims to address different aspects of occupational cancer among women, with a focus on three categories of female workers who may be exposed to carcinogenic factors: beauticians and hairdressers, farmers, and healthcare workers.Barbers, hairstylists, and cosmetologists represent an important occupational group with 1.7 million workers in Europe  and moreHair care products contain more than 5000 chemicals with mutagenic and endocrine disrupting properties in vitro, and their possible role as a carcinogen in animals and humans . For exaDue to the widespread use of these hair and beauty products by barbers, hairstylists, and cosmetologists, even a small increase in the risk of developing cancer, would have important consequences for this population. However, although some studies found an increased risk of cancer among barbers, hairstylists, and cosmetologists ,18,19, oGiven the increasing number of women in the workforce it is possible that occupational exposure to hazardous agents, in particular organic solvents, increasingly contributes to breast cancer incidence . SignifiRegarding hematopoietic cancer, most studies have found elevated risks of all , or otheExcess bladder cancer incidence has been observed in previous studies ,35,36, aElevated rates of lung cancer were also consistently observed among female hairdressers in cohort studies ,36,40, aRegarding mortality, a study evaluated the mortality patterns among hairdressers, cosmetologist and barbers using 7.2 million death certificates in 24 US states from 1984 to 1995 . MortaliThe incidence risk was observed to increase for cancers in different anatomical sites, including those presented above. This plurality should be attributed to the existence of multiple exposure pathways including dermatologic, respiratory and systemic ones, but also the common etiology that some cancers share. Overall, work can create a life condition and an environment which may turn into a risk or a protective factor against cancer . FarmersThese exposures primarily occur through inhalation and dermal contact . p < 0.001), where smoking represents the main risk factor of bladder cancer. In many countries, in particular in traditional societies, farming and agriculture are usually family-led activities where men and women are both involved and share a common environment. In addition, agricultural workers, including laborers, comprise many women. Indeed, several studies on agricultural workers included both sexes, allowing an analysis of exposures and cancer risk among women employed in this industry. One example is the prospective cohort of farm owners and agricultural workers in France (AGRICAN) . BoulangThe risk of lung cancer and brain cancer were also investigated within the AGRICAN cohort. The exposure to carbamate insecticides resulted in concern for a smaller proportion of women (around 17%). Meningioma more often occurred in women (69% of the cases) . AnotherThe main evidence of cancer in agricultural workers derives from the International consortium of agricultural cohort studies (AGRICOH) , includi2 = 95%) for men and 0.77  for women. In particular, women working in the agricultural sector had a lower risk of breast cancer  and cervical cancer  than general population. Conversely, a higher risk of skin melanoma  and multiple myeloma  was observed in women. Despite the overall small number of multiple myeloma cases, the data suggested an excess of multiple myeloma, particularly in female farmers. The authors related these findings to the outdoor farming tasks that are commonly performed by women, including harvesting and re-entry tasks that can increase their exposure of skin to UV radiation and pesticides.The meta-SIRs for overall cancer incidence based on the pooled analysis were 0.84  project . A signiThe same study found increased risk for female farmers in thyroid cancer , non-Hodkin lymphoma , and Hodkin lymphoma in both sexes with mildly higher risk in the female sex .Overall, a lower risk of cancer was shown in both sexes and was explained as the consequence of lower exposure to industrial carcinogens. The authors also noticed that all of the lowest-risk occupations among the women are typically “male occupations” which require heavy physical activity, suggesting the role of this factor as protective towards cancer development.In 2019 about 73% of people employed as healthcare practitioners and technical occupations in the United States were women . NumerouThe antineoplastic drugs are used as a treatment for cancer, but also for multiple sclerosis, psoriasis and rheumatoid arthritis. The toxicity and health risks associated with antineoplastic drugs may occur through absorption by direct contact with skin or by inhalation of the aerosolized drugs during the preparation or administration . The IntThe healthcare setting may expose workers to ionizing radiation, through the use of X-rays or radioactive materials used in either diagnosis or treatment of patients as fluoroscopically guided procedures and administration of radionuclides for nuclear medicine procedures. Workplace exposure to radiation usually consists of protracted exposure to low level radiation, which differs from the extensively studied cancer risks associated with a single acute or fractionated high-dose radiation exposure in the Japanese atomic bomb survivors . EpidemiStudies investigating cancer risk among female healthcare workers (HCW) have mainly focused on nurses ,64,65,66The IARC has classified shift work in group 2A of “probable carcinogens to humans”. Exposure to artificial light at night has been hypothesized to increase the risk of breast cancer as a result of a decrease in the secretion of the hormone melatonin and a subsequent increase in circulating estrogens. Various studies reported a relationship between increased breast cancer risk and cumulative years of working on night shifts ,70. A quAn increased risk of leukemia has been found in physicians and nurses occupationally exposed to antineoplastic drugs ,73. MortHCW are exposed to biological risk through several infections, including carcinogenic microorganisms like HBV, HCV, HIV, HHV-8, HPV, EBV and Helicobacter pylori (Hp) ,80.Percutaneous exposure and sharp injuries represent the most common ways of transmission of HBV and HCV infections in the hospital workplace . The lonOverall, 16,000 HCV, 66,000 HBV, and 1000 HIV infections may have occurred in the year 2000 worldwide among HCWs due to their occupational exposure to percutaneous injuries . The fraThe risk of contamination is higher among certain healthcare professionals, such as surgeons and nurses, and socioeconomic settings, such as Asian countries and Africa.While the prevalence of injury is in the order of 20–30%, the risk of contracting the clinical hepatitis is around 1–6% .A recent review described a wide variation in the prevalence of needlestick injuries in HCW during their entire career, ranging from 32.4% in Ethiopia to 86.2% in China, while the incidence was reported as 0.97 injuries per HCW per year in Kenya, and 2.18 exposures/person-years . The revA prospective study conducted in the 90s found a risk of HIV infection 1.5% for a surgeon working 5 years in Zambia, against 0.1% in more developed countries . This trThe HPV DNA rate in nasal epithelial cells of gynecologists (84% women) performing procedures generating surgical smoke  was found to be higher than gynecologists who did not perform such procedures, with a relationship between the risk of infection and the duration of electrosurgery . Indeed,Among the potentially hazardous agents, Hp should be accounted, as linked to gastric cancer and MALT-lymphoma of the stomach . HealthcKheyre et al. recently reviewed the occupational risk of occupationally acquired Hp infection, where health professionals were the working category at higher risk of infection, especially considering those working in gastrointestinal disease units. As argued by the authors, a limit in these estimates is accounting for the reference group, which usually falls into occupational groups.Infectious-related cancers need a long time to develop. While HBV, HCV and HIV are frequently monitored in the occupational setting as accounted as potential hazards in HCW, other infections, including EBV, HPV and Hp, are much more common and are not accounted as potential occupational hazards. Thus, estimating the attributable fraction of cancer related to these additional agents is currently very difficult. The extension of occupational risk factors to other agents such as Hp and HPV may imply their early detection and treatment, besides encouraging the use of PPE and the adoption of hygienic measures in the healthcare setting.Indeed, all these infective exposures are preventable by applying hygiene measures and following international guidelines for infection control .Female breast cancer was the most commonly diagnosticated cancer, with an estimated 2.3 million new cases (11.7% of new cases of cancer) and more than 600,000 new deaths in 2020 . BaselinIn more recent years there has been a transition from men-focused studies to studies designed and conducted specifically to address occupational risks among women. Beyond the three industries reviewed in detail in the previous sections there are other occupational exposures which may affect primarily women. These include risk factors for female cancers such as breast cancer  and cervical cancer , as well as cancers which are prevalent in both genders, such as lung cancer  and head and neck cancer . Moreover, women employed in a specific sector may go through living conditions that shift their risk of certain cancers compared to the general population, e.g., the reduced risk of breast cancer in agricultural workers may be due to the age at first birth; this is not particularly influenced by farming rather than in occupations requiring higher educational levels, which implies long study time, and the higher number of children registered in farmers.In conclusion, women might be exposed to carcinogens on the workplace, but the amount and quality of available data are in general lesser than for male workers. Investigations among men may not fully characterize the situation in women because of differences in exposure circumstances for the same job title, biologic differences, and distribution of cancers. A less studied aspect of the problem of occupational cancer in women is that of possible differences in risk according to gender following comparable exposure. The ability of individual studies to detect gender-related differences in risk has been limited by a small number of events in individual studies, in particular among female workers: assessing differences between genders in the risk of developing occupational diseases depends, therefore, on the availability of high-quality data from a large series of cases in both men and women.Since the epidemiological research on occupational cancers in males has always been quantitatively superior to that reserved for females, we should expand our knowledge of occupational risks among women both through future specific studies on this focus and through more complete analyses where data are already available. In particular, more detailed analyses of occupational studies with small numbers of women relative to the number of men could provide the basis and guide future research. It is necessary to improve the quality of occupational exposure measures in occupational studies of cancer among women, and the methodological investigation must consider information on possible confounding factors. In the future, studies investigating occupational cancers in women are expected to be large in order to achieve desired statistical power for specific exposures.


BRCA1/BRCA2 (BRCA) genes are at a substantially increased lifetime risk for developing breast, ovarian, and (to a lesser extent) other cancer types. Multiple national and international surveillance guidelines and recommendations to facilitate the early detection of cancer in these high-risk women have existed for more than 2 decades. Yet, inconsistencies pertaining to the medical management of cancer-free carriers linger, and surveillance recommendations are not globally harmonized. In this review, we discuss the differences between existing surveillance guidelines for BRCA P/LPV carriers, emphasizing the importance of future studies to enable guidelines harmonization and personalized risk stratification for optimal, effective surveillance strategies.Female carriers of germline pathogenic/likely pathogenic variants (P/LPVs) in the BRCA1/BRCA2 (BRCA) P/LPV are offered a tight surveillance scheme from the age of 25–30 years, aimed at early detection of specific cancer types, in addition to risk-reducing strategies. Multiple national and international surveillance guidelines have been published and updated over the last two decades from geographically diverse countries. We searched for guidelines published between 1 January 2015 and 1 May 2022. Differences between guidelines on issues such as primary prevention, mammography screening in young (<30 years) carriers, MRI screening in carriers above age 65 years, breast imaging (if any) after risk-reducing bilateral mastectomy, during pregnancy, and breastfeeding, and hormone-replacement therapy, are just a few notable examples. Beyond formal guidelines, BRCA carriers’ concerns also focus on the timing of risk-reducing surgeries, fertility preservation, management of menopausal symptoms in cancer survivors, and pancreatic cancer surveillance, issues that, for some, there are no data to support evidence-based recommendations. This review discusses these unsettled issues, emphasizing the importance of future studies to enable global guideline harmonization for optimal surveillance strategies. Moreover, it raises the unmet need for personalized risk stratification and surveillance in BRCA P/LPV carriers.Females harboring germline  BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) genes were the first clinically significant genetic risk factors identified in families displaying an unusual cluster of breast and ovarian cancer—Hereditary Breast Ovarian cancer syndrome (HBOC) [BRCA2) to pancreatic cancer [BRCA2 P/LPVs are associated with a statistically significant risk for stomach cancer, while associations of BRCA1 P/LPVs carriers with prostate cancer or cutaneous melanoma could not be confirmed [Germline pathogenic/likely pathogenic variants (P/LPVs) in the 1 OMIM 11705 and Bc cancer , male brCA2 OMIM 00185 genBRCA genotyping was offered primarily in order to evaluate the carrier’s cancer risks, guide the surveillance scheme, or offer risk-reducing measures [BRCA-associated breast, ovarian, pancreatic, and prostate cancers [BRCA genotyping is expected to result in increased rates of BRCA P/LPV among cancer patients. In addition, wider use of somatic genomic analyses in advanced cancer settings for the possible identification of molecular targets to guide oncological treatment [BRCA P/LPVs germline carriers. Recent studies in unselected populations demonstrated much higher population prevalence rates of BRCA P/LPVs (1:200–1:270) than previously estimated [BRCA genotyping in specific populations is becoming more acceptable and implemented. Noteworthy, while there is no need for pre-test genetic counseling, anyone who is found to harbor BRCA P/LPSV as a result of this screen is provided with a formal oncogenetic counseling session. For example, genotyping for Ashkenazi Jews has been included in the health basket in Israel (and hence covered by the HMOs) since January 2020, and soon similar population-based screens will be offered by the NHS for the Jewish population in the UK. In addition, population-based genetics efforts , the UK biobank ), combined with more accessible and affordable direct-to-consumer genetic testing are all expected to lead to a substantial increase in the rates and numbers of asymptomatic BRCA P/LPV carriers worldwide.Traditionally, germline measures . With th cancers ,10, genereatment ,12 will stimated ,14,15. Tstimated . Thus, pBRCA P/LPVs carriers raises challenges for the health care systems: shortage of genetic counselors, paucity of community-based high-risk clinics and qualified physicians for carrier comprehensive surveillance management, and resource thin MRI, to name a few. Multiple national and international surveillance guidelines have been established, published, and updated since the early 2000s (some of them will be reviewed herein). However, these recommended schemes are variable and differ from each other by country and continent. In this review, we describe and discuss some of the most urgent controversies and open questions relating to the management recommendations for healthy BRCA P/LPVs carriers. Hopefully, highlighting the common themes and the differences between existing guidelines may promote international discussion and harmonization efforts.This prospect of increasing numbers of cancer-free BRCA P/LPVs carriers were included.MEDLINE and web-based sources were searched for guidelines updated or published in English (or translated to English) by national and international professional societies or working groups, between 1 January 2015, to 1 May 2022. Guidelines referring to surveillance of healthy  carriers of germline BRCA P/LPVs carriers were extracted and compared: primary active risk-reducing approaches by modifying lifestyle, chemoprevention, and/or risk-reducing surgeries, early detection screens (secondary prevention), management of menopausal symptoms and effects of lack of endogenous hormones following risk-reducing bilateral oophorectomy (rrBSO) prior to menopause, and fertility preservation.From all guidelines identified, multiple aspects of management of healthy Fifteen guidelines were included in this review, and only three of them were published by governmental bodies—the National Institute for Health and Care Excellence (NICE), the French National Cancer Institute (INCa), and the Australian Government eviQ guidelines. The additional 12 guidelines were published by professional bodies. The recommendations in these geographically diverse guidelines are presented in the context of the existing literature. Several guidelines cover only issues related to breast cancer screening, while others focus on the gynecologic management of the carriers.BRCA P/LPV carriers have been postulated or assumed by extrapolation from studies of non-carrier women. A meta-analysis of 44 studies published in 2014 focusing on hormonal and exogenous risk factors for breast cancer in BRCA P/LPV carriers reported that the only variable displaying a statistically significant association with reduced breast cancer risk is late age at first live birth (>30 years vs. younger and 25–29 years vs. younger) in BRCA1 (but not in BRCA2) P/LPV carriers  [BRCA1 P/LPV carriers compared with non-carriers, or (2) the possible effect of rrBSO or bias in ascertainment. Although data assessing many additional potential modifiable risk factors did not reach statistical significance, possible associations with increased breast cancer risks were shown for oral contraceptive use (both for BRCA1 and BRCA2) and smoking (BRCA2), whereas decreased breast cancer risks were demonstrated with breastfeeding and late age at menarche (BRCA1), and decreased ovarian cancer risk with breastfeeding, tubal ligation (BRCA1) and oral contraceptives (BRCA1 and BRCA2) [BRCA P/LPV carriers.Some modifiable factors of cancer risk in to 0.99) . This trto 0.99) . Two hypd BRCA2) . Additiod BRCA2)  and NICEBRCA P/LPVs carriers. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention trial , tamoxifen reduced breast cancer risk by 62% in BRCA2 P/LPV carriers , but not in BRCA1 P/LPV carriers , similar to the reduction in the incidence of ER-positive breast cancer among non-carriers in the same P-1 trial [BRCA P/LPV carriers . In large chemoprevention studies of cancer-free postmenopausal women at increased risk for breast cancer as assigned by family history (but not genotyped for BRCA P/LPVs), both raloxifene and aromatase inhibitors (AIs) were associated with a lower risk of breast cancer [BRCA P/LPV carriers but do refer to it as an option to be discussed with women at high risk for breast cancer unless they have undergone bilateral risk-reducing mastectomy [BRCA P/LPV carriers but recommend that assessment of risks and benefits for the individual woman should be performed by an experienced medical professional [BRCA P/LPV carriers in the context of clinical trials [Limited data are available on cancer risk reduction using hormonal modifying agents  as primary chemoprevention for -1 trial . It shout cancer ,23,24. Tt cancer , Spanisht cancer , Americat cancer , and Natt cancer  suggest stectomy . The Ausl trials .BRCA P/LPVs carriers [BRCA P/LPV carriers [BRCA P/LPV carriers as for average-risk women [BRCA1 mutations, the opposing effects of potentially increased risk of breast cancer versus lifetime protection against ovarian cancer by taking OC should be discussed [Combined hormonal contraceptive  use was shown to be an effective method of chemoprevention for ovarian/tubal/peritoneal cancer both for women in the general, average-risk population and for carriers ,31,32. Acarriers ,34, sevecarriers ,32,35, ncarriers . The concarriers ,26,27,37sk women . Accordiiscussed . eviQ guiscussed .BRCA P/LPVs [BRCA1 P/LPV carriers, but not BRCA2 P/LPV carriers in a multicenter cohort study [BRCA1 P/LPV carriers and that RRM counseling should be individualized [Two meta-analyses concluded that risk-reducing mastectomy (RRM) decreased breast cancer rates, with one of them showing that it also decreased all-cause mortality ,39. In bA P/LPVs ,44,45,46rt study ,48, whicrt study ,50. Thisrt study . The Gerdualized .BRCA1 P/LPV carriers tend to develop ovarian cancer at younger ages than BRCA2 P/LPV carriers [BRCA1 P/LPV carriers, and between 40 and 45 years of age for BRCA2 P/LPV carriers  reduced ovarian cancer risk and overall mortality ,53,54,55carriers . INCa guo age 45 . NICE guo age 45 . Belgiancarriers . ESMO gucarriers . Indian carriers .Notably, none of the guidelines reviewed herein considers salpingectomy without oophorectomy as a standard of care in the absence of safety data from randomized trials.BRCA P/LPVs, specifically for serous papillary carcinoma [BRCA P/LPV carriers. While the procedure is not justified for uterine cancer prevention per se, it should be discussed and individualized in the context of unopposed estrogen replacement therapy in cancer-free women or tamoxifen therapy in breast cancer survivors. This issue is addressed by the Society of Obstetricians and Gynecologists of Canada (SOGC), ACOG, NCCN, National Breast Cancer Consultation of Netherlands (NABON), and eviQ guidelines [Several studies reported an increased risk for uterine cancer in women with arcinoma ,72,73,74idelines ,28,67,75Physical examination. Most guidelines call for “breast awareness” from age 18 years and/or clinical breast examination (CBE) every 6–12 months from 25 years of age or starting 5–10 years prior to the age of the youngest breast cancer patient in the family, whichever is earlier  [BRCA P/LPV carriers over age 65 years continue to be at increased risk of breast cancer, with remaining lifetime risk approaching 20%, implying continued MRI screening beyond age 70 years, as suggested by some of the guidelines. However, the optimal surveillance intervals, combining MRI with additional modalities, and the management of younger (<30 years) and older (>70 years) carriers remain controversial and inconsistent among various guidelines, as can be seen in tiveness ,78,79,80 status) , a large status) . Potenti status) , and lim status)  showed tMammography. Screening mammography (MG) has been used as the standard modality for early breast cancer detection for average-risk women over the last few decades, as it demonstrated reduced breast cancer mortality in women older than 40 years [BRCA P/LPV carriers. The lower sensitivity of MG may be attributed to younger median age at diagnosis, a time in a woman’s life when breast density is high [BRCA1 P/LPVs under the age of 40 years [BRCA1 and BRCA2 P/LPV carriers [BRCA1 P/LPV carriers undergoing annual MRI screening [40 years ,84,85,86 is high , biologi is high , and hig is high . Tomosyn is high ,91,92. N is high . Analysi is high . Phi et 40 years . While tcarriers , while tcreening ,66,69. MBreast Ultrasound. Whole-breast ultrasound (US) was shown to increase the detection rate of clinically favorable cancers, but this was accompanied by an increased rate of false positive findings [findings ,97. In afindings ,98,99. MSurveillance during pregnancy and breastfeeding. The incidence of pregnancy-associated breast cancer is low in the general population (~1 in every 3000 pregnancies) [BRCA P/LPV carriers screened by breast US during 7 years follow-up [BRCA P/LPV carriers [nancies) . Recentlollow-up . This locarriers . Only 3 carriers ,68,69.Surveillance following RRM. Since RRM significantly reduces the risk of breast cancer, with an absolute risk of up to 1.5% at follow-up ranging between 2 to 13 years [13 years , none of13 years ; however13 years .Breast cancer screening in male carriers. The cumulative male breast cancer risk is estimated at 0.1–1.5% in BRCA1 P/LPV carriers and at 1.9–7.7% in BRCA2 P/LPV carriers [BRCA2 P/LPV carriers , with no routine screening for BRCA1 carriers [carriers ,51,64,69carriers ,27 and fMultimodality screening with transvaginal ultrasound (TVUS) and CA-125 versus either TVUS alone or no screening showed that multimodality screening is more effective at detecting early-stage cancer ,105,106.BRCA2 P/LPVs and 7 had BRCA1 P/LPVs), and the average follow-up was 63 months. By contrast, the analysis of the multicenter Cancer of Pancreas Screening (CAPS5) study, which included 269 BRCA2 P/LPV carriers and 68 BRCA1 P/LPV carriers with a median follow-up of 4 years, found that 77.8% of the PDACs diagnosed within the high-risk cohort  had stage I disease and 5-year survival of 73.3%. This is compared with the 5-year overall survival of 11% in patients with PDAC in the US [BRCA P/LPV carriers: in the Dutch study, 58% carried a P/LPV in the CDKN2A gene, whereas in the CAPS5, less than 5% carried P/LPV in the same gene, and CDKN2A-associated PDAC are considered to have a more aggressive disease course. Until more robust data are published, specifically in BRCA P/LPV carriers, there is no consensus in the reviewed guidelines regarding optimal PDAC surveillance, especially given the low lifetime risk for PDAC in BRCA P/LPV carriers, estimated at around 5% [BRCA P/LPV carriers regardless of family history (unlike in previous guidelines), although stating that this recommendation has very low quality of evidence [Two studies on pancreatic ductal adenocarcinoma (PDAC) surveillance outcomes in genetically predisposed high-risk individuals have been published recently with conflicting results. The Dutch Familial Pancreatic Cancer Surveillance Study Group did not find survival advantage for annual screening with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRCP) . In thisn the US . The difround 5% , and queevidence . The guievidence ,28,64,68evidence , and encevidence . NABON, BRCA-related prostate cancer was shown in several studies to be more aggressive and affects men at a younger age than sporadic prostate cancer [BRCA2 P/LPV carriers (n = 902) had a higher incidence of prostate cancer, younger age of diagnosis, and clinically significant tumors compared with non-carriers (n = 497) [BRCA2 P/LPVs. Knowledge of germline mutational status during screening is considered a factor in a decision regarding surgery versus active surveillance [BRCA1 P/LPV carriers was not confirmed in a recent family-based cohort [e cancer ,114,115.eillance . The seers n = 49 [BRCA2 PBRCA P/LPV carriers (RR = 2.17 for BRCA1 and RR = 3.69 for BRCA2), slightly increased risk for biliary tract cancers in BRCA1 P/LPV carriers (RR = 3.34), and for colorectal cancer in BRCA1 P/LPV carriers (RR = 1.48) [A recent large retrospective, family-based study suggested a small, but statistically significant, increased risk for gastric cancer in  = 1.48) ,25,27.BRCA1 P/LPV carriers treated with HRT, but in those taking combined (estrogen plus progesterone) HRT, the 10-year actuarial risk of breast cancer was 22%, as compared with 12% in those taking estrogen alone, with no statistically significant differences based on age [The use of Hormone Replacement Therapy (HRT) for the management of menopausal symptoms in carriers after rrBSO is controversial since data from the few available studies are conflicting. Kotsopoulos et al. did not find an increased risk for breast cancer in d on age . The PROd on age . In a red on age . The guid on age .Genitourinary syndrome of menopause, which includes dyspareunia and vaginal dryness, is frequent after rrBSO . There aBRCA P/LPVs carriers. They also recommend considering the fact that cycle-guided breast MRI for screening may be more difficult to plan and interpret in women who experience levonorgestrel-containing IUD-associated amenorrhea [BRCA1 carriers should be individualized, taking into account the risks and benefits [Other than the use of OC as a measure of risk-reduction for ovarian cancer (discussed above), the issue of safe contraception should be discussed with young carriers. Besides recommendations described in the chemoprevention section and enorrhea . eviQ guenorrhea . SOGC pobenefits , while Abenefits .BRCA P/LPV carriers was assessed in 2008 by a group from Toronto’s Women’s College Hospital. That study reported that neither a history of infertility and the use of fertility medications, nor IVF were associated with an increased breast cancer risk [BRCA P/LPV carriers [BRCA P/LPV carriers reported no association between fertility treatments  and increased breast cancer risk [The safety of in vitro fertilization (IVF) in cer risk . Data pucarriers . A histocer risk . A matchcer risk . SOGC gucer risk . Additiocer risk ,37,64,68As shown in BRCA1 and BRCA2 genes, including risk-reducing options, secondary prevention (screening), as well as treatment of iatrogenic sequela of risk-reducing interventions. Controversies and inter-guidelines inconsistencies pertaining to the medical management of the carriers exist. This variability may be attributed to a different interpretation of the data presented in the published literature, insufficient levels of evidence for certain recommendations, or possibly national specific cost–benefit analyses, as well as international and cultural variations in the perception of risk and the acceptance of risk-reducing measures. These inconsistencies are mostly notable in breast imaging, including surveillance intervals, combining MRI with additional imaging modalities, and screening of younger (<30 years) and older (>60 years) carriers. Some of these inconsistencies may be explained by rapidly changing data regarding risk assessment, paucity of robust data from prospective randomized trials, literature interpretation, frequency of guideline updates, and cost-effectiveness analyses used by each group/society. These controversies may account for the fact that some medical centers use self-developed protocols rather than national guidelines for carriers’ surveillance [BRCA P/LPV carriers.This review depicts multiple aspects of management for cancer-free carriers of germline P/LPVs in eillance . These cBRCA1 P/LPV carriers (NCT04711109), may offer more options with a potentially lower rate of deleterious effects on quality of life in the future. In addition, personalized risk stratification should be investigated by international consortia to enable personalized “next generation” surveillance since this may not only save multiple unnecessary screening procedures for lower-risk carriers and cost for healthcare systems but also encourage higher-risk carriers to consider risk-reducing strategies instead of (hopefully) early detection of cancer. Therefore, when available, women should be encouraged to participate in relevant clinical trials.Since screening for cancer does not actively reduce cancer risk but only offers a passive way to a possible earlier stage at diagnosis (with an unclear effect (if any) on survival), in a sizeable number of cases having to endure morbid oncological treatments , the impBRCA1 and BRCA2 P/LPV carriers result in varying recommendations by international societies. Updated international consensus guidelines are warranted for synchronized counseling and surveillance strategies. In parallel, it is important to educate primary care physicians and discuss with the patients the risks and benefits of primary prevention, risk-reducing strategies, and limitations of screening procedures to enable informed and shared decision making.Multiple controversies pertaining to the medical management of healthy