To assess the risks of breast cancer associated with different types and durations of hormone replacement therapy (HRT).Two nested case-control studies.UK general practices contributing to QResearch or Clinical Practice Research Datalink (CPRD), linked to hospital, mortality, social deprivation, and cancer registry (QResearch only) data.98 611 women aged 50-79 with a primary diagnosis of breast cancer between 1998 and 2018, matched by age, general practice, and index date to 457 498 female controls.Breast cancer diagnosis from general practice, mortality, hospital, or cancer registry records. Odds ratios for HRT types, adjusted for personal characteristics, smoking status, alcohol consumption, comorbidities, family history, and other prescribed drugs. Separate results from QResearch or CPRD were combined.Overall, 33 703 (34%) women with a diagnosis of breast cancer and 134 391 (31%) controls had used HRT prior to one year before the index date. Compared with never use, in recent users (<5 years) with long term use (≥5 years), oestrogen only therapy and combined oestrogen and progestogen therapy were both associated with increased risks of breast cancer  and 1.79 (1.73 to 1.85), respectively). For combined progestogens, the increased risk was highest for norethisterone  and lowest for dydrogesterone . Past long term use of oestrogen only therapy and past short term (<5 years) use of oestrogen-progestogen were not associated with increased risk. The risk associated with past long term oestrogen-progestogen use, however, remained increased . In recent oestrogen only users, between three (in younger women) and eight (in older women) extra cases per 10 000 women years would be expected, and in oestrogen-progestogen users between nine and 36 extra cases per 10 000 women years. For past oestrogen-progestogen users, the results would suggest between two and eight extra cases per 10 000 women years.This study has produced new generalisable estimates of the increased risks of breast cancer associated with use of different hormone replacement preparations in the UK. The levels of risks varied between types of HRT, with higher risks for combined treatments and for longer duration of use. Hormone replacement therapy (HRT)  or menopausal hormonal therapy (MHT)) is prescribed to relieve the symptoms of menopause, which can be life changing. HRT is used by millions of women, sometimes over extended periods. A range of hormone combinations are available, each with different efficacy and side effects. HRT can bring several improvements to quality of life, and it can prevent osteoporosis. Concerns about adverse effects, particularly the increased risk of breast cancer associated with HRT,Randomised trials using enrolled participants are now impractical to investigate the risks of breast cancer associated with HRT because of the numbers required and the length of follow-up. Trials would also be difficult to justify ethically, given the known harms that are associated with some types of HRT. Earlier trials have been limited, focusing on specific age groups possibly unrepresentative of women likely to request HRT or selecting specific types of HRTOur study focused on exposure to all the commonly prescribed types of HRT in the UK over the past 20 years in a representative primary care population. We assessed the differences in risks associated with the individual component hormones used in HRT, including dydrogesterone. Our findings are based on prospectively collected electronic health records from the two largest UK primary care databases linked to secondary care data sources. We analysed these separately and then combined the results. In contrast with data and analytical designs used in studies included in the recent meta-analysis,Full details for this study are available in the published protocol.Across both databases, we identified all cases between 1 January 1998 and 31 December 2018. From the QResearch database, we identified all cases of incident breast cancer using general practice, hospital admission, mortality, and cancer registry records. From CPRD, when practices were linked, we used general practice, hospital admission (up to 31 December 2017), and mortality data records (up to 13 February 2018) to identify cases, and, when not linked, general practice records only. Each case was matched to a maximum of five controls by year of birth and general practice using incidence density sampling.We extracted prescription information for all oestrogens, progestogens, and tibolone from practice records. Symptoms indicative of developing breast cancer before diagnosis could have resulted in cessation of HRT. To minimise this source of possible protopathic bias, we excluded prescriptions issued in the year before the index date.Exposure to HRT was taken as the date from when a woman received her first prescription containing systemic oestrogen  indicated to treat menopausal symptoms. If a woman received no prescription that contained a progestogen after this date, she was classified as an oestrogen only therapy user. If a woman received any prescription that contained a progestogen, she was classified as a combined therapy user. We also included topical oestrogen preparations  and tibolone, because both are commonly prescribed to menopausal women.A large proportion of women switched between different combinations of oestrogens and progestogens, so we analysed each hormonal preparation as a separate exposure. For oestrogen only users, we distinguished between types, doses, and application method, whereas for combined therapy users we analysed combinations of any oestrogen, concentrating on progestogen type and application method. If combined therapy users had also used oestrogen only therapy, we analysed the women as oestrogen-progestogen users but adjusted the combined exposure results to account for periods of oestrogen only treatment. For all treatments, the reference category was no exposure (never users) to HRT.At the time of our study, two types of oestrogen (conjugated equine oestrogen and estradiol) and four types of progestogen  were commonly prescribed in the UK and were included in our analyses. Of these, sufficient data were available for estradiol, estradiol-norethisterone, and oestrogen-levonorgestrel to facilitate separate analysis of application methods—oral, transdermal, or injection, and (for levonorgestrel) intrauterine. We investigated two daily dosage levels of oestrogen: low  and high . Median dosages for each oestrogen and for each woman were also calculated and analysed.We have not specified the type of oestrogen for combinations with progestogens, but in our data conjugated equine oestrogen was by far the most commonly prescribed drug in combination with medroxyprogesterone (only 16% of prescriptions included estradiol) and levonorgestrel (only 5% included estradiol). Estradiol was the only oestrogen prescribed in combination with norethisterone and dydrogesterone.Our data showed that HRT prescriptions were frequently issued for three months, so we assessed the durations of use by summing the lengths of prescriptions in days, including gaps of fewer than 90 days between prescriptions. Most (79%) repeated prescriptions were, however, issued within 30 days. We then categorised durations of use as never (0), less than 1 year, 1-2 years (≥1 and <3), 3-4 years (≥3 and <5), 5-9 years (≥5 and <10), and 10 years or more. Excluding prescriptions in the past year, the gap between the end of the last prescription and the index date was categorised as 1-2 years (>1 and <2), 2-4 years (≥2 and <4), 5-9 years (≥5 and <10), and 10 years or more.Because some women discontinued HRT more than a year before the index date, and associated breast cancer risks might have diminished noticeably, we investigated two recency related exposures: recent, if the women had a prescription more than one year and less than five years before the index date (this includes current users of HRT at one year before the index date), and past, if their last prescription ended before that period (≥5 years before). Using these, we analysed different durations of exposures in relation to the recency of the last prescription.Analyses were all adjusted by the same factors—those that might have affected a doctor’s prescribing decision for HRT or might have affected a woman’s decision to take HRT or are associated with an increased breast cancer risk.As data from QResearch and CPRD cannot be pooled, for all analyses we processed extracted datasets in parallel as similarly as possible. To calculate associations between breast cancer risk and different exposures to HRT, we used conditional logistic regression to estimate odds ratios with 95% confidence intervals. A small proportion of women had missing values for BMI, smoking status, and alcohol consumption, which we assumed to be missing at random. We imputed these separately for each dataset using chained equations over 10 imputed datasets, where the imputation model included all listed confounders, exposures, and case-control status indicators, and we combined the odds ratios obtained from the imputed datasets using Rubin’s rule.We considered duration of exposure both in the form of defined categories of exposure and as a continuous variable. For ease of comparability with other studies and to simplify interpretation, our main results are presented using defined categories of exposure, with duration of HRT expressed in years. We used a meta-analytical technique to combine the obtained odds ratios from the separate analyses run on each database.To model exposures as continuous variables, we ran separate analyses on each database using fractional polynomials to explore non-linear risk associations for durations of exposure, measured in days.To assess possible age related differences in risks associated with exposures to hormone, we performed additional analyses for different age categories at the index date: 50-59 years, 60-69 years, and 70-79 years. We ran another subgroup analysis for women in three different BMI groups: less than 25, 25 up to 30, and 30 or more. In this analysis, we included only controls in the same body mass category as their matched case.For the main analysis, we considered women to have recently used HRT if they had a prescription between one and five years before the index date. The risk associated with HRT has been found to decrease rapidly after discontinuation,It is possible that some women were classified as never exposed only because they were not registered with the practice at the time when they had used HRT. Although any systematic difference between cases and controls is unlikely, we addressed this possible misclassification of exposure by repeating the analysis in a subgroup of women with at least 10 years of medical records. Another sensitivity analysis dealt with unknown adherence to HRT, because it is possible that some women with apparent gaps between prescriptions had in fact spread their HRT supply over longer periods. In this analysis, we defined duration of HRT use as the period between the first HRT prescription and the last one prior to one year before the index date.The main analysis was run on women aged 50 to 79, which may include some premenopausal and perimenopausal women who have a higher risk of breast cancer.To check our assumption of missing at random for some confounders, we compared patterns of missingness in exposed and non-exposed women and repeated the analyses, including only cases and controls with recorded values. In the final sensitivity analysis, we dealt with problems that might have arisen from the different levels of linkage in QResearch and CPRD. All QResearch practices were linked to deprivation, hospital, mortality, and cancer registry data, so cases could be identified using all sources of data. For CPRD, however, only 60% of practices were linked to deprivation, hospital, and mortality data, so to include data from all usable practices, we were limited to identifying cases from all available data. To assess the possible effect on our results, we ran an analysis using only fully linked CPRD practices.To estimate the excess of breast cancer cases associated with different HRT exposures we calculated the incidence rate in the unexposed female population for different age categories  using the underlying cohort from CPRD. The rate in the exposed population was derived by multiplying the baseline rate by relevant odds ratios obtained from the combined analysis.We used Stata v16 for all analyses. A 1% level of statistical significance was used to allow for multiple comparisons. To facilitate comparison with other studies, however, we present the results as odds ratios with 95% confidence intervals.The BMJ both had lay involvement. No other lay people were involved in setting or extending the research question or the outcome measures in our study, nor were they involved in developing plans for the design or implementation of the study. However, to better understand motivations for starting HRT and possible adherence issues related to prescribed treatment, formal and informal conversations with some women taking HRT were also organised. In these, women generally reported high levels of adherence, regardless of whether they had sought treatment themselves or were recommended it by a doctor. Some of the women involved have also agreed to help further with interpretation and dissemination of the results through women’s menopausal forums.This epidemiological study investigated a research question recommended by a National Institute for Health and Care Excellence committee, which included lay members.Overall, 59 999 cases of breast cancer were identified in QResearch between 1 January 1998 and 31 July 2018, using general practice, hospital admissions, mortality, and cancer registry records. In total, 38 612 breast cancer cases were identified in CPRD between 1 January 1998 and 31 December 2018, using general practice records and, for linked practices, also using hospital admission records (until 31 December 2017) and mortality records (until 13 February 2018) .v 50%), to be former smokers (29% v 27%), to have a record of benign breast disease (9% v 6%) or other cancers (3.1% v 2.6%), or to have a family history of breast cancer (4% v 2.5%).Across both databases, 33 703 (34%) cases and 142 391 (31%) controls had ever been exposed to HRT. Of those, 8860 (26%) cases and 42 799 (30%) controls had been exposed to oestrogen only therapy and 24 843 (74%) cases and 99 592 (70%) controls had been exposed to oestrogen-progestogen therapy (supplementary eTable 1). Women in the 60-69 age category were relatively more exposed to oestrogen only (47% in cases and controls) and oestrogen-progestogen therapies (48% in cases and controls). A high proportion of women using oestrogen only therapy had undergone oophorectomy or hysterectomy (89% cases and 90% controls), but, overall, users of oestrogen only and oestrogen-progestogen therapies had characteristics broadly similar to those of never users for most confounders. Some women switched between hormones during HRT exposure. About 20% of oestrogen only users had exposure to both oestrogens. About 57% of combined therapy users had only one oestrogen-progestogen combination recorded. About 0.6% of cases and controls started HRT in the year before the index date, but these are considered as never users in the analyses.Overall (or ever) exposure to HRT was associated with an increased risk of breast cancer . The increased risk was mostly attributable to oestrogen-progestogen therapy , with oestrogen only therapy showing a small increased risk , both compared with never users (supplementary eTable 2). No increased risk was associated with oestrogen cream or vaginal preparations (supplementary eTable 3). The risks associated with HRT increased with duration of use, but the associations were less strong for oestrogen only therapy and for tibolone than for oestrogen-progestogen therapy, apart from estradiol-dydrogesterone preparations. Norethisterone, levonorgestrel, and medroxyprogesterone were associated with similar risks, increasing across all duration categories longer than one year. For all exposure durations, the combined treatment with the lowest associated risk increase was estradiol-dydrogesterone. No differences were found between low and high doses of oestrogens or between different application methods for estradiol, norethisterone, or levonorgestrel (supplementary eTable 4).Associations between use of HRT and risk of breast cancer rapidly decreased with increasing years of discontinuation . For oestrogen only, estradiol combined with norethisterone and dydrogesterone, and tibolone, no significantly increased risk was found from two years after discontinuation. For medroxyprogesterone, the risk was reduced after two years but remained raised until after five years; for levonorgestrel until after 10 years.Recent users of HRT  comprised 56% (18 879) of cases and 50% (70 931) of controls ever exposed to HRT. A further restriction to recency (defined now as one prescription or more in the period 1-2 years before the index date) resulted in fewer women in each category of exposure, but the increased risks associated with longer exposures were even more pronounced . In HRT users, 40% (13 463) of cases and 32% (44 972) of controls ever exposed to HRT had one or more prescriptions in the period 1-2 years before the index date. The patterns of risks for these recently exposed women were similar to those of overall exposures, but the risks were consistently higher and more pronounced for progestogens. For women with a last exposure more than two years before the index date, risks associated with long exposures to levonorgestrel (>3 years) remained high, but for other hormones the risks were not statistically significant .Risk increases for recent users were more pronounced than for past users, and different types of HRT showed different patterns of increase as the durations of exposure increased. Oestrogen-medroxyprogesterone and oestrogen-levonorgestrel formulations showed the greatest increases with duration. Oestrogen only (including separately conjugated equine oestrogen and estradiol), tibolone, and estradiol-dydrogesterone formulations showed the smallest increases with duration.The subgroup analyses for different age categories showed similar patterns in magnitudes of risk for recent and past exposures  per 10 000 women years, whereas the crude incidence rate in women not exposed to HRT was 31.5 (31.1 to 31.7) per 10 000 women years. The rate for unexposed women varied with age, with the lowest rate in younger women . The highest rate in the 60-69 years group was consistent with national data from cancer registration statistics in England.The sensitivity analysis run on women with at least 10 years of recorded data showed similar patterns of risks associated with different durations of HRT use, but the risks appeared slightly higher, particularly for exposure to oestrogen-progestogen combinations of between five and 10 years . The sensitivity analysis on the subgroup of women aged 55 to 79 showed similar patterns of risks, with all values consistent with the subgroup analyses for different age groups . The sensitivity analysis with duration of exposure defined as from the first prescription of HRT to the end of the last prescription showed results similar to those of the main analysis (supplementary eTable 15). The results of analyses run on cases and controls without missing data for smoking status, alcohol consumption, and BMI were similar to those of the main analyses—as were the analysis restricted to CPRD cases and controls with linked data.This large observational study found that exposure to most HRT drugs is associated with an increased risk of breast cancer. In comparison with a recent meta-analysis, however, our findings generally suggest lower increased risk associations between longer term HRT use and breast cancer, and we report a more noticeable decline in risks once HRT has stopped. Risk increases were mostly associated with oestrogen-progestogen treatments, but small increases were also associated with oestrogen only treatments. For all exposure durations, the combined treatment with the lowest associated risk increase was estradiol-dydrogesterone. Associations for all treatments depended on duration, with no increased risks for less than one year of treatment but increasing risks for longer exposures to medroxyprogesterone, norethisterone, and levonorgestrel. Associations were more pronounced for older women and less noticeable for obese women.The main strengths of this original study are its size, consistent sources of primary care data, almost complete follow-up of diagnoses using linked data, consistent design, and resulting generalisability of the findings. Combining results from the two largest UK primary care research databases with national coverage has provided increased power, representiveness, and wide geographical coverage of included practices. The study relates to an important health problem and used only objective information on prescriptions for HRT in the UK, facilitating inclusion of the full range of preparations available within this national setting and presenting in detail the increased risk of breast cancer associated with usage patterns. The follow-up and validation of breast cancer diagnoses through linkages to hospital, mortality, and cancer registry (QResearch only) data reduced both ascertainment and recording bias. As our study was based on routinely collected data, it was also not susceptible to recall bias. Matching by general practice enabled consideration of possible differences in prescribing and recording patterns across practices. Differences in menopause onset and age at start of HRT were partially dealt with through matching by age. The results were also adjusted for information on lifestyle, comorbidities, and use of other drugs, and the study presents subgroup analyses for women in different age groups and in different BMI categories. Protopathic bias, from diagnostic and prescribing problems created by symptoms common to early breast cancer and onset of menopause, was minimised by excluding prescriptions issued in the year before the index date.Some limitations of this study arise from inevitable shortfalls in completeness and accuracy within any routinely collected dataset. A small proportion of women had missing information on smoking status, alcohol consumption, and BMI, but these were dealt with by multiple imputation. As we did not have reliable data for age at onset of menopause for all women, we estimated onset from the first menopause specific record before the earliest HRT prescription. For women with no such record we assumed onset within the most common age range of 50 to 54 years. We did not investigate the differences between continuous and sequential HRT because these regimens are prescribed at different times after menopause. As our cases and controls were matched by age, they would likely have been prescribed similar regimens, making a comparison infeasible. Our primary focus, anyway, was recent long term exposure.No reliable data were available for established risk factors for breast cancer, such as parity or time of the first pregnancy, but there is no evidence to show that these are related to HRT use. No data for physical activity were available, but a possible risk reduction for active women has been shown not to be influenced by menopausal status.Our study used a nested case-control design, so it did not follow women prospectively from the start of HRT or assess average lifetime risks. Rather, it looked back at already recorded exposures to HRT for women with a diagnosis of breast cancer and matched controls in the age range 50 to 79 and produced comparisons of risks averaged across all time points at which diagnoses in the datasets occurred. The study is based on data derived from real world treatment settings, when women might not have had a constant supply of a preparation and might have needed to switch drugs during the study period. Including all exposures prescribed over time allowed us to present information for a wide range of common types of HRT.Most trials produced results for a more restricted number of treatments. A meta-analysis of existing trials,Our estimates were consistent with previous observational studies.In general, some inconsistency was found between the proportions of women exposed to HRT in data used for our study and those used in the 2019 meta-analysis.v 63 in our sample) but no age range was reported. The estimations of risk for overall use of HRT in our CPRD analysis  were, however, similar to the CPRD specific estimations reported in the meta-analysis . For recent use (prescriptions 1-2 years before the index date), when the proportions of HRT users in CPRD data used in our study and in the meta-analysis were closest, the estimates of risk were also similar. In our analysis of CPRD data on recent use, the odds ratios were 1.25 (1.17 to 1.34) for oestrogen only and 1.91 (1.83 to 1.99) for oestrogen-progestogen, whereas for the CPRD data used in the meta-analysis the corresponding findings were 1.36 (1.25 to 1.4) and 2.16 (2.02 to 2.31).We cannot speculate on reasons for these differences in the CPRD data used because we do not have access to relevant information for the 2019 meta-analysis. That sample contained slightly older cases  use of more than five years  were lower than those from the meta-analysis .v 1.41, 1.17 to 1.71).For dydrogesterone, our study found lower risks associated with more than five years of exposure than in the meta-analysis  and for oestrogen-progestogen use  are in line with findings from the meta-analysis to 1.39 The adiposity of included women differed between our study and previous studies. Mean BMI in our study (27.7 in cases) was higher than in other observational studies (average 25)This study delivers more generalisable estimates of the different risks of breast cancer associated with specific progestogen components of HRT, while confirming no increased risks from short term use of oestrogen only, estradiol-dydrogesterone, and tibolone. Increasing duration of use was generally associated with increased risk, with tibolone and estradiol-dydrogesterone showing the smallest risks. The frequency of prescribing for treatments including dydrogesterone was, however, much lower than for those including norethisterone, medroxyprogesterone, or levonorgestrel.In our study protocol we did not prespecify analyses relating to cancer stage or tumour type because these lay outside the main question of interest. Although information on risk related to individual progestogens could be improved, previous studies have shown that the associated risks between HRT and tumour types might differ, with higher risks of developing oestrogen receptor positive tumours and lobular tumours.This large observational study of HRT and breast cancer risk based on two large primary care databases analysed in an identical manner has confirmed the excess risk to be attributable mostly to combined treatments, with the lowest risks associated with use of the least commonly prescribed dydrogesterone. Rarely prescribed tibolone also showed low increased risks.Our findings of generally lower increased risks for combined HRT treatments and of more pronounced declines in risk once HRT has stopped, provide some counterbalance to the higher than expected risks reported in a recently published meta-analysis.Long term systemic use of hormone replacement therapy (HRT) is associated with increased risks of breast cancer, mostly attributable to the progestogens medroxyprogesterone, norethisterone, and levonorgestrelAfter discontinuation of treatment, the increased risks decline, but remain raised for some yearsA recent large meta-analysis has reported higher than expected breast cancer risks associated with HRTThe study confirmed increased risks of breast cancer associated with long term use of oestrogen only therapy and combined oestrogen and progestogen therapyThe combined treatment associated with the lowest risk increase was estradiol-dydrogesteroneThe findings suggest lower increased risks of breast cancer associated with longer term HRT use, and a more noticeable decline in risks once treatment is stopped compared with the meta-analysis


Compared to tamoxifen users, AI users had a higher risk of any arthritis  and carpal tunnel syndrome . No significant difference was observed in the risks of any arthritis and carpal tunnel syndrome across different AIs. Taxane use was not associated with any arthritis  or carpal tunnel syndrome  compared to other chemotherapies. Taiwanese women with breast cancer-initiating AIs had an increased risk of arthritis and carpal tunnel syndrome compared to those who initiated tamoxifen.Tamoxifen or aromatase inhibitor (AI) therapy may prevent breast cancer recurrence, however, adverse effects may lead to treatment discontinuation. Evidence regarding the occurrence of AI-associated musculoskeletal problems among Asians is scarce. We identified women with breast cancer-initiating tamoxifen or AIs from the Taiwan National Health Insurance Research Database (2007–2012). Using multivariable cause-specific hazard models, we examined the association between endocrine therapy and the risk of any arthritis and carpal tunnel syndrome, adjusting for age, prior cancer treatment, and other health status factors. Among 32,055 eligible women with breast cancer (mean age = 52.6 ± 11.5 years), 87.4% initiated tamoxifen, 3.9% initiated anastrozole, 8.0% initiated letrozole, and 0.7% initiated exemestane. AI users had a higher 1-year cumulative incidence for any arthritis (13.0% vs. 8.2%,  Breast cancer is the most common newly diagnosed and prevalent female cancer, with 1.7 million new and 6.3 million prevalent cases worldwide in 2012 [Musculoskeletal problems occur commonly among AI users ,4, with n < 400) from Japan found that 35% to 72% of AI users reported joint pain [Approximately 40% of women with newly diagnosed breast cancer are Asians  but the int pain ,11,12. Cint pain , responsint pain . The Firint pain  found thOur data sources were the Taiwan National Health Insurance Research (NHIRD) and Catastrophic Illness Patient Databases (CIPD) from 2004 to 2013. NHIRD is the administrative claims data of the Taiwan National Health Insurance (NHI) Program that has covered >99% of the Taiwanese population (>23 million unique people) since 1997. NHIRD datasets include enrollment information, medical claims including inpatient, outpatient and emergency department visits, and prescription claims reimbursed by the NHI Program. The CIPD registry covers more than 30 major chronic diseases  and requires histological and/or clinical validations for CIPD eligibility.In this retrospective cohort study with new user design, we identified women with breast cancer-initiating endocrine therapy from 2007 to 2012. We identified endocrine therapy including tamoxifen and AIs  using the Anatomical Therapeutic Chemical (ATC) Classification System codes  Table S. ConsideTwo separate outcomes were examined in the 12 months after initiation of endocrine therapy: time to the first episode of (1) any arthritis including osteoarthritis, rheumatoid arthritis, and other arthritis and (2) carpal tunnel syndrome. Any arthritis and carpal tunnel syndrome were identified by at least one inpatient claim or two outpatient claims that were more than 30 days apart . Based on the prior literature on breast cancer treatment, we adjusted for a series of covariates to address potential confounding ,6. Covarp < 0.05).Patient characteristics were summarized by endocrine therapy groups with appropriate descriptive statistics . We used multivariable cause-specific hazard models to estimate the risk of any arthritis and carpal tunnel syndrome within a year across different AIs compared to tamoxifen, adjusting for the covariates mentioned above such as age and history of chemotherapy within a year prior to initiation of endocrine therapy. Both unadjusted and adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) were presented. Statistical significance was determined based on 2-tailed tests .Given that patients initiating different endocrine therapies or chemotherapy regimens may have different disease severity and characteristics, we conducted two additional sensitivity analyses for each outcome using propensity score (PS) matched cohorts to ensure comparability. We then estimated the risk of outcomes of interest using multivariable cause-specific hazard models. We matched the cohorts using the optimal caliper widths method with widths of 0.2 standard deviations of PS . Detailsp < 0.0001), more likely to have more taxane-based chemotherapy (14.8–37.8% vs. 10.8%), a higher NCI index ≥2 (12.1–13.7% vs. 5.9%), more non-cancer comorbidities such as hypertension (45.5–48.4% vs. 30.5%), and more opioid use (8.0–11.2% vs. 4.4%), as shown in p < 0.0001).Among 32,055 eligible Taiwanese women with breast cancer (mean age: 52.6 ± 11.5 year), 87.4% initiated with tamoxifen, 3.9% with anastrozole, 8.0% with letrozole, and 0.7% with exemestane. Compared with tamoxifen users, AI users were older . Overall, AI users were associated with a 21% higher risk of any arthritis in the year after treatment initiation  compared to tamoxifen users. Among AIs, only letrozole users were associated with a statistically significant increased risk of any arthritis compared to tamoxifen users . Other factors significantly associated with an increased risk of any arthritis included older age , previously receiving radiation therapy , hypertension , dyslipidemia , affective disorders , opioid use , and NSAIDs/acetaminophen use  (As shown in 19–1.47) . Prior ep = 0.008). Overall, AI users were associated with a 68% higher risk of carpal tunnel syndrome in the year after treatment initiation  compared to tamoxifen users. Among AIs, anastrozole and letrozole users were associated with a statistically significant increased risk of carpal tunnel syndrome  compared to tamoxifen users. Other factors significantly associated with an increased risk of carpal tunnel syndrome included age of 45 to 54 years  and having a history of affective disorders  ( − 1.70) . Prior eAs shown in Our study using nationwide claims data in Taiwan yielded three key findings regarding the association between type of endocrine therapy use and the occurrence of musculoskeletal problems within a year after treatment initiation. Overall, over one-tenth of Taiwanese women with breast cancer-initiating endocrine therapy experienced any arthritis within the first year of treatment, whereas the occurrence of carpal tunnel syndrome was less than 2%. Secondly, women who used AIs were associated with a 21% and 68% increased risk of any arthritis and carpal tunnel syndrome, respectively, compared to those who used tamoxifen after adjustment for relevant confounders such as age, prior cancer treatment, and other comorbidities. Thirdly, there are no significant differences in the risk of any arthritis or carpal tunnel syndrome for women initiating letrozole versus anastrozole in the sensitivity analyses using PS-matched cohorts. Notably, prior exposure to taxane was not a risk factor for either outcome of interest in the main and sensitivity analyses.To our knowledge, this is the first study to assess the effect of different endocrine therapies on the subsequent risk of musculoskeletal problems using a real-world, population-based claims dataset of Asian women with breast cancer. Our incidence rate of any arthritis (8% to 14%) after initiation of endocrine therapy was lower than the rates reported from the previous studies 20% to 74%) , while o% to 74% Consistent with prior studies ,20,21 ouMoreover, relationships between any arthritis and carpal tunnel syndrome and other factors including age, taxane use, affective disorders, and analgesic use observed in our study have noteworthy implications for future research and patient care. AI use may increase arthritis risk or worsen arthritis symptoms, especially among older adults. Prior exposure to taxane use has been considered a risk factor of musculoskeletal problems based on one small cross-sectional study , but thiStrengths of the current study include use of a nationwide claims database that covers nearly all Taiwanese women with breast cancer, the ability to capture complete information on comorbidities, treatments, procedures, and medications reimbursed by the NHI, and use of sophisticated PS matching approaches to balance numerous confounding factors that may influence the risk estimates. Furthermore, we recognized death as a competing risk in our analysis . We applied cause-specific Cox models and included the National Cancer Institute Index  as a facOur study has several limitations. First, our study relied on administrative claims data that lacked information on cancer stage, laboratory results, and socio-behavioral information . However, we excluded women who had a history of bone metastasis and included prior cancer treatments, procedures and image work-ups as surrogates for cancer staging in our analyses. Second, due to the inherent limitations of an observational retrospective study using claims data, it is unknown whether the dispensed drugs were actually taken by the patients. Potential unmeasured confounders cannot be ruled out from our observational study. Third, we grouped women based on their initial endocrine therapy, but they might switch to different therapies. A previous study using NHIRD data has shown that 16% of the tamoxifen users switched to AIs, 6% of the AI users switched to tamoxifen, and less than 4% of women had multiple switches . If a hiIn conclusion, in this population-based study using nationwide claims data, Taiwanese women with breast cancer-initiating AIs had an increased risk of any arthritis and carpal tunnel syndrome compared to those who initiated tamoxifen. Prior exposure to taxane was not a risk factor of any arthritis and carpal tunnel syndrome. Our findings provide real-world evidence for clinicians to consider the possibility of AI-associated musculoskeletal problems when women initiate endocrine therapy and provide timely and proper management to avoid discontinuation of AI therapy.


The smallest p-value was observed for PCB-153 . Neither parity nor body mass index modified the associations. Our results do not support an association between higher MD and serum levels of PBDEs, PCBs, or PFASs commonly detected in postmenopausal women.There are little epidemiological data on the impact of persistent organic pollutants (POPs) and endocrine disruptors on mammographic density (MD), a strong predictor of breast cancer. We assessed MD in 116 non-Hispanic white post-menopausal women for whom serum concentrations of 23 commonly detected chemicals including 3 polybrominated diphenyl ethers (PBDEs), 8 per- and polyfluoroalkyl substances (PFASs), and 12 polychlorinated biphenyls (PCBs) had been measured. Linear regression analyses adjusting for potential confounders were used to examine the associations between the levels of the chemical compounds, modeled as continuous and dichotomized (above/below median) variables, and square-root-transformed MD. None of the associations were statistically significant after correcting for multiple testing. Prior to correction for multiple testing, all chemicals with un-corrected  The impact of persistent organic pollutants (POPs) on breast cancer has been of interest due to the estrogenic and endocrine disruptive properties of certain chemicals in this class ,2, althoPolychlorinated biphenyls (PCBs), a class of compounds consisting of over 200 different chlorinated aromatic hydrocarbons, are the most extensively studied POPs in relation to breast cancer risk. The manufacture of PCBs was banned in most countries during the 1980s. However, PCBs are still commonly detected in the general US population, both in blood  and in bData on other classes of POPs such as polybrominated diphenyl ethers (PBDEs) and per- and poly-fluoroalkyl substances (PFASs) remain scarce and inconsistent ,20,21,22Mammographic density (MD) is a measure of the relative amounts of epithelium and stroma in the breast and is one of the strongest known predictors of breast cancer risk ,24,25. Cn = 57).Study Participants: Study participants were drawn from control participants of a breast cancer case–control study nested in the CTS . The CTSData collection and MD assessment: Participants mailed back a signed informed consent, an HIPAA form, and a completed questionnaire on important covariates such as height, weight , menopausal status, hormone therapy (HT), location and year of recent mammogram screenings. Mammograms were collected for all 155 women. After excluding 15 mammograms presenting technical difficulties, one of the authors (GU) assessed MD for 140 mammograms using the USC Madena software, a validated computer-assisted method to quantitatively assess MD ,38,39. ILaboratory measurements: Blood samples were processed within hours of collection, and the separated serum stored at −20 °C until analysis. Laboratory methods for the measurement of serum levels of PBDEs, PFASs, and PCBs were described previously ,16,40. B 12 PCBs .2), parity , and estrogen–progestin combined hormone therapy use  at the time of mammography. Additional analyses that adjusted for the type (manufacturer) of the mammography systems , modeled the serum levels as continuous variables, and used untransformed MD did not change the results; thus, these variables were not used in the final model. We conducted stratified analyses by parity, BMI (≥25 vs. <25 kg/m2), and estrogen–progestin combined hormone therapy (never or ever used) and calculated p values for the interactions by introducing product terms and conducting Wald tests. The p-values were corrected for multiple testing using the Bonferroni method.Statistical Analysis: Analyses were restricted to 116 non-Hispanic white women due to the small numbers for each of the other race/ethnic subgroups . The association between each chemical (above vs. below median) and square-root-transformed MD was examined using multivariable linear regression, adjusting for age, body mass index (BMI)  and 138 (p = 0.010), but these associations did not remain statistically significant after Bonferroni correction , indicating an inverse association, if any. All p-values for the interactions with parity, BMI, or EPT use were >0.05 before correcting for multiple testing.Of the 23 chemicals analyzed, the smallest rrection . We did p-values of 0.03, 0.004, 0.04 (not corrected for multiple testing), which are directionally consistent with our results [MD is a strong risk factor for breast cancer and increases in response to exogenous hormone use in postmenopausal women ,38. Desp results . PBDEs aWhereas the data on MD are sparse, substances in these chemical families  have been studied with respect to breast cancer risk. Results on PCBs in relation to breast cancer risk are inconsistent with the null findings in relation to MD  were collected on average 35 months after diagnosis and treatment . AlthougCYP17A1 -34T/C (rs743572) and COMT Val158Met (rs4680) has been proposed [Similarly, PFASs were not, or were at most inversely, associated with breast cancer risk in the CTS . The onlproposed ,43; howeproposed  were onlproposed ,44. TakeOur study has several limitations, and our results need to be interpreted with caution. Our chemical measurements were based on blood samples collected at approximately the same times of the outcome (MD) measurement and were restricted to postmenopausal women. Therefore, the measured chemical levels may not represent etiologically relevant exposure. Our study cannot address the question whether elevated levels of these chemicals in earlier time periods with different hormonal milieux, such as childhood, puberty, premenopausal period or menopausal transition, are associated with MD and with breast cancer risk. Additional studies in younger women need to be conducted before excluding POPs and PFASs as risk factors in the general population. The suggestion that POPs may cause reproductive abnormalities in women , which iFindings from our cross-sectional study do not support a positive association between PCBs, PBDEs, and PFASs and MD among postmenopausal women.


To date, twenty variants in BRCA1, BRCA2, and PALB2 that predispose families to breast and ovarian cancer have been identified as recurring in the French-Canadian founder population. Our objective was to evaluate the clinical efficacy and validity of targeted genetic testing for these variants in Montreal French Canadians. A total of 555 breast cancer cases unselected for family history or age of diagnosis were genotyped, along with 1940 controls without a personal or family history of cancer. A Sequenom genotyping assay identified a pathogenic variant in 0.2% (5 of 1940) of cancer-free controls, and 3.8% (21/555) of breast cancer cases. Almost 10% (12/113) of early onset cases were heterozygous for founder BRCA1 or BRCA2 pathogenic variant. Of twenty variants tested, only seven were identified in this study. The option of providing this test as population-based screening is discussed.Inherited germline pathogenic variants are responsible for ~5% of breast cancer globally. Through rapid expansion and isolation since immigration in the early 17 A strong family history of breast and/or ovarian cancer, as well as a personal history of early-onset or bilateral breast cancer, are suggestive of a heterozygous germline variant in a high-risk breast cancer susceptibility gene. BRCA1 and BRCA2 are the canonical genes in this family2, and the risks for breast cancer to age 80 among female BRCA1 or BRCA2 heterozygotes is 72% and 69%, respectively3. Partner and localizer of BRCA2 (PALB2) is essential to homologous recombination repair in response to double-stranded breaks in DNA4 and is a more recently identified breast cancer predisposing gene. Average cumulative risk of developing breast cancer with a pathogenic germline PALB2 mutation is approximately 35% by age 70, and risk is higher in women with a family history of breast cancer (58%)5.Breast cancer is the most prevalent cancer worldwide (excluding non-melanoma skin cancer) and the second leading cause of death by cancer in womenth century. Since then, settlers from countries other than France have immigrated to Canada, but early French founders contribute more to the present genetic landscape6. Variants more prevalent in the French-Canadian population have been identified in established breast cancer predisposition genes BRCA1, BRCA2, and PALB214. For many years, genetic testing for recurrent pathogenic variants , c.3545_3546delTT (p.Phe1182Ter), and c.8537_8538delAG (p.Glu2846GlyfsTer22). Thirteen variants were not observed in any samples tested , and 21 in cases . Of the five heterozygotes in controls, two carry a pathogenic variant in BRCA1/2 heterozygotes (43.6 years) was significantly younger than that of wild-types . BRCA1 and BRCA2 heterozygotes had a mean age of diagnosis of 39.3 and 44.0, respectively (p = 0.344). When examining early-onset breast cancer cases, 12/21 (57.1%) of heterozygotes were diagnosed at 45 years or younger, compared with 113 of 534 (21.1%) in wild-types (p < 0.001). BRCA1/2 heterozygotes were more than twice as likely to have a family history of cancer  than wild-types  (Table The mean age of first invasive breast cancer diagnosis in %) Table . 17 of 2BRCA1/2 heterozygotes had other cancer diagnoses in their lifetime  of breast cancer cases unselected for age or family history and 0.2% (5/1940) of cancer-free controls. Our previous, smaller study of a series of breast cancer cases found 3.1% of French-Canadians cases had one of seven previously reported founder variants15, comparable to this study. Increasing the number of variants genotyped to twenty therefore did not increase sensitivity in this project.Genotyping BRCA116. In a study of 236 Ashkenazi Jewish women with breast cancer, one of three founder BRCA1/BRCA2 variants was found in 25% of early-onset breast cancer cases (diagnosed under 45 years of age) and 18.5% of women diagnosed after 45 years of age17. Another study of 412 Ashkenazi Jewish women found 12% of breast cancers can be attributed to one of these three founder variants18. Further, 88 of 847 unselected Icelandic breast cancer cases (10.4%) carry a known founder variant19 . No cancer-free women were identified as heterozygotes (of 969), confirming the high penetrance of these variants. FLOSSIES is a large-scale sequencing project of 9884 European and African American women above age 70 with no personal history of cancer (www.whi.color.com). A search of likely pathogenic variants in FLOSSIES  results in approximate allele frequencies of 0.03%, 0.13%, and 0.07% in BRCA1, BRCA2, and PALB2, respectively.This study found a 0.2% allele frequency for PALB2 c.2323 C > T. This was striking, as a previous study identified this variant in 0.6% (2/356) of French-Canadian early onset or familial breast cancer cases, though it was not identified in 6440 newborn controls from the Quebec City region14. The variant was identified twice more when screened for in 71 hereditary breast or breast/ovarian cancer families, indicating its association with breast cancer in French Canadians22. Another genotyping study found 0.7% of early-onset (diagnosed younger than 50 years of age) French Canadian breast cancer cases were heterozygous for this variant23. Our study was the first to genotype the variant in unselected breast cancer cases, with few early onset or familial cases, which likely accounts for the lower prevalence in this case series. PALB2 is a rare, moderate to high penetrance gene24. The lifetime risk varies by family history25. Current guidelines suggest annual mammograms for patients with PALB2 variants, with insufficient evidence to recommend risk-reducing mastectomy26. Moreover, as we did not observe this variant in any subjects in this study , screening for this variant in the French-Canadian population is not currently recommended.This study found no heterozygotes for BRCA2 variants significantly associated with affected status. One study of early-onset breast cancer cases and newborn controls in Quebec found that majority of heterozygotes identified harboured a BRCA2 founder variant rather than BRCA123. Among newborns, similar variant frequencies were found in both BRCA1 and BRCA2, comparable to control frequencies seen in this study. A similar pattern of only BRCA2 variants was seen in 127 French Canadian breast cancer cases unselected for age or family history15. There is some evidence to suggest BRCA2 variants may also be more prevalent in breast cancer cases outside of the French-Canadian population18. Taken together, it is presumed that the prevalence of pathogenic founder BRCA2 variants is higher than that of BRCA1 variants in French Canadians of Quebec.Of all variants tested, only seven were identified in this case series. Notably, only 23. In another study genotyping only early-onset French Canadian cases, an identical percentage  diagnosed under 40 were found to have pathogenic variants in BRCA1 or BRCA29.Earlier age of cancer onset typically associates with genetic predisposition to breast cancer. Genotyping 20 previously reported variants in this French-Canadian series identified 12 among 125 breast cancer cases diagnosed younger than 45 years of age. Therefore, variant-specific testing was able to identify pathogenic variants in 9.6% of unselected breast cancer cases in Montreal French Canadians. This is consistent with our previous study, which found that testing for known founder variants in unselected French-Canadian cases was able to identify 13% of unselected breast cancer cases diagnosed between 25 and 4027, but this is dependent on patients opting to undergo the surgery. In a recent study looking at 128 breast cancer patients in Korea with a BRCA1 or BRCA2 carriers, only 8 chose to undergo contralateral prophylactic mastectomies28.Among French-Canadians of Quebec who carry BRCA1 or BRCA2 variants, preventive options including bilateral prophylactic mastectomies are less popular than in other regions of Canada29, with only 8% of Quebec women heterozygous for a pathogenic variant opting for the surgery compared to 22–46% in other regions of Canada. Despite this, population-wide genetic screening could identify up to 10% of early-onset cases prior to a diagnosis. This would provide more options for these women as well as potentially increasing awareness of these options in the general population and improving the acceptability of such preventive intervention measures among Quebec women.Our study identified heterozygotes for seven pathogenic variants that accounted for approximately 10% of early onset cases, and as high as 25% of early onset cases with a self-reported family history of cancer. The women with a founder variant in their germline likely were not tested previously and may not be aware of their elevated risk of breast cancer. With this knowledge, family members could be screened and heterozygous women would have the option to take preventive measures for breast cancer. Prophylactic mastectomies are likely effective in reducing breast cancer incidenceBRCA1 or BRCA2 heterozygotes. Notably, many of these heterozygotes would not have been identified following government-suggested guidelines for genetic testing (such as the NCCN in the United States). Large-scale genotyping of founder variants in the French-Canadian population may therefore be a feasible choice that would be more effective in identifying heterozygotes than the current standard of evaluating family history alone30.Population-based screening for cancer predisposition has previously been tested in founder populations such as Ashkenazi Jews and Poles. Testing for two to three founder variants in each population served as a cost-effective method in each case to screen large cohorts of individuals and was able to identify up to 4.5% of individuals as 30. Preventive strategies such as prophylactic mastectomies and salpingo-oophorectomies of known heterozygotes are also more cost-effective than typical MRI-based screening. Psychological impact is also a factor to be considered: Are patients relieved or worried when receiving a positive test result for pathogenic BRCA1/2 variants? One study found that the psychological burden associated with population-based screening  is not significantly different from that of standard family-based screening31. Another study found that Black women with breast cancer will only choose to have BRCA1/2 testing if the test is both necessary and affordable32. More work is needed to examine the accessibility and affordability of population-based screening.Health economic analyses of population-wide genetic screening found screening for founder variants is likely affordable for some healthcare systemsIn our study, one in 10 early-onset cases was heterozygous for one of seven founder variants. Providing population-wide screening to French Canadians would be feasible, and these numbers suggest the impact on breast cancer incidence would be positive, though economic costs and psychological outcomes would need to be evaluated.http://rrcancer.ca/en/home/) solid tumor breast cancer biobank. Eligible breast cancer cases included women with a surgically-resectable invasive breast cancer diagnosis at under 70 years of age and French-Canadian descent . Controls were French Canadian as determined by French first language, Canadian origin of all four grandparents and a city of birth within Quebec. Participants reported no personal history of cancer and no cancer in any first-degree relatives. Controls for this study were restricted to individuals recruited within the greater Montreal area . Methods were carried out in accordance with relevant guidelines and regulations.14 SNP/indel pathogenic variants were genotyped in breast cancer cases and cancer-free controls. These included 11 BRCA1 variants, 8 BRCA2 variants, and 1 PALB2 variant. DNA samples were subjected to whole genome amplification using the Qiagen REPLI-g Mini Kit according to manufacturer’s instructions. Genotyping was performed using the Sequenom iPLEX Gold Genotyping Technology34 with at least 600 ng of whole-genome-amplified DNA per sample through the McGill University and Genome Quebec Innovation Centre. Exactly 346 samples failed the Sequenom assay for PALB2 c.2323 C > T (p.Gln775Ter) only. To resolve this deficiency, genotyping was complemented by a PALB2 exon 5 high resolution melting assay for the variant, as previously described35. Genotyping failed for 90 samples at all loci ; these samples were removed from the analysis.Twenty previously reported® Peltier Thermal Cycler for 35 cycles at 95 °C for 30 seconds, 60 °C for 30 seconds, and 72 °C for 30 seconds, followed by 72 °C for 3 minutes. PCR products were diluted 2X with formamide and bromophenol blue loading buffer, then loaded on a 1.5% agarose gel with RedSafe Nucleic Acid Staining Solution. PCR products were then Sanger sequenced through the McGill University and Genome Quebec Innovation Centre with the forward primers used in Sequenom genotyping.Select germline heterozygotes were confirmed by amplifying the region of interest by polymerase chain reaction (PCR), followed by Sanger sequencing. PCR reactions were performed in 25 uL volumes containing 20 ng genomic DNA; 10 x PCR buffer with 15 mM magnesium chloride (Qiagen); 100 uM of each dATP, dCTP, dGTP, and dTTP; 25–35 nmoles of each primer used in Sequenom genotyping; and 2.5 units/uL HotStarTaq DNA polymerase (Qiagen). Reactions were amplified in a Bio Rad DNAEnginep < 0.05 as a significance cut-off. Comparisons of means were conducted using a two-tailed T-test, using p < 0.05 as a significance cut-off. All statistical analyses were conducted in RStudio Version 1.1383.All comparisons related to breast cancer cases are based on the first invasive breast cancer diagnosis for each patient. Comparisons of proportions were conducted using Fisher’s Exact Test, using This study was supported by a grant from the Quebec Breast Cancer Foundation (QBCF) to WDF. SB received personal financial support from a Canadian Institute for Health Research CGS-M grant and a Research Institute of the McGill University Health Centre Masters Studentship Award.Supplementary information.


Earlier age at menarche is an established risk factor for breast cancer. While age at menarche has been fairly stable over the past half-century, age at breast development (thelarche) has continued to decrease. Recently, earlier age at thelarche and a longer time between thelarche and menarche  were shown to be associated with increased breast cancer risk. Our objective was to examine how breast cancer risk was associated with pubertal timing and tempo in a prospective US cohort.N = 50,884). At enrollment, participants reported their ages at thelarche and menarche. Pubertal tempo was age at menarche minus age at thelarche. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each pubertal milestone and risk of breast cancer  using Cox proportional hazards regression. We examined whether associations between age at thelarche and breast cancer risk were modified by birth cohort, race/ethnicity, weight at age 10, and extent of breast cancer family history, as characterized by a Bayesian score based on first-degree family structure.Women ages 35–74 years without a history of breast cancer, but who had a sister previously diagnosed with breast cancer, were enrolled in the Sister Study from 2003 to 2009 (During follow-up (mean = 9.3 years), 3295 eligible women were diagnosed with breast cancer. Early ages at thelarche  and menarche  were positively associated with breast cancer risk. Pubertal tempo was not associated with breast cancer risk . When considering early thelarche (< 10 years) and early menarche (< 12 years) jointly, women with both had a 30% greater risk of breast cancer compared with women with neither risk factor (95% CI 1.07–1.57). The association between age at thelarche and breast cancer risk did not significantly vary by birth cohort, race/ethnicity, childhood weight, or Bayesian family history score.Earlier ages at thelarche and menarche may enhance susceptibility to breast carcinogenesis. Age at thelarche is an important risk factor to consider given secular trends towards earlier development. Earlier age at menarche is an established risk factor for breast cancer . Age at . Earlier thelarche and longer time period between thelarche and menarche were independently associated with a 20–30% increased risk of breast cancer in the Generations Study cohort [ In contrast to age at menarche, few studies have examined other pubertal markers in relation to breast cancer risk, particularly age at thelarche. The timing of thelarche may be more biologically relevant to breast cancer risk than the timing of menarche as thelarche represents the onset of the vulnerable window of rapid breast developmenty cohort . In thaty cohort . Age reay cohort , a pubery cohort . An invey cohort –17, but y cohort , studiesOur objective was to examine associations between pubertal markers and breast cancer risk in a prospective US cohort. These markers include age at thelarche, age at menarche, age at attainment of adult height, and the timing between these events. Given recent secular declines in age at thelarche , 4, 5, wThe Sister Study is a prospective cohort designed to investigate environmental and genetic risk factors for breast cancer . From 2Women completed a computer-assisted telephone interview at baseline which included information on demographics, medical and family history, and reproductive and lifestyle factors. During follow-up, women are asked to complete annual health updates and more extensive questionnaires every 2–3 years. Response rates have ranged from 91 to 96% throughout follow-up . This anAll participants provided written informed consent. The institutional review boards of the National Institute of Environmental Health Sciences, National Institutes of Health, and the Copernicus Group approved the study.Participants reported diagnoses of breast cancer on annual health updates and detailed follow-up questionnaires. Women who reported an incident breast cancer were asked for diagnostic information and permission to obtain medical records, including pathology reports. Medical records and/or pathology reports were obtained for more than 80% of women with a self-reported breast cancer. Agreement between self-reports and medical records has been high  , so selfDuring the baseline interview, women reported the age in years when they first noticed their breasts developing. Women who did not know the age were asked to report their grade in school, which we converted to age (1.2% of the cohort reported grade). Women also reported the age in years and months when they had their first menstrual period. If age was unknown, women were asked to report their school grade  or if their period started before, around the same time as, or after other girls . We truncated age at menarche at years since few women reported months (~ 3%). Women responded to the question “How old were you when you first reached your full adult height? This is usually before the age of 20” with age in years. Women who did not know the age were given categorical options of 10–13, 14–17, and 18–20 years . We calculated thelarche-menarche tempo as age at menarche minus age at thelarche and menarche-adult height tempo as age reached adult height minus age at menarche.n = 738); women with implausibly late ages (n = 260), defined as ≥ 21 for thelarche, ≥ 22 for menarche, and ≥ 26 for age reached adult height; and women who reported never having a menstrual period (n = 7). We selected these cut-offs to define implausible ages after exploring the distributions of self-reported ages at pubertal events in our data, as well as reviewing previous literature [n = 112) for a final analytic sample of 49,686 women.Of the 50,884 women enrolled in the cohort, we excluded 3 women who withdrew their data from the study; 75 women diagnosed with breast cancer prior to, at the same age as, or unknown relative to the completion of all baseline study components; and 3 women with uncertain cancer diagnoses  and 95% confidence intervals (CIs) for associations between pubertal exposures and breast cancer risk. Women accrued person-time from age at study enrollment until age at diagnosis of breast cancer or age at last study follow-up, loss to follow-up, or death. We tested for violations of the proportional hazard assumption using Wald or joint Wald tests of interaction terms between exposures and follow-up time. The assumption was not violated for the exposures of interest except where noted in table footnotes for secondary analyses.We examined pubertal timing and tempo variables continuously and in categories. We considered models using the same categories examined in the Generations Study . We straWe modeled each pubertal exposure separately since exposures were correlated . We also examined effect modification by familial risk using a continuous Bayesian family history score (BFHS) incorporating the family size, number of breast cancer cases in first-degree relatives, age at diagnosis for cases, and current age or age at death for non-cases .We examined whether associations between age at thelarche and breast cancer risk were modified by birth cohort, race/ethnicity, weight relative to peers at age 10 years (heavier vs. same weight or lighter), and height relative to peers at age 10 years  through stratification and tested for statistical heterogeneity using the Wald or joint Wald test. We excluded women with missing data for the modifier of interest in stratified models and also in models including main effects and interaction terms that tested for statistical heterogeneity . Thils, see . We straWe considered heterogeneity in the association between age at thelarche and breast cancer risk by tumor invasiveness, estrogen receptor (ER) status, and menopausal status at diagnosis. For models examining invasive and DCIS disease separately, women with the alternate type were censored at age at diagnosis. For ER status, we included invasive and DCIS cases and censored women with the alternative subtype, with missing subtype information, or with a borderline test result at age at diagnosis. We calculated effect estimates and tested for statistical heterogeneity by invasiveness and ER status using fully adjusted joint Cox models additionally stratified by type . We censWe conducted sensitivity analyses to consider how error in the recall of age at thelarche may have biased associations between age at thelarche and breast cancer risk. Because thelarche is expected to occur prior to menarche, we assumed that thelarche occurred either 1 year or 2 years earlier than what they had reported for women who reported that thelarche occurred at the same age or later than menarche (tempo ≤ 0 years) in order to quantify the bias arising from misclassification of age at thelarche. We also ran analyses restricting the study population to women more likely to have accurate recall. We limited models to women younger than 60 years at enrollment, as older women may be less likely to accurately report age at thelarche. In separate models, we excluded women with implausible thelarche-menarche tempo, as extreme tempos may reflect inaccurate reporting of age at thelarche. We defined implausible thelarche-menarche tempo in three ways: (1) tempo below the observed 5th percentile (menarche reported > 2 years before thelarche) or above the 95th percentile (menarche reported > 3 years after thelarche), (2) tempo < 0 years (menarche reported before thelarche) or > 4 years, and (3) tempo ≤ 0 years (menarche reported at the same age or prior to thelarche).We recalculated thelarche-menarche tempo after adjusting age at thelarche as described above in sensitivity analyses examining thelarche-menarche tempo and breast cancer risk. We also ran tempo analyses excluding women ages 60 and older at enrollment. In addition, we conducted a probabilistic bias analysis of the thelarche-menarche tempo and breast cancer relationship. To do so, we first evaluated the distribution of pubertal tempo among women who reported that menarche occurred at least 1 year after thelarche. We then assigned women with a thelarche-menarche tempo ≤ 0 years a new tempo value based on a random draw from that distribution. We ran this simulation 20 times and combined the measures of association from fully adjusted Cox models across datasets using Rubin’s rules .We used robust variance estimates to account for correlations between sisters in the study sample. We conducted analyses using SAS 9.4 (SAS Institute Inc.).r = 0.6) and age reached adult height (r = 0.3), and negatively correlated with time from thelarche to menarche (r = − 0.4) . Women with thelarche prior to 10 years of age were younger at enrollment and more likely to be non-Hispanic black or Hispanic, be heavier and taller than their peers in childhood, and grow up in a poor family . Thelarche before 10 years of age was associated with a 23% greater risk of breast cancer compared with thelarche at 12–13 years , but we observed an inverse association between tempo and risk after adjusting for age at thelarche , but there was no increase in risk associated with reaching adult height at an early age Table . These pp values for the differences in the association between age at thelarche and breast cancer risk by median BFHS were 0.19 for the categorical exposure model and 0.06 for the continuous model. When BFHS was considered as a continuous variable, the heterogeneity p values were 0.33 for the categorical age at thelarche model and 0.86 for the continuous model. The association between age at thelarche and breast cancer risk did not vary by birth cohort, race/ethnicity, or relative weight or height during childhood , early thelarche (< 10 years) was associated with increased breast cancer risk, while there was no significant decrease in risk associated with late thelarche Fig. . In contAssociations between age at thelarche and breast cancer risk did not differ significantly by tumor invasiveness, menopausal status at diagnosis, or ER status  . We did Age at thelarche has declined over time , and thiThe attributable risk of breast cancer due to earlier puberty may be higher in populations where early thelarche is more common. Age at thelarche is earlier, on average, in black and Hispanic girls in the USA than in non-Hispanic white girls , 19. In Women in our study have at least one sister with breast cancer and have, on average, approximately twice the risk of breast cancer than women without a first-degree family history . The conConsistent with prior studies , we alsoWe did not observe an association between the time from thelarche to menarche, or tempo, and breast cancer risk, in contrast to the positive association observed in the Generations Study . Our cohWe also observed a decreased risk of breast cancer associated with reaching adult height at a later age. Our findings are consistent with previous studies , 13–17, Strengths of this study include the large sample size; prospective design, which limited differential recall of pubertal timing by breast cancer status; and inclusion of multiple pubertal markers. We were able to assess whether the association between age at thelarche and breast cancer risk varied by breast cancer characteristics including ER status. We further examined effect modification by factors associated with early thelarche, including race/ethnicity, childhood body size, and extent of breast cancer family history, which to our knowledge have not been investigated previously.Analyses were limited by recalled data on ages at pubertal milestones, which may be reported with error. We categorized the exposures to limit bias resulting from measurement error, although we also examined ages at pubertal milestones continuously to facilitate comparisons with prior studies. The validity of age at menarche, for example, has been shown to be improved when categorized as early, normal, and late . Age at Our findings suggest that earlier age at attainment of pubertal milestones may enhance susceptibility to breast carcinogenesis. Early age at thelarche is an emerging breast cancer risk factor that may have considerable public health impact, given secular declines in age at thelarche in the USA and abroad. Studies with prospective measures of pubertal tempo are needed to clarify whether the time between thelarche and menarche is a particularly vulnerable period in relation to breast cancer risk.Additional file 1: Figure S1. Flow chart of eligible study population.Additional file 2: Table S1. Spearman correlations between pubertal variablesAdditional file 3: Table S2. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between age at thelarche and incident breast cancer in the Sister Study cohort stratified by characteristics associated with age at thelarcheAdditional file 4: Table S3. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between age at thelarche and incident breast cancer in the Sister Study cohort by breast cancer characteristicsAdditional file 5: Table S4. Sensitivity analyses for the association between age at thelarche and incident breast cancer in the Sister Study cohortAdditional file 6: Table S5. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between pubertal timing and tempo and incident breast cancer in the Sister Study cohort using the same categories as in the Generations Study [ns Study


Dear Editor,Breastfeeding and its duration appear to have a protective effect against the risk of breast cancer, especially for women with mutations in predominantly the BRCA1 gene but also the BRCA2 gene. The interaction between breastfeeding and cancer is an area of significant importance that should be highlighted when engaging during antenatal care.1 have shown that if women in developed countries were breastfeeding six months longer there would be a 5% reduction in the incidence of breast cancer every year. However, if they had been breastfeeding for more than 12 months, the reduction would be 11%. Similarly, Jernstrom et al.2 found that women with a mutation in the BRCA1 gene, who were breastfeeding their babies for over one year, were 45% less susceptible to breast cancer compared to those who did not breastfeed. In contrast, they found no correlation between maternal breastfeeding and women with mutations in the BRCA2 gene.Specifically, Giudici et al.3 in a Sri Lanka population suggested that an average of 12 months or more of breastfeeding reduces the risk of breast cancer. In particular, they found that for a breastfeeding duration of 12 to 23 months, the risk of developing breast cancer decreased, as supported by the study of Awatef et al.4 that noted a significantly reduced risk of breast cancer for women who had 2 to 3 children and a breastfeeding duration of 72 months.Research by De Silva et al.5, it was found that breastfeeding protects against the incidence of breast cancer in women with the BRCA1 gene mutation. In contrast, maternal breastfeeding is not protective of women with BRCA2 gene mutation, possibly due to different mechanisms of carcinogenesis.In another study, by Kotsopoulos et al.1 found that breastfeeding reduces the likelihood of another Luminal B invasive breast cancer in premenopausal White women for every 12 months of breastfeeding. In contrast, it does not appear to reduce the likelihood of developing a milder type of breast cancer such as Luminal A.Furthermore, Giudici et al.6 in a Korean population have shown that the combination of an increase in the breastfeeding period to over 13 months and having at least two children leads to a reduction in the risk of breast cancer by 50%. Additionally, women who had been breastfeeding for more than 25 months had a reduced risk of breast cancer by 56%, regardless of their menopausal status. Finally, even women having only one child may have a reduced risk of developing breast cancer after breastfeeding.Results of research by Jeong et al.The benefits of breastfeeding for mothers, infants, the economy and the environment are of unparalleled value. Hence, it is essential in midwifery practice to further raise awareness among health professionals, women and young mothers regarding the advantages of breastfeeding, so that more mothers and infants enjoy the benefits of breastfeeding, which may also provide long-term protection against breast cancer.


Endometrial cancer is the most common gynecologic cancer and is predominantly endocrine-related. The role of unopposed estrogen in the development of endometrial cancer has been investigated in numerous studies. Different reproductive factors such as younger age at menarche, late age at menopause, infertility, nulliparity, age of birth of the first child, and long-term use of unopposed estrogens during hormone replacement therapy have been associated with an increased risk of endometrial cancer. In contrast, there is a growing body of evidence for a protective role of oral contraceptives. Most of the published data on the association between infertility and polycystic ovary syndrome are inconclusive, whereas the effect of tamoxifen on the risk of endometrial cancer has been well established. With this review, we aim to summarize the evidence on the association between infertility, polycystic ovary syndrome, oral contraceptives, and tamoxifen and the development of endometrial cancer. Endometrial cancer is the most common gynecologic cancer . There aThe aim of this review is to investigate the relationship between infertility, polycystic ovary syndrome (PCOS), OCs, and tamoxifen (TAM) and the risk of endometrial cancer.Various previous studies suggested a correlation between nulliparity and endometrial cancer . HoweverFor example, a pooled analysis of 2 cohort studies and 12 case–control studies with 8153 cases and 11,713 controls investigated the association between infertility and incident endometrial cancer [This risk was similar after adjustment for infertility . Infertility itself was also associated with an increased risk of endometrial cancer risk, with OR of 1.22 (95% CI 1.13–1.33) and 1.20 (95% CI 1.11–1.30) after adjustment for parity and number of deliveries, respectively. Furthermore, the influence of several other putative risk factors of endometrial cancer was investigated. For example, a significantly elevated risk was found for anovulation/PCOS among nulliparous women, whereas an association between endometriosis and endometrial cancer risk was not statistically significant. These data demonstrate that parity and infertility independently contribute to endometrial cancer risk [The strengths of the study by Yang et al. are the large sample size and the fact that in most cases the confounding factors were adequately considered. Nevertheless, several limitations should be mentioned. The self-reported infertility raises the question of potential bias. Furthermore, the infertility definition was not consistent across the included studies, and there was a significant difference in the prevalence of infertility among cases and controls. The influence of fertility treatment was only investigated in a small number of patients. Since infertility treatment has been reported to potentially influence endometrial cancer risk , its conRecently, further observational studies have looked into the issue of infertility and endometrial cancer. For example, in a nationwide population-based cohort study, Lundberg et al. investigated the risk of breast and gynecological cancers among women with a diagnosis of infertility . They foOne of the most important drawbacks of the study by Lundberg et al. is the missing data regarding infertility, body mass index (BMI), and the use of OCs. BMI and OCs might significantly influence the risk of endometrial cancer among women with infertility and should therefore be considered relevant confounders.In another recent study, the risk of developing gynecologic cancers was analyzed in infertile US women using claims data . In thisIn summary, when taking into account the available data and the limitations of most studies, a reliable conclusion regarding the association between infertility and the risk of endometrial cancer should be made with caution. The most important challenges in analyzing such data are the low incidence of malignancies in reproductive-age women, a short follow-up in the included studies, the heterogeneity of the study populations, and the influence of additional reproductive factors such as PCOS, endometriosis, or infertility treatment, which were accounted for. In particular, the effect of infertility treatments on the risk of endometrial cancer is the topic of an ongoing debate. The available data provide somewhat conflicting results . For exaIn summary, a thorough analysis of the data especially regarding different control groups strongly suggests that the key factor triggering endometrial cancer risk might be infertility and the factors leading to and associated with infertility, rather than infertility treatment itself.The hormonal imbalance caused by anovulation in patients with PCOS is associated with unopposed estrogen action . EstrogeIn the last decade, the association between PCOS and endometrial cancer has been investigated in numerous studies. In a meta-analysis of eight eligible studies published between 1968 and 2008, an almost three-fold increased risk of endometrial cancer for women with PCOS was documented . In anotTherefore, data regarding a possible association between PCOS and endometrial cancer should be evaluated after adjustment with other well known risk factors, which are associated with PCOS . The difThe association between the prolonged use of OC and cancer has been investigated in numerous studies. Although the studies are very heterogeneous, a significant decrease of endometrial cancer incidence has been observed for women using OC compared to never users . In a reThe reduction of endometrial cancer risk was greater with a longer use of OCs. Specifically, each 5-year period of use was associated with a risk ratio of 0.76 (95% CI 0.73–0.78) and persisted for more than 30 years. The effect was observed even for OCs with higher estrogen doses used in the 1960s, 1970s, and 1980s. Of note, the effect was only significant for endometrial carcinomas , whereas no risk reduction was observed for sarcomas of the uterus . The protective effect of OC did not vary after adjustment for BMI, parity, menopausal status, smoking, and age at menarche.The strong and persisting protective effect of OCs regarding endometrial cancer was confirmed in a large retrospective study with a median follow-up of 44 years . In thisMichels et al. investigated the influence of various lifestyle characteristics on the protective effect of OCs on endometrial cancer risk. In a cohort study of 2337 women with endometrial cancer and a prior use of OCs, the modulating effect of cigarette smoking, alcohol consumption, BMI, and physical activity was evaluated in detail . In thisAll of the above cited data are supported by a systematic review regarding the use of hormonal contraceptives and the risk of endometrial cancer . This reIn conclusion, the risk of endometrial cancer is significantly lower among women who have ever used OCs. This effect persists for at least 30 years after stopping OCs and increases with a longer duration of OC use. In addition to the direct anti-estrogenic effects of synthetic progestogens used in OCs, OC use might also decrease the estrogenic effects of known risk factors for endometrial cancer.TAM is a selective estrogen receptor modulator (SERM) used for the treatment of women with breast cancer. TAM can increase the risk of endometrial pathologies such as endometrial hyperplasia and endometrial carcinoma by its estrogenic activity in this tissue . SpecifiThe relative risk to develop endometrial cancer was 2.53 (95% CI 1.35–4.97) and regarded predominantly in women aged 50 years or older. Notably, all endometrial cancers in the tamoxifen group were limited to the uterus, and no endometrial cancer-related deaths were noted. A follow-up report of this study with a median follow-up of 7 years demonstrated that the risk of endometrial cancer was even higher than previously noted, i.e., about 29% higher than in the original report . After TIt is well documented that an increased duration of TAM treatment is associated with an increased risk of developing endometrial cancer. For example, in the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with breast cancer who received TAM for 5 years were randomly allocated to continue TAM for another 5 years or to stop treatment (control group) . In thisThe pathophysiological mechanism of TAM-induced endometrial pathology could be explained by the estrogen-agonistic effect of TAM on the endometrium , specifiIn contrast to TAM, the selective estrogen receptor modulator raloxifene does not seem to increase the risk of endometrial cancer. In the NSABP STAR/P-2 trial, for example, 4739 women received TAM, and 4717 women received raloxifene . The incIn conclusion, TAM is associated with a significantly increased risk of endometrial cancer, with its longer use increasing the risk. This increased risk of developing endometrial cancer is only evident during the treatment with TAM and no longer after stopping the drug .In this review, we have summarized the evidence on the association between infertility, PCOS, the use of OCs, and the use of TAM and the risk of endometrial cancer. Although the risk-increasing effect of TAM and the risk-decreasing effect of OCs are evident and well established, the association between infertility and PCOS and endometrial cancer remains controversial, largely due to the unclear interactions with several confounders, and needs to be investigated further.


Background: Statin, a lipid-lowering drug, has been suggested to confer anticancer efficacy. However, previous studies evaluating the association between statin use and prognosis in breast cancer showed inconsistent results. A meta-analysis was performed to evaluate the association between statin use and clinical outcome in women with breast cancer.Methods: Cohort studies comparing recurrence or disease-specific mortality in women with breast cancer with and without using of statins were identified by search of PubMed, Embase, and Cochrane's Library databases. A random-effect model, incorporating the inter-study heterogeneity, was used to combine the results. Subgroup analyses were performed to evaluate the influences of study characteristics on the outcomesResults: Seventeen cohort studies with 168,700 women with breast cancer were included. Pooled results showed that statin use was significantly associated with a lower risk of breast cancer recurrence  and breast cancer mortality . Subgroup analysis showed that timing of statin use, statin type, study design, sample size, or quality score did not significantly affect the outcomes. However, statin use was associated with more remarkably reduced breast cancer recurrence in studies with mean follow-up duration ≤ 5 years  than that in studies of >5 years .Conclusions: Statin use is associated with reduced recurrence and disease-specific mortality in women with breast cancer. These results should be validated in randomized controlled trials. Although advances have been achieved in the prevention and treatment of breast cancer in recent decades, the disease remains one of the most common malignancies in women , 2. It hThe meta-analysis was designed and performed in accordance with the MOOSE   and CochElectronic databases of PubMed, Embase, and the Cochrane's Library were systematically searched using the combination of the following terms: (1) “statin” OR “3-hydroxy-3-methyl-glutaryl CoA reductase inhibitor” OR “CS-514” OR “simvastatin” OR “atorvastatin” OR “fluvastatin” OR “lovastatin” OR “rosuvastatin” OR “pravastatin” OR “pitavastatin”; (2) “breast cancer”; and (3) “survival” OR “prognosis” OR “mortality” OR “death” OR “recurrence” OR “surgery” OR “operation.” The search was limited to human studies with no restriction of publication language. The reference lists of original and review articles were also manually analyzed. The final literature search was performed on February 24, 2020.Studies were included if they met the following criteria: (1) published as full-length articles; (2) designed as cohort studies with the minimal follow-up duration of 1 year; (3) included women with breast cancer; (4) use of statin was identified as exposure of interest; (5) documented the incidence of breast cancer recurrence or breast cancer mortality during follow-up; and (6) reported the adjusted hazard ratios  and their corresponding 95% confidence intervals (CIs) for the above outcomes in women with breast cancer with and without the use of statin. Reviews, editorials, preclinical studies, and non-cohort studies were excluded.Literature search, data extraction, and study quality assessment were independently performed by two authors according to the predefined inclusion criteria. If inconsistencies occurred, discussion with the corresponding author was suggested to resolve these issues. The following data were extracted: (1) name of the first author, publication year, country, and study design; (2) characteristics, number, and mean age of women with breast cancer, definition and timing of statin use, and follow-up period; and (3) number of cases with breast cancer recurrence and breast cancer mortality, and the adjusted variables when presenting the HRs. The quality of each study was evaluated using the Newcastle-Ottawa Scale (NOS) . This scI2 statistic was also calculated. A significant heterogeneity was considered if I2 > 50%. A random-effect model was used to pool the results since this model has been indicated to incorporate of the potential heterogeneity among the included studies and therefore could provide a more generalized result. Sensitivity analysis by omitting one study at a time was performed to evaluate the stability of the results  from each study were logarithmically transformed . The Coc results . Predefi results , includi results , 25, 27, results . The RevThe flowchart of database search was shown in Overall, this meta-analysis included 17 cohort studies –28 with I2 = 26%). Pooled results with a random-effect model showed that statin use was associated with a significantly reduced breast cancer recurrence . Stratified analyses showed that the results were not statistically different between studies with statin use at the diagnosis or after the diagnosis of breast cancer  than that in studies with mean follow-up duration >5 years  with significant heterogeneity . Stratified analyses showed that the results were not statistically different for studies with statin use before, at, or after the diagnosis of breast cancer .The funnel plots for the associations between statin use and breast cancer recurrence and mortality were shown in In this meta-analysis of cohort studies, we found that compared to the non-users, statin use was associated with significant lower recurrence and disease-specific mortality in women with breast cancer, even after adjustment of potential confounding factors including age, cancer stage, and anticancer treatments. Subgroup analysis showed that study characteristics such as timing of statin use, statin type, statin exposure time, study design, sample size, quality score, adjustment of menopausal status, hormonal receptor status, or comorbidities did not seem to significantly affect the association between statin use and improved prognosis in women with breast cancer. However, a more remarkably reduced breast cancer recurrence was observed in studies with shorter follow-up duration (≤5 years) compared to that in studies with longer follow-up duration (>5 years). Taken together, these findings suggest that statin use is associated with reduced recurrence and disease-specific mortality in women with breast cancer, which supports the implementation of a randomized clinical trial.Several meta-analyses have been performed to evaluate the association between statin use and prognosis in women with breast cancer –32. AlthThe mechanisms underlying the potential association between statin use and lower breast cancer recurrence and mortality remain largely unknown at current stage. A previous cohort study including 191 Korean women with breast cancer who underwent resection showed that a higher tumor expression of HMG-CoA reductase was associated with poor disease-free survival, which suggests that the potential benefit of statin on clinical outcomes in breast cancer may involve its pharmacological effect on HMG-CoA reductase inhibiting . A recenOur study has limitations, which should be considered when interpreting the results. Firstly, although we combined HR data after multivariate adjustment, residual factors that potentially confound the association between statin use and prognosis in breast cancer may remain existing. Secondly, definition and exposure time of statin use varied among the included studies. Although our stratified analyses did not show that timing, category, or exposure time of statin use may significantly affect the outcome, these results should be validated in randomized clinical trials. In addition, our results of subgroup analyses were based on data of study level rather than individual patient level. The findings of subgroup analyses should be validated in large-scale prospective studies. Finally, a causative relationship between statin use and improved prognosis in women with breast cancer should not be retrieved from our results. Randomized clinical trials are needed to confirm whether additional treatment with statin could improve the clinical outcomes in women with breast cancer.In conclusion, our meta-analysis showed that statin use was associated with significant reduced recurrence and disease-specific mortality in women with breast cancer. These findings support the implementation of a randomized clinical trial to evaluate the potential benefits of statins on clinical outcomes in women with breast cancer.All datasets generated for this study are included in the article/supplementary files.HL and PH designed the study and drafted the manuscript. HL and DS performed database search, study inclusion, quality evaluation, and data extraction. MF, YC, FX, ZW, and YW performed statistical analyses and interpreted the data. All authors critically reviewed the manuscript and approved its submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.