Breast cancer (BC) is mainly considered a disease in women, but male BC (MaBC) accounts for approximately 1.0% of BC diagnoses and 0.5% of malignant neoplasms in the western population. The stigmatization of MaBC, the fact that men are less likely to undergo regular health screenings, and the limited knowledge of health professionals about MaBC contribute to men being diagnosed at more advanced stages. The aim of this article is to increase the visibility of MaBC among urologists, who have more contact with male patients. This review highlights key points about the disease, the risk factors associated with MaBC, and the options for treatment. Obesity and increased population longevity are among the important risk factors for MaBC, but published studies have identified family history as extremely relevant in these patients and associated with a high penetrance at any age. There is currently no screening for MaBC in the general population, but the possibility of screening in men at high risk for developing BC can be considered. The treatment of MaBC is multidisciplinary, and, because of its rarity, there are no robust clinical studies evaluating the role of systemic therapies in the management of both localized and metastatic disease. Therefore, in current clinical practice, treatment strategies for men with breast cancer are extrapolated from information arising from studies in female patients. Breast cancer (BC), despite being commonly considered a disease in women, can also affect men. However, male BC (MaBC) is rare, accounting for approximately 1.0% of BC cases and 0.5% of malignant neoplasms in the general western population . It was In Brazil, the most common cancers in men, excluding non-melanoma skin cancer, are prostate and colorectal cancers. Despite its rarity, it is estimated that MaBC accounts for at least 1% of all BC cases in the country . As 66,6Older studies have shown that the interval between symptom onset and the diagnosis of BC in men can reach 21 months, whereas more recent studies have shown that this duration can still be as long as 12 months . HistoriThe objective of this article is to increase the visibility of MaBC among urologists, as they have more contact with male patients. Here, we highlight key points about MaBC, the associated risk factors, and the options for treatment. In addition to individual factors, an increasing number of studies have shown that genetic predisposition seems to play a very important role in these patients, and this knowledge is essential for professionals to improve care for patients and their families. By expanding the information to these professionals, we hope to improve access to information and promote quality primary care for the entire population .The risk factors for female BC (FBC) are widely known. The most well-known risk factors are those that increase the time and concentration of female hormones active in the breast tissue over time. These include age (with increased incidence from 40 years old and peak incidence over 50 years old), early menarche, late menopause, indiscriminate use of hormone replacement therapy, nulliparity, late age at first pregnancy (over 30 years old), and contraceptives . In addiThere are also known risk factors for MaBC, including obesity and increased population longevity , 10; howFactors associated with an increased risk of MaBC that should be known by healthcare professionals who see these patients on a regular basis are: general  and familiar/hereditary . However, some men without these risk factors still develop CM, although in some cases there may be uninformed, unknown or incorrectly collected data. There was an increase in the incidence of MaBC in the United States from 1973 to 1998; however, associated risk factors were not analyzed . In a stThe existing studies indicate that risk factors linked to family history are highly relevant in this group of patients, and this information has the potential to change the entire approach when a man is diagnosed with BC, including assessing risk with the patient’s family , 12. WheBRCA1/2, CDH1, PALB2, PTEN, and p53. According to this increased risk, there is an indication for self-examination and clinical examination of the breasts starting at age 35. According to the recommendations followed by the AC Camargo Cancer Center do Brasil  criteria  (2021), o Brasil  for MC tBreast cancer ≤45 yearsBreast cancer ≤50 years and one of the following:b 1) Second primary breast cancerb 2) Family with breast cancer at any ageb 3) ≥1 family member with pancreatic cancerb 4) ≥1 family member with prostate cancer (Gleason score ≥ 7)b 5) Limited family history Triple-negative breast cancer ≤60 yearsBreast cancer at any age if:d 1) ≥2 family members with breast, pancreatic, or prostate cancer (Gleason score ≥7)d 2) ≥1 family member with breast cancer <50 yearsd 3) ≥1 family member with ovarian cancerd 4) ≥1 family member with male breast cancerd 5) Ashkenazi ancestryMale breast cancerPatient without breast cancer, but based on family history (discuss interpretation limitations for the family):f 1) 1st- or 2nd-degree relative meeting the testing criteriaEpigenetic events also play an important role in CMM carcinogenesis, often associated with earlier age at diagnosis, and these changes are associated with worse prognosis .ATM, BRCA1, PALB2, RAD51B, and XRCC3 have epigenetic signatures in MaBC that are absent in corresponding normal tissue and gynecomastia samples obtained from patients without cancer or with a family history of BC. The RAD51B and XRCC3 signatures can accurately discriminate MaBC from gynecomastia, with normal breast tissues showing methylation of these gene promoters at lower levels than in MaBC, suggesting the existence of a tumorigenesis pathway  (Unlike 0 years) , 15.For women, the lifetime risk of BC is one in eight, whereas for men, the lifetime risk is one in a thousand , 5. MammIn a study of 3,806 MaBC cases and 571,115 FBC cases, the mean age at diagnosis was higher in men than in women  . FurtherThe common complaints associated with FBC are often addressed in cancer prevention campaigns and are among the main motivations for seeking medical evaluation. However, as male breast complaints are rare, they are rarely commented upon, so they appear as a concern only in their occurrence, not as reasons for preventive conduct. As in women, breast complaints in men, including pain or enlargement of the mammary gland, are generally associated with benign issues (gynecomastia secondary to the use of medication) or physiological issues (teenager or senile gynecomastia). However, the presence of breast complaints, as well as misinformation on MaBC, can cause great discomfort and fear about the diagnosis  22, 23), 2322, 2The main symptom of MaBC is the presence of a painless retroareolar mass . DependiThe current recommendation of the American College of Radiology (ACR) for the assessment of palpable changes in the male breast differs in relation to the age at onset of symptoms . In patiThe main differential diagnosis is gynecomastia, which can be differentiated from carcinoma using imaging methods. As fibroadenomas and cysts are very rare in men due to the lack of development of terminal ducto-lobular units in the male breast, any solid mass identified on imaging should be considered suspicious for malignancy (BI-RADS 4). In these cases, ultrasonography-guided percutaneous biopsy followed by histological examination of the biopsy specimen is necessary. Because of the small breast dimensions, the indication for mammography-guided biopsy is very rare .MaBC usually presents on mammography as irregular, dense masses, with microlobulated, indistinct or spiculated margins, and eccentric in relation to the nipple-areola complex. Calcifications are less common than in women and present in approximately 30% of cases. On ultrasonography, the typical appearance is hypoechoic, solid, round or oval masses, with non-circumscribed margins . The higThe treatment of BC is multidisciplinary, and recognition of the histopathological subtype, as well as the initial staging, are the first steps toward optimal treatment.Surgical treatment of MaBC, whether upfront or after neoadjuvant chemotherapy, generally employs total mastectomy combined with sentinel lymph node dissection or axillary emptying because of the small breast volume and the presence of tumors close to the nipple-areola complex in most cases. Leone et al.  found thThe indication for sentinel lymph node dissection in these patients follows the recommendation for FBC, i.e., patients with no initial clinical or radiological signs of axillary metastasis (N0) or those with N1 disease with clinical and radiological complete response after neoadjuvant chemotherapy. According to Leone et al., only patients who did not undergo axillary dissection had poorer survival .A.C.Camargo Cancer Center between 2000 and 2021 included 65 men with MC, 61 of whom underwent surgical treatment, including total mastectomy (58/61) and breast-conserving surgery (3/61). Of the patients for whom we had information about the axillary approach, 38 underwent axillary dissection and 21 underwent exclusive resection of the sentinel lymph node (unpublished data).An ongoing study with patients treated at the Because of the rarity of MaBC, there are no robust clinical studies evaluating the role of systemic therapies in the management of both localized and metastatic disease. Hence, in current clinical practice, treatment strategies for men with BC are extrapolated from information arising from studies of FBC -28.Since most BCs in men are hormone receptor-positive, endocrine therapy is the mainstay of treatment in these patients. The effectiveness of hormone deprivation, which initially involves orchiectomy, has long been established in the metastatic disease setting . CurrentAromatase inhibitors  perform better in the adjuvant setting than tamoxifen for postmenopausal women and are therefore the standard adjuvant therapies for FBC . HoweverAdjuvant endocrine therapy in men with BC has potential adverse effects that, as in women, can lead to treatment dropout. Up to 50% of men do not complete tamoxifen for 5 years after surgery. Sexual dysfunction/loss of libido and weight gain are the most common adverse effects, and hot flashes, mood alterations/depression, cognitive deficits, and thrombotic events may also occur .Although the role of adjuvant chemotherapy in MaBC has not been established by prospective randomized clinical studies, observational studies have shown that it increases OS , 34. HowTreatments developed with the aim of overcoming endocrine resistance primarily in the female population, such as fulvestrant, mTOR inhibitors, and more recently CDK4/6 inhibitors and PI3K inhibitors, have also been indicated for the treatment of men with BC , 27, 35.BRCA2, the use of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) is of particular interest. In patients with these alterations, PARPi  are an important therapeutic option for metastatic disease , Leydig or Sertoli Cells;✓Adrenal: androgen - or estrogen - secreting tumors; mainly carcinomas ;✓Ectopic production of HCG (human chorionic gonadotropin), such as choriocarcinoma;Leydig cell tumors are the most common of the 5% of sex cord-stromal tumors; they are generally benign lesions, with only 5-10% being considered malignant. Due to Leydig cells’ hormonally active properties, they can present with gynecomastia (the most common hormone-related presentation), precocious puberty, breast tenderness, reduce libido, erectile dysfunction, azoospermia, primary infertility, or even Cushing syndrome .Sertoli cells tumors are often hormonally active, secreting estrogen. Males present with gynecomastia, advanced bone age, and rapid growth with short stature . These tIn the case of enlargement of the breast and palpable glandular breast tissue, it is necessary to investigate the suspected tumor, through testicular palpation, ultrasound and referral to a urologist. Likewise, breast tissue hard, non-tender and/or joining underlying structures, the need for biopsy, referral to a breast cancer specialist and oncologic treatment  should be evaluated .Steroid hormones play an important role in the tumorigenesis of both MBC and prostate cancer. Prostate cancer is androgen-dependent and responsive to androgen blockade, whereas MaBC is estrogen-dependent and responsive to estrogen blockade in the vast majority of cases . DespiteMen with BC are at an increased risk of developing second primary neoplasms. In a multicenter study that included 3409 men with BC, 426 (12.5%) developed a second cancer , which iBC accounts for approximately 0.09% of second primary cancers in men previously diagnosed with prostatic adenocarcinoma , 49. A 2Little is known about the risk of BC in transgender patients because of the small number of studies, the underestimation of the number of cases, and the lack of recommendations for specific screening. However, BC diagnoses in transgender individuals are becoming more common, and knowledge on the subject is necessary for proper care . To prop–Cisgender man (or cis man): an individual designated male at birth who identifies and lives as someone of the male gender.–Cisgender woman (or cis woman): an individual designated female at birth who identifies and lives as someone of the female gender.–Transgender man (or trans man): an individual designated female at birth who identifies and lives as someone of the male gender.–A transgender woman (or trans woman): an individual designated male at birth who identifies and lives as someone of the female gender (e gender .The risk of BC in these patients is considered to be similar to the risk of BC in cis men. Trans men frequently undergo breast reduction surgeries, similar to risk-reducing surgeries for patients with hereditary syndromes, and these surgeries, in addition to the administration of testosterone, reduce the risk of BC by approximately 90% . HoweverIt is expected that the risk of BC in this group is higher than FBC, as these patients receive female hormones; however, this increase does not reach the risk of BC in cis women . There iBRCA1 mutation. However, a BRCA1 mutation increases the risk of BC 6% in cis men and more than 78% in cis women. Therefore, if the patient does not want preventive removal of the breasts, they should be screened as high-risk cis women (In relation to screening, despite the insufficient literature on the subject, biannual mammography is indicated from the age of 50 onwards, or from 5 to 10 years after the start of female hormone administration. We also lack data to support case management of trans women with a is women  (Table-4Despite its rarity, MaBC represents an important problem in men’s health that can be neglected if professionals who have higher access to this population are uninformed. Therefore, urologists can play an important role in the early diagnosis of MaBC because their work involves a broader scenario in which the focus is greater than sexual dysfunction and screening for prostate cancer. The promotion of care, whether for cis men, trans men, or their families, is the responsibility of these professionals.


Nearly all breast cancer patients survive for more than five years when the tumor is found early and in the localized stage. Regular clinical breast examinations, mammograms, and monthly self-exams of the breasts all contribute to early detection. However, late-stage breast cancers are common in many Asian countries. Low-income countries suffer from a lack of resources for breast cancer screening. High-income countries, on the other hand, are not benefiting fully from national breast screening programs due to an underutilization of the preventive healthcare services available. Existing reviews on Asian breast cancers are heavily focused on risk factors. The question of whether we should adopt or adapt the knowledge generated from non-Asian breast cancers would benefit from an extension into screening guidelines. In addition, several Asian countries are piloting studies that move away from the age-based screening paradigm.Close to half (45.4%) of the 2.3 million breast cancers (BC) diagnosed in 2020 were from Asia. While the burden of breast cancer has been examined at the level of broad geographic regions, literature on more in-depth coverage of the individual countries and subregions of the Asian continent is lacking. This narrative review examines the breast cancer burden in 47 Asian countries. Breast cancer screening guidelines and risk-based screening initiatives are discussed. In 2020, 2.3 million new breast cancer cases were diagnosed worldwide, overtaking lung cancer as the most common cancer . Breast Breast cancer strikes Asian women earlier than it does Western women ,3. In AsIt should be noted that confounding by calendar-period and/or birth cohort effects may be an issue in cross-sectional analyses . The youWhile the burden of breast cancer has been examined at the level of broad geographic regions , literatThis narrative review seeks to provide a broad perspective on the breast cancer burden in Asia, the prevailing breast cancer screening guidelines, and risk-based screening initiatives.Publicly available data on female breast cancer statistics and estimates of age-standardized incidence and mortality for 47 countries in the Asian continent was obtained from GLOBOCAN 2020 ,8. InforThis study was not subject to an informed consent or ethical assessment as only country-specific aggregate data was used.The risk of developing breast cancer increases with age . The ageThe age-standardized mortality rate (ASMR) of breast cancer is measured as the number of deaths resulting from the disease over a specified period, accounting for the population age structure. The ASMR in 2020, expressed per 100,000 females, for Asia (11.6) is also the lowest in the world, compared to Oceania 13.2), Latin America and the Caribbean (13.5), Europe (14.8), Northern America (16.9), and Africa (19.4) [.2, LatinThe mortality-to-incidence ratio (M/I), defined as the number of deaths that occurs compared to the number of breast cancers diagnosed each year, is generally used as a high-level comparative measure to identify inequities in cancer outcomes. Although Asia has the lowest ASMR and ASIR, the M/I in Asia (0.32) is higher than the world’s average (0.28), and the second-highest in the world by region . In contWithin Asia, there is a large variation in M/I ,13,14 F. In the Income is directly associated with ASIR and inversely associated with ASMR ,16,17,18Recently, Kerlikowske and team reported that the most accurate way to define advanced cancer associated with breast cancer death was the American Joint Committee on Cancer (AJCC) prognostic pathologic stage IIA or higher . AccordiBreast cancer mortality rates in LMICs are higher than in their high-income counterparts . Timely The high proportion of late-stage breast cancers at diagnosis may pose a bigger healthcare burden on low-income countries, as the cost of breast cancer treatment increases with more advanced cancers . At the Between the 1930s and 1970s, breast cancer mortality rates remained stable . Breast Serial mammography screening in asymptomatic women can detect breast abnormalities early before any symptoms or signs are present . EvidencMammography screening is often an opportunistic event in Asia, while several European countries have reported mammography participation rates of over 75% . Only 13BRCA1/2 mutation carriers) starting from the age of 25 [Beginning in the 1990s, 13 countries in Asia have progressively implemented population-based mammography screening, starting as early as the 1990s in Israel and only in 2019 in Brunei . Overallge of 25 .Zohre Momenimovahed et al. reviewed 71 papers and found that barriers to mammography screening in Asia include factors such as personal beliefs, fatalism, fear of pain and embarrassment, religion, lack of support from loved ones, sociodemographic factors, and financial constraints . AdditioIn high-income countries such as South Korea, Japan, Singapore, Brunei, Kuwait, and Saudi Arabia, the underutilization of mammography screening is attributed to differences in insurance coverage, the lack of awareness of mammography screening in their country, and personal beliefs ,107,108.Compared to countries with national screening programs in place, LMICs have fewer mammography units; the number of mammography units per one million women aged 50 to 69 years in these countries ranges from 0 in Bhutan to less than 40 in Mongolia . MammogrThe benefits of mammography screening have been contested . DespiteThe mammography screening modality reportedly offers high sensitivity (77% to 95%) and high specificity (94% to 97%) in detecting breast abnormalities ,116. HowRadiologists face more difficulty in mammographic assessments of Asian women, given their higher breast density ,121. ForDespite advances in mammography techniques, it is estimated that 10 to 29% of breast cancers are not found by this screening modality ,126. CanWhen abnormalities on a mammogram are discovered, the patient is brought back for further imaging and tests. A false positive result occurs when diagnostic testing shows negative results and she remains cancer-free for a specified period, usually six months to a year . False pHigh false positive rates can outweigh potential survival benefits and improved quality of life, thus limiting the efficacy of mammography screening at a national level . An extrWhile considering the downsides of high recall and false positive rates, it should be noted that recall status itself may be associated with an increased risk of developing breast cancer later in life . In a stOverdiagnosis is the detection and diagnosis of non-fatal breast cancers that will not progress during a woman’s lifetime . IndolenScreen-discovered breast cancers are typically smaller than clinically detected tumors, which is attributed to a temporal shift in breast cancer detection. This lead time is the additional time that results from early diagnosis or the period of time between the time a tumor was discovered by screening and the time at which a cancer diagnosis would have been made based on symptoms . Even whOne of the practices that have been established in many Western countries is mammography quality assurance programs, which ensure high-quality screening examinations are performed . Basic rMammography quality across Asia is highly variable. A review by Siavashpour et al. suggests that quality mammography is lacking in many countries . In partCost-effectiveness analysis is an examination that compares the costs and health benefits of an intervention to that of another intervention . FactorsStudies on cost-effectiveness are based on specific assumptions  that must be met for mammography screening to be considered cost-effective ,169,170.Studies that evaluated their screening programs based on the current screening landscape found that underutilization or the overestimation of screening benefits can result in ineffective screening programs. In Singapore, the actual mammography screening participation rate is 40%, which falls short of the 50% required for the national program to be cost-effective . In HongThe current standard of care for breast cancer screening provides a uniform strategy for women in the target population based only on their age, while the best recommendations for specific subgroups of high-risk women may vary ,175,176.It has been proposed that to improve the risk-benefit ratio of mammography screening, the age-based strategy should be replaced with a stratified approach (risk-based) ,181. A sStratified screening can be accomplished using non-genetic and genetic breast cancer risk factors. A widely used non-genetic prediction tool, the Gail model , estimates a woman’s risk of developing breast cancer over time . It incowww.cancer.gov.hk/en/bctool (accessed on 1 July 2022) [Several efforts worldwide are underway to refine and tailor breast cancer screening based on individual risk ,189. A ply 2022) ,193.In Taiwan, general population screening was deemed not cost-effective and unnecessary, due to the low incidence rate of breast cancer ,194. HenBREAst screening Tailored for HEr (BREATHE) is a pilot stratified mammography screening study in Singapore . The proWith increasing interest worldwide in using a risk-based approach to breast cancer screening rather than the current age-based paradigm, a common question raised by policymakers and the public is “How much value does genetics add?”ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and breast cancer PRS [A case-only analysis by Ho et al. looked at 7600 Asian breast cancer patients diagnosed between the ages of 30 and 75 years . The brencer PRS ,198,199.Real-world applications of a stratified approach may face resistance in the adoption and implementation of new paradigms. Chong et al. conducted a scoping review and key stakeholder interviews on the topic of personalized medicine in four focus countries—Indonesia, Malaysia, Singapore, and Thailand . The stuBiobanks are an important component of personalized health and medicine, and they contribute significantly to scientific advancement in population-based disease stratification . In AsiaBreast cancer is a growing public health problem in most parts of Asia. Despite the establishment of screening guidelines globally, Asia has been slow to adopt breast cancer screening. High-income countries are not benefiting fully from national breast screening programs due to an underutilization of the preventive healthcare services available. On the other hand, LMICs are unable to adopt screening programs implemented in high-income countries, due to resource constraints. The full potential of mammography screening cannot be achieved, as there is still room for improvements in the procedure . These gaps may be filled by incorporating stratified screening, with the use of both genetic and non-genetic risk factors. However, while studies are underway to evaluate the use of these risk factors to refine individual breast cancer risk in healthy populations, questions regarding appropriate risk thresholds to define above-average risk, type of personalized screening recommendations offered, and implementation challenges, among others, remain to be answered before the verdict is out on the utility of risk-based screening. Ultimately, it is important to note that mammography screening is an imperfect test that is associated with limitations and biases, and these may undermine real survival benefits. It is important to weigh the hazards of screening against the risks of not screening.


In conclusion, smog significantly affects the risk of adverse birth outcomes by different exposure time windows.Pregnant women are more susceptible to smog pollution than the general population. This study focused on the association between smog and birth outcomes, considering both pregnant mothers and their offspring. In this retrospective study, conducted in Baoding between 2013 and 2016, we enrolled 842 participants. Birth outcomes were low birth weight (LBW), pregnancy-induced hypertension (PIH), gestational diabetes mellitus (GDM), and premature rupture of membranes (PROM). The overall prevalence of LBW, PIH, GDM, and PROM was 8.2%, 14.8%, 16.5%, and 12.1%, respectively. Compared with lower pollution level, higher pollution level of fine particulate matter (particulate matter with aerodynamics diameter <2.5 μm) (PM2.5), inhalable particle (particulate matter with aerodynamics diameter <10 μm) (PM10), and CO increased the risk of term with LBW. PM2.5, PM10, and NO Less thSmog seriously threatens human health and has become a hot topic for research and the public. Pregnant women and fetus are more susceptible to environmental factors, including smog pollution, than the general population. Exposure to PM2.5 (particulate matter with aerodynamics diameter <2.5 μm) in trimester 2 of pregnancy was associated with an increased risk of gestational diabetes mellitus (GDM) . The risApart from the adverse effects on pregnant women , smog poWith this background, we performed a population-based retrospective study in Baoding, Hebei, a region with serious fog and haze pollution in China , to exam22.12), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). Median was used to represent the average concentration of individual pollutants during different trimesters, and the category of air quality index (AQI) that corresponded to the median value was used for the statistical analysis. AQI was categorized into good, mild pollution, moderate pollution, and above (Tables A1 and A2). Classification of pollutants in the current study is based on the degree of its impact on human health. “Good” means that the air had minimal effect on healthy population, “mild pollution” indicates that pollution caused irritation symptoms in healthy population, and “moderate pollution” means that it affects the heart or respiratory system in healthy population.From October 2013 to October 2016, the ongoing population-based retrospective study was conducted mainly to investigate the impact of environmental factors on pregnant outcomes. Data on smog pollutants were obtained from the Baoding Environmental Protection Bureau, located in Baoding, Hebei, China. This bureau is a subordinate unit of the Ministry of Ecology and Environment of the People’s Republic of China, which is responsible for the supervision and administration of environmental pollution prevention and control. An automated data reporting system equipped with satellite remote sensing, meteorologic, and land use information was used to collect the 24 h average concentration of six kinds of smog pollutants, namely, PM2.5, inhalable particle (particulate matter with aerodynamics diameter <10 μm) (PM10), sulfur dioxide , gestational weight gain (n = 31), number of pregnancies and parity (n = 43), education level (n = 41), and follow-up time (n = 11). Finally, 842 women were included in the statistical analysis  women is 12.5–18.0 kg, the weight gain for normal-type (18.5 kg/m2 ≤ BMI ≤ 24.9 kg/m2) women is 11.5–16.0 kg, the weight gain for overweight (25 kg/m2 ≤ BMI ≤ 29.9 kg/m2) women is 7.0–11.5 kg, and the weight gain for women with obesity (BMI ≥ 30 kg/m2) is 5.0–9.0 kg. In different BMI groups, gestational weight gain was appropriate when it was within the recommended range. People who had weight values below the recommended range had insufficient weight gain. By contrast, people who had weight values above the recommended range had excessive weight gain   . The curThe current study also revealed that parity is a protective factor for term PROM, resulting in the gradual decrease in the risk of term PROM as parity increased , conforming to the study accomplished by Jiang et al. in Beijing .2 is a strong risk factor for GDM [No association between smog pollutants and GDM was found in this current study. However, the risk of GDM gradually increased with the increase in pre-pregnancy BMI during the entire pregnancy and individual three trimesters. Dave found that BMI ≥25 kg/m for GDM . In the  for GDM . The facIt is more comprehensive to focus on the adverse pregnancy outcomes of both pregnant mothers and the newborns in the present study. And the city we concerned could be regarded as a representative of cities with serious air pollution in North China. The results may shed light on pregnant women’s health, medical institutions’ rational resource allocations, and decision-makers’ choices of environmental measures.There are several limitations in this study. First, the lack of available information regarding physical activity, nutritional status, smoking, and alcohol consumption might have effects on the association between smog and birth outcomes. Second, this study was an observational, single-centered study. Further studies with multi-city, multi-center, and larger samples are needed for more evidence.52 increased the risk of PIH during different trimesters, while PM10 increased the risk of PROM during trimester 3. The findings of our analysis may help decision-makers to develop targeted policies and environmental measures to reduce the health hazards of air pollution.In this population-based retrospective study, the susceptible exposure windows between smog pollutants and the risk of birth outcomes were revealed. Compared with the lower pollution level, the higher pollution level of PM2.5, PM10, and CO increased the risk of term LBW during trimester 1, trimester 3, and the entire pregnancy. PM2.5, PM10, and NO


To investigate the secular trends in breast cancer burden with attributable risk factors, and make projections over time, which would contribute to the control and prevention of breast cancer.We extracted detailed data on breast cancer incident cases and age‐standardized incidence rate (ASIR), deaths and age‐standardized mortality rate (ASMR), disability‐adjusted life‐years (DALYs), and age‐standardized DALYs rate (ASDR), as well as the attributable risk factors in China from the Global Burden of Diseases Study 2019. The estimated annual percentage change (EAPC) was calculated to quantify the changing trends. The national DALYs attributable to Socio‐demographic Index (SDI) values were also presented. Projections to 2030 were estimated using the Bayesian age‐period‐cohort model.From 1990 to 2019, the number of breast cancer incident cases increased fourfold to 375,484, with deaths and DALYs over doubling to 96.306 and 2,957,454, respectively. The ASIR  and ASMR  increased, while the ASDR decreased with the EAPC of −0.13  at the same period. The ASDR varied across provincial regions, which appeared to be in a wave‐like upcurve with SDI values increasing. High body mass index became the first contribution to breast cancer DALYs for females in 2019, and alcohol use for males. Breast Cancer incident cases and deaths would increase to 587.7 and 125.6 thousand in 2030, of which there will be 577.1 and 122.7 thousand for females, and 10.6 and 2.9 thousand for males, respectively.Breast cancer remains a major public health problem in China. The absolute burden has been increasing over time, and varied across sex and regions. To control the potential risk factors and develop specific strategies will help to reduce the disease burden. The study aimed to describe the spatiotemporal trends in breast cancer burden along with the attributable risk factors in China. From 1990 to 2019, the national number of breast cancer incident cases increased fourfold to 375.5 thousand, and the number of deaths and DALYs over doubled to 96.3 thousand and 2957.5 thousand, respectively. The projected numbers will continue to increase until 2030 for both sexes. High body mass index became the first contribution to breast cancer DALYs for females in 2019, and alcohol use for males. They were reported as the annual estimates with its 95% uncertainty intervals (UIs), which were determined using the 2.5th and 97.5th centiles for a parameter estimate of the ordered 1000 draws.In GBD 2019, breast cancer was defined as the ICD‐10 code C50‐C50.9, D05‐D05.9, D24‐D24.9, D48.6, and D49.3, and the ICD‐9 code 174–175.9, 217–217.8, 233.0, 238.3, 239.3, and 610–610.9.2.2The whole estimation framework began with cancer mortality.Breast cancer DALYs were the sum of years of life lost and years lived with disability. On one hand, years of life lost were calculated as the product of estimated breast cancer deaths and the standard life expectancy at age of death. On the other hand, SEER mortality, incidence, and survival data were obtained from the SEER*Stat Databases to establish models of correlation between the relative survival and the SEER MIRs using Poisson Regression. Then these models were applied to the GBD data to calculate the relative survival data, which were further adjusted for the background mortality to calculate the absolute survival data. The prevalence was estimated by combining the survival data with the GBD incidence estimates, and divided into four sequelae: Diagnosis/treatment, remission, metastatic/disseminated, and terminal phase. Years lived with disability were calculated by multiplying the prevalence of each sequela and the disability weights for the health state associated with this sequela, and by adding the complications caused by breast cancer treatment.http://ghdx.healthdata.org/gbd‐2019/data‐input‐sources).Finally, the GBD world population age standard was used for the age standardization. An updated age‐standardized population structure was generated using the non‐weighted mean of 2019 age‐specific proportional distributions of all countries/regions with a population >5 million people in the GBD 2019 population estimates.2.3Detailed subnational estimates of breast cancer burden were not provided for China by GBD 2019, while a relevant study estimated the disease burden metrics at the province level in China using the GBD methods,2.4The attributable burden of breast cancer was estimated by the comparative risk assessment framework, which contained six steps: Inclusion of risk‐outcome pairs; estimation of relative risks (RRs) as a function of exposure; estimation of exposure levels and distributions; determination of the counterfactual level of exposure; determination of the theoretical minimum risk exposure level; computation of population attributable fractions (PAF) and attributable burden; and estimation of mediation of different risk factors through other risk factors.2.5y = α + βx + ɛ, was fitted to the natural logarithm of the rates, where y referred to ln(ASR), and x the calendar year. EAPC was calculated as 100 × (exp[β] − 1) and its 95% confidence intervals (CIs) were obtained from the linear model.CI were positive, downward if they were negative, and otherwise stable. Moreover, to explore the average annual percentage change of breast cancer ASRs in China from 1990 to 2019, we conducted the Joinpoint Regression analysis, for this model could provide visualized and interpretable results. Joinpoint Regression uses a piecewise linear‐regression to estimate the adaptive trends by one or more line‐segments,We showed the secular trend in breast cancer burden along with its attributable risk factors by sex, year, and age. The estimated annual percentage change (EAPC) was introduced to measure the temporal trends in age‐standardized rates (ASRs). A regression line, ηij = log(λij) = μ + αi + βj + γk, was fitted as a log‐linear Poisson model, in which λij indicated the number of cases, μ was the intercept, and αi, βj, γk were age, birth cohort and the period in which the event occurred, respectively.i (1 ≤ i ≤ I) indicated age group at time j (1 ≤ j ≤ J), and the birth cohort index k, k = j + M(I − i), depended on the age group and period index, as well as the width of age groups and period intervals, where M indicated the width of age groups  divided by the period intervals. BAPC model (the BAPC package via software R) fitted with Integrated Nested Laplace Approximation (the INLA package via software R) was used to project breast cancer burden by sex until 2030, based on the hypothesis of inverse‐gamma prior distribution of the GBD 2019 data we retrieved, including age, period, and cohort effects  to adjust for excessive dispersion. The reference in 2020–2030 was calculated with the positive side as increasing by 1% every year and the negative side as decreasing by 1% every year based on the observed rates in 2019. All results were visualized by ggplot2 and RcolorBrewer packages via software R (Version 4.1.3).Projected numbers and ASRs of incidence and mortality until 2030 were extrapolated from the Bayesian age‐period‐cohort (BAPC) model. The BAPC model turned out to be the most appropriate statistical methods of projecting the cancer burden compared with generalized additive model, smooth spline model, Nordpred model, Joinpoint model, and Poisson regression, especially for short‐term projections.33.1UI: 296,626, 469,983), 96,306 deaths  and 2,957,454 DALYs  occurred in 2019. From 1990 to 2019, the number of incident cases increased fourfold, and the ASIR increased with an EAPC of 2.84 . Meanwhile, the number of deaths and DALYs over doubled, but ASMR and ASDR had little change, with an EAPC of 0.06 and −0.13  and mortality  were observed in 95+ age group, and the highest age‐specific DALY rate  was in 90–94 age group , although ASDR in some high‐SDI provinces, including Beijing , Macau SAR  and Shanghai  were much lower than expected . Tobacco (5.17%) and high BMI (4.68%) were the major contribution to female breast cancer DALYs in 1990, whereas high BMI (10.76%) became the first contribution in 2019, following by tobacco (4.96%), high fasting plasma glucose (4.92%) and diet high in red meat (4.84%). For male breast cancer DALYs, alcohol use was always the first contribution (12.67%–14.80%) from 1990 to 2019.Figure In 2019, the proportion of DALYs attributable to these risk factors also varied with sex and age Figure . For bot3.4The projections of breast cancer incident cases, deaths and corresponding ASRs for 2020–2030 were presented in Figure 4In this analysis, we presented the spatiotemporal trends in breast cancer burden along with six attributable risk factors from 1990 to 2030 in China. The results suggested that breast cancer was still a major health burden for China, with 375,484 incident cases, 96,306 deaths, and 2,957,454 DALYs occurring in 2019, and the absolute burden of breast cancer would continue to increase until 2030. Breast cancer DALYs varied with the provincial SDI values, with the higher ASDR mainly observed in high and high‐middle SDI provinces. High BMI was the first contribution to breast cancer DALYs for females, and alcohol use for males.China always had the largest absolute burden of breast cancer worldwide from 1990 to 2019.A continuous increase in ASIR was found from 1990 to 2019, especially for people aged 55–85 years. China was always in an increasing aging society since early 1980s,We also found that the breast cancer ASMR and ASDR showed a slight change, or even decreased during this period, especially for individuals aged 40–59. In China, female breast cancer screening guidelines suggested that females aged 45–70 should be screened and take an ultrasound test of breast cancer every 1 to 2 years.High BMI and high fasting plasma glucose were identified as two potential risk factors contributing to breast cancer DALYs. The proportion of DALYs attributable to high BMI increased obviously from 1990 to 2019, which had become the first contribution by 2019. According to the study of NCD Risk Factor Collaboration,Male breast cancer, distinct from female breast cancer in the biological standpoint, was a rare and usually ignored disease.However, several limitations should be taken into consideration when interpreting the results. First, the disease burden of breast cancer at the provincial level in China was only assessed based on GBD 2017 from a previous study,In conclusion, we demonstrated the spatiotemporal trend in breast cancer burden along with attributable risk factors in China from 1990 to 2019, and made projections until 2030. The number of breast cancer incident cases, deaths, and DALYs in China was in an upward trend over the past three decades, and would continue to increase in the next 11 years. The socioeconomic status and relevant risk factors of breast cancer varied with sex and time, based on which the precise control and prevention strategies should be specifically developed for males and females.All authors contributed to the study design. Jie Li and Jinjin Nie performed the data collection, analysis, and result visualization. Cui Chen, Lili Wang, and Zhen Zhang contributed to the interpretations of results. The first draft of the manuscript was written by Jie Li and all the other authors carried out the manuscript revising. All authors read and approved the final manuscript.The authors have no relevant financial or non‐financial interests to disclose.https://vizhub.healthdata.org/gbd‐results/).All data could be extracted from the online Global Health Data Exchange (GHDx) query tool (The GBD 2019 study is a publicly available database and all data were anonymous. The study protocol was exempted by the Ethical Board Review of our institute.Appendix S1Click here for additional data file.


Anticancer treatment gives rise to adverse effects such as increased pain and changes to body weight and menstrual cycles, with negative effects on activities of daily living. To analyze the effect of food orientation combined with supervised  versus home-based (HB) aerobic training on lifestyle  levels), body composition, metabolic profile and cardiorespiratory fitness, among breast cancer survivors. Clinical trial study (six months) conducted at a public university in Presidente Prudente, Brazil. Twenty-three female breast cancer survivors (40-75 years old) were allocated to aerobic training groups, either FF or HB. Both groups were trained and received food orientation. They were evaluated through a dietary record, ergometric treadmill test and blood test and the Baecke questionnaire. After six months, both groups had reduced their lipid levels, total energy consumption and polyunsaturated fat intake, and had increased their PA levels and treadmill test durations. However, only the HB showed reduced carbohydrate percentage and increased folic acid; and only the FF showed reduced lipid, saturated fat and sodium levels, along with increased carbohydrate and protein levels. No differences in body composition or metabolic profile were found. These results demonstrated the feasibility of HB aerobic training. In isolation, HB showed greater regulation of carbohydrate percentage and increased folic acid levels. Moreover, these breast cancer survivors presented improvements in food consumption, PA levels and cardiorespiratory fitness, while also maintaining their body composition and metabolic profile after the intervention, independent of the group. Hormone therapy is an adjuvant treatment used by breast cancer patients to reduce the risk of tumor recurrence through hormonal blocking, among those with positive hormonal receptors.On the other hand, food orientation allied with physical activity (PA) has been demonstrated to improve quality of life among breast cancer survivors.,Home-based interventions can be developed in different areas and places, such as public squares and patients’ homes. Hence, this approach has also been used to increase adherence.Aerobic training has been the form of exercise most recommended for breast cancer patients, due to its safety.Conversely, some studies are still showing controversial results. In one such study, 22 overweight or obese black breast cancer survivors who underwent an aerobic intervention combined with nutritional counseling for 12 weeks did not show any body weight reduction.The aim of this study was to analyze the effect of food orientation combined with face-to-face versus home-based aerobic training on lifestyle , body composition, metabolic profile and cardiorespiratory fitness among women undergoing hormone therapy for breast cancer.Twenty-three women without current aerobic training who were undergoing hormone therapy (either still in treatment or with treatment concluded) for breast cancer, consisting of use of either tamoxifen or aromatase inhibitors, volunteered to participate in this study. The women who had concluded their treatment had had at least five years of hormone therapy. To be included, the participants needed to have not had any aerobic training for at least three months before the intervention. Potential participants were excluded if they presented any mental disorder or physical condition that would not allow them to perform the aerobic training. In addition, any women who were incapable of verbal communication or had physical impairments or were pregnant or breastfeeding at that time were also excluded. Participants were also excluded if they withdrew from the training or suffered any physical injuries. The women were allocated either to a face-to-face training group (FF) (n = 10) or to a home-based training group (HB) (n = 13).This study was approved by the Research Ethics Committee of the School of Science and Technology, São Paulo State University , in Presidente Prudente, Brazil, under protocol number 78971417.9.0000.5402 , and was registered at clinicaltrials.gov under the number NCT03494400 . All the procedures were conducted in accordance with the Declaration of Helsinki. Thus, potential participants were informed of the aim and procedures of the study, with a complete explanation, and those who agreed to participate signed a written informed consent statement.To recruit potential participants, phone numbers of female breast cancer patients who were undergoing hormone therapy were obtained from cancer hospitals. Social media were also used to publicize the study, in order to facilitate inclusion of women living in nearby municipalities or who were not on the phone lists. All the participants were blindly coded and allocated 1:1 with sequence boundaries in the random sequence generator random.org.The participants’ clinical characteristics were verified at the baseline through an anamnesis. All evaluations were carried out before and after the 24-week intervention.The participants’ nutritional status was determined through a dietary record, which was applied on three occasions: on two workdays and on one weekend day. This dietary record, which consisted of recording all food consumed throughout the day, was collected at the baseline and after the 24 weeks of the intervention.,In order to evaluate the daily physical activity (PA) level, the Baecke questionnaire was applied. This questionnaire has been validated for the Brazilian adult population.Anthropometric measurements were made on a mechanical scale (Filizola) to the nearest 0.1 kg; and on a fixed stadiometer (Sanny) to the nearest 0.1 cm or with a measuring tape (Sanny) to the nearest 0.1 cm. The body mass index was also calculated.,A bioelectrical impedance device  was used to obtain resistance and reactance data. The participants received recommendations regarding clothing, food and drug use, to be evaluated.The participants’ metabolic profile was analyzed by assaying their glycemia, insulin, triglyceride, total cholesterol and cholesterol fraction levels. For this, blood samples were collected in vacuum tubes with gel without anticoagulant. An enzymatic colorimetric kit was used and the samples were processed in an Autohumalyzer A5 device .The modified Naughton test was performed on an ergometric treadmill , with a maximum capacity of 180 kg, inclination of 26% and velocity of 24 km/h, in a climate-controlled laboratory. This ramp test involved incremental increases in velocity and inclination, and each stage was maintained for two minutes.The aerobic intervention combined with food orientation lasted for 24 weeks. The aerobic training followed a recommended duration of 150 minutes per week.max), according to age (220-age).,The aerobic training protocol for the FF was undertaken on an ergometric treadmill  in an air-conditioned laboratory. The participants trained three times a week on non-consecutive days . The intensity of the training was controlled using a heart rate monitor  and was adjusted for the maximum heart rate .,,Both FF and HB received dietary recommendations for breast cancer survivors,Descriptive statistics were calculated: means, confidence intervals and absolute and relative frequencies. Data normality and variance homogeneity were verified through the Shapiro-Wilk and Levene tests, respectively. The participants’ characteristics were analyzed using Student’s t test for body mass index and Fisher’s exact test for menopause status, medications, chemotherapy and/or radiotherapy utilization, cancer recurrence and/or metastases, time and type of hormone therapy used, with comparisons between FF and HB.2. The SPSS 21.0 software  was applied to perform the statistical analysis. A statistical difference was considered to be present when P < 0.05.Repeated ANOVA measurements (within-between interactions) were calculated to assess food consumption, daily PA level, body composition and metabolic profile. Subsequently, the Bonferroni post-hoc test was used to verify any statistical differences. The chi-square test and Fisher’s exact test were used to verify body composition and metabolic profile classification at the baseline and after the 24 weeks of the intervention. The chi-square test was used to analyze total cholesterol, low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol (non-HDL-C), triglycerides and glycemia; while Fisher’s exact test was used to analyze HDL-C and insulin. The effect size was calculated by means of ηpTwenty-eight women undergoing hormone therapy for breast cancer participated in this study, and 23 of them completed the 24-week intervention . It was 2 = 0.419) and difference in the time analysis , with increased levels in FF (P = 0.007). The groups differed at the baseline (P = 0.022) (We observed that the participants’ lipid consumption (g) presented reductions, as shown in the post-hoc test: for FF, P = 0.001; and for HB, P = 0.008. The percentage of lipid consumption decreased only for FF (P = 0.002). The carbohydrate percentage presented interaction  .2 = 0.602), with a reduction for FF (P = 0.010), such that there was a difference between the groups at the end of the 24-week intervention (P = 0.027). Conversely, the carbohydrate percentage (P = 0.029) presented a reduction and folic acid (mg) presented an increase (P = 0.018) in HB  and polyunsaturated fat (g) showed reductions in the FF group , as also did HB , in the post-hoc test. The FF group presented an increase in protein (%) (P = 0.005) and a reduction in saturated fat (g) (P = 0.016). The sodium level (mg) was influenced over time  in HB .2 = 0,519), with different increases in FF (P = 0.010) and in HB (P = 0.038)  and the HB group  . The dur= 0.038) .Body composition and metabolic profile did not present significant differences . NonetheIn this study, the nutritionist’s recommendations were given in person and online via smartphones. It is worth mentioning that in the literature, it has been established that informative interventions combined with aerobic training seem to be more efficient with regard to improving quality of life, compared with interventions alone.Hence, food orientation seems to be a means for changing habits. On the other hand, changes in dietary habits might also be due to alterations related to physical exercise, which generate improvements in the anti-inflammatory process. Consequently, leptin and insulin signaling in conjunction with the central nervous system improve the signaling of the satiety command in the hypothalamus.Our results showed that total energy consumption  decreased, both in FF and in HB. This finding corroborated the data in the literature. A feasibility study among 22 overweight and obese black female breast cancer survivors who participated in an aerobic intervention for 12 weeks found that reductions in energy intake and fat consumption occurred.Another noteworthy finding in this study was the decreases in macronutrient intake, such as lipid (g) and polyunsaturated fat (g) consumption. These data indicate that our intervention enabled adjustment of fat consumption in both groups and adjustment of lipid consumption in FF.We observe broader alterations in the FF group, which included simultaneously increased protein (%) and carbohydrate (g) intake, along with reduced lipid (%) and saturated fat (%) levels. However only HB showed a carbohydrate reduction (%). Especially for FF, these results indicated that the balance in macronutrient consumption was enhanced. This was possibly because the adjustments that macronutrients were able to provide to the liver and muscle fat became better. In this regard, overfeeding on sucrose and fat, combined with low protein content, has been seen to increase storage of intrahepatocellular and intramyocellular lipids, consequently increasing fat accumulation in the liver and muscles.The sodium (mg) consumption was also reduced in both groups, which seems to be a prevention factor against breast cancer recurrence. A cohort study carried out among South African women showed that there was an association between salty foods and the risk of breast cancer development during the post-menopause period.We observed that in the HB group, the amount of folic acid intake was enhanced. In both groups, folic acid patterns were within normality after the intervention. Folic acid is composed of vitamin B, which is essential for biological reactions since folates provide carbon for deoxyribonucleic acid (DNA) biosynthesis and thus assist in maintaining the gene balance. Furthermore, folate deficiency is associated with cardiovascular and brain diseases, and also cancer.In the literature, it has been proposed that changes to food habits through aerobic home-based training interventions may be a differential in clinical research. This may be due to changes in consumption of fiber and processed meat, along with better choice of purchases, such that vegetables, whole grains, proteins and legumes are bought instead of sweets and processed snacks.In the present study, similar results for FF and HB were observed regarding increases in PA levels and maintenance of body composition and metabolic profile. These results are in accordance with those from a study in which 100 women with breast cancer were assessed. The sample was separated into three groups: one of them received counselling via telephone, another received on-site recommendations and the third was a control group. The two intervention groups received counselling aimed at decreasing their energy intake, and underwent regular aerobic PA combined with behavioral therapy, for six months.Our data indicated that changes in lifestyle occurred, along with increased PA levels and improved food consumption. However, these improvements did not provide body weight loss. The results from this study are in agreement with data in the literature, in which no significant improvements in body composition were found after six months of aerobic intervention and nutritional counselling, among 61 breast cancer women undergoing chemotherapy.Regarding the effects of hormone therapy on body weight gain, no significant differences between aromatase inhibitors and tamoxifen were observed in comparison with a placebo.In this study, most of the participants were within the recommended range of metabolic profile.Clinically, cancer survivors show metabolic alterations, as well as dysfunction or increased cardiac overload, in comparison with individuals of a similar age without a diagnosis of cancer.Some limitations of the present study need to be acknowledged. These include prescription of training on the basis of HRmax, which may present variability between participants of a mean of 12 heartbeats/minute.We suggest that multicenter studies should be conducted on this population, with analysis on inflammatory cytokines, in order to better comprehend the nutritional alterations caused by the relationships of body composition and metabolic profile with the central nervous system.The aerobic intervention combined with food orientation was a feasible strategy for promoting improvements in food consumption, daily PA and cardiorespiratory fitness, and for maintaining body composition and metabolic profile, among women undergoing hormone therapy for breast cancer.The groups also stood out individually, such that in the FF group, there was greater regulation of macronutrients and, in the HB group, the folic acid level increased and the percentage of carbohydrates decreased. These results demonstrated the feasibility of HB aerobic training, as a complementary treatment for breast cancer survivors.


ANGPT2) single nucleotide polymorphisms (SNPs) and breast cancer subtypes remains unclear. This case–control study included 464 patients with malignant breast neoplasms and 539 cancer-free females. We explored the effects of ANGPT2 SNPs on the susceptibility for a malignant breast neoplasm in a Chinese Han population. Five ANGPT2 SNPs  were analyzed using TaqMan SNP genotyping. Carriers of the variant GG allele of rs1823375 were less likely than wild-type carriers to be diagnosed with clinically staged breast cancer, while females with human epidermal growth factor receptor 2 (HER2)-enriched disease carrying the CG or the CG+GG genotype at rs1823375 were significantly less likely than CC genotype carriers to be of lymph node status N1–N3. We also found that the T-T-C-A-T ANGPT2 haplotype significantly increased the risk for developing a malignant breast neoplasm by 1.385-fold . Our study is the first to document a correlation between ANGPT2 polymorphisms and the development and progression of a malignant breast neoplasm in females of Chinese Han ethnicity.Breast cancer causes morbidity and mortality among women worldwide, despite much research illuminating the genetic basis of this disease. Anti-angiogenesis therapies have been widely studied, although the association between angiopoietin-2 ( Thus, female breast cancer is a critical component of the global health burden and this disease is particularly problematic for China, because Chinese women have the highest age-standardized rates of cancer incidence worldwide 2 and breast cancer was the most commonly diagnosed type of tumor in women living in China in the year 20153.The latest GLOBOCAN estimates of cancer incidence have revealed that female breast cancer is the most commonly diagnosed cancer worldwide, with around 2.3 million cases in 2020, which equates to 11.7% of all cancer cases4, increasing numbers of women who are detected early in the disease process, as well as increased access to effective treatments for breast cancer and greater amounts of government funding for cancer control4, breast cancer remains a major health issue among Chinese women3. The current situation regarding the high burden of malignant breast neoplasms in China leaves much room for improvement.Despite recent improvements in 5-year patient survival rates (from 73% between 2003–2005 to 82% in 2012–2015)5. Several genome-wide association studies have identified gene-environment interactions and breast cancer susceptibility single nucleotide polymorphisms (SNPs) that are associated with breast cancer risk7. Thus, exploring risk-associated SNPs may help to estimate individual risks for developing breast cancer and assist with its earlier diagnosis.The precise etiology of breast cancer remains unclear, although the main risk factors have been identified as female gender, older age and having a family history of breast cancerANGPT2) is a protein coding gene found on chromosome 8 that is capable of serving as a permissive angiogenic signal in the presence of the angiogenic inducer, vascular endothelial growth factor (VEGF), as this combination may facilitate endothelial cell migration and proliferation, whereas in the absence of VEGF, ANGPT2 induces endothelial cell apoptosis and subsequent vascular regression9. Interestingly, a case–control study involving Turkish patients with gynecological cancers found no evidence in support of DNA sequence variations in VEGF and ANGPT2 genes and their contribution to ovarian, cervical and endometrial cancers10. In contrast, in a study involving 421 critically ill patients with acute kidney injury (AKI) who were of European ancestry, a genetic variant (rs2920656) near the ANGPT2 gene significantly lowered the risk of developing the AKI sub-phenotype AKI-SP2 and lowered plasma Ang2 levels11. In a study that enrolled Chinese Han subjects, those who had the ANGPT2 SNP rs12674822 were at increased risk for rheumatoid arthritis12, while another investigation that also involved Chinese Han subjects reported that two ANGPT2 SNPs, rs12674822 and rs11137037, were correlated with the development of lung cancer and its progression13. These findings suggest that it is worth exploring a possible correlation between ANGPT2 gene polymorphisms and breast cancer diagnosis.Angiopoietin-2 . Clinicopathological data included age, cigarette smoking status, alcohol consumption, clinical stage, pathological grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 status. Pathohistological diagnosis relied on the World Health Organization breast tumor classification criteria and tumors were graded by the Scarff-Bloom-Richardson method16. Malignant breast neoplasms were classified into the following 4 subgroups: Luminal A ; Luminal B ; HER2-enriched , or as triple-negative breast cancer 19. A standardized questionnaire at study entry collected sociodemographic data and electronic medical records provided clinicopathological information.Between 2013 and 2018, we enrolled 464 female patients (cases) diagnosed with a malignant neoplasm of the breast at Dongyang People's Hospital  and 539 healthy, cancer-free females (controls), each of whom provided one 5-mL blood sample. The control group inclusion criteria specified that the enrolled patients underwent physical examination in the same hospital. A healthy status was defined as an absence of cancer history or other chronic diseases. Fully informed written consent was obtained from all study participants before study entry. The trial was performed in accordance with the principles of the Declaration of HelsinkiANGPT2 SNPs selected for this study were identified from multi-allelic copy number variation (CNV) profiles encompassing the q23 region of chromosome 8 containing ANGPT2 genes. We screened some of these ANGPT2 SNPs with minor allele frequencies > 5% from the records held on the 1000 Genome Projects website , to ensure the accuracy of our genotyping. Finally, nonsynonymous SNPs rs2442598, rs734701, rs1823375, 11,137,037, and rs12674822 were selected and validated by the Single Nucleotide Polymorphism database (dbSNP) (https://www.ncbi.nlm.nih.gov/snp/), as previously described20.The 20. Extracted DNA was stored at − 20 °C and prepared for genotyping by polymerase chain reaction (PCR). DNA was dissolved in TE buffer  and stored at − 20 °C until quantitative PCR analysis. Five ANGPT2 SNP probes were purchased from Thermo Fisher Scientific Inc. (USA), and allelic discrimination analysis of ANGPT2 SNPs was assessed using a QuantStudio™ 5 Real-Time PCR system , according to the manufacturer’s instructions. Data were further analyzed with QuantStudio™ Design & Analysis Software (Applied Biosystems)23. Genotyping PCR was carried out in a total volume of 10 μL containing 20–70 ng genomic DNA, 1 U Taqman Genotyping Master Mix (Applied Biosystems) and 0.25 μL probes. The protocol included an initial denaturation step at 95 °C for 10 min, followed by 40 cycles of 95 °C for 15 s and 60 °C for 1 min.Total genomic DNA was extracted from peripheral blood leukocytes using a QIAamp DNA blood mini kit , according to the manufacturer’s instructionsANGPT2 rs2442598, rs734701, rs1823375, rs11137037 and rs12674822 in the cancer-free controls (2 degrees of freedom [df2]). Between-group differences were considered significant if p-values were less than 0.05. Since the data were independent and normally distributed, chi-square analysis or the Fisher’s exact test was used to compare relationships between ANGPT2 SNPs and clinicopathological parameters. Odds ratios (ORs) with their 95% confidence intervals (CIs) calculated associations between genotype frequencies and the risk of a malignant breast neoplasm. To further exclude the impact of confounding variables, adjusted odds ratios (AORs) with 95% CIs were estimated by multiple logistic regression models that controlled for age. Analysis of variance (ANOVA) was used to compare the age distribution of the cases and controls, and the Scheffé test was applied for post hoc analysis. The linkage disequilibrium (LD) haplotype analysis was observed using Haploview software (version 4.2) analysis.Testing for Hardy–Weinberg equilibrium was performed to examine the genotypic frequencies of p < 0.05). The majority of study participants did not smoke cigarettes or consume alcohol; among those who did, smoking was significantly more common in the control cohort than in the case cohort , while alcohol consumption was more common among cases than controls . Most cases were diagnosed with clinical stage I/II disease (78.7%), but pathological grade II/III (90.3%). Tumors were mostly ER+ (71.8%), PR+ (59.7%), or HER2– (66.6%)  in controls. The frequencies of rs734701, rs1823375, rs11137037 and rs12674822 also satisfied the Hardy–Weinberg equilibrium . In cases and controls, most of those with the rs2442598 SNP and rs11137037 SNP were homozygous for the AA genotype, most of those with the rs734701 SNP were homozygous for the TT genotype, most of those with the variant rs1823375 were homozygous for CC, while most of those with the variant rs12674822 were homozygous for GG  and clinical stage  was observed, which persisted when estimated by multiple logistic regression models   , which was therefore chosen as the reference. Compared with the reference, the T-T-C-A-T ANGPT2 haplotype significantly increased the risk for developing a malignant breast neoplasm by 1.385-fold  (Table ANGPT2 SNPs is shown in Fig. We further explored the haplotypes to evaluate the combined effects of the C-C-A-G 2.4%, whicC-C-A-G 2.4%, whic26. A recent investigation attributed 18% of the familial risk of breast cancer risk to SNPs6, although any potential correlation between ANGPT2 gene polymorphisms and malignant breast neoplasms has not been explored so far. Previous studies have reported finding similar genetic characteristics in breast tumors for Chinese Han women and women of European ancestry28. ANGPT1, ANGPT2 and FGF2 have been linked in a US study to pathological complete responses to bevacizumab, the first approved recombinant humanized monoclonal antibody for breast cancer29, although most investigations into breast cancer genetic polymorphisms have focused on BRCA1/231. Our previous work found nonsynonymous ANGPT2 gene polymorphisms in lung and colorectal cancers20, which suggests that ANGPT2 SNPs might also be associated with a risk for breast cancer. It is therefore important and appropriate to investigate the impacts of ANGPT2 genetic variants upon the risk of malignant breast neoplasms among women of Chinese Han ethnicity.Several genome-wide association studies have used genetic SNPs as potential markers for early diagnosis and targeted therapy in breast cancerANGPT2 SNPs. We therefore sought to determine whether any of the ANGPT2 SNPs correlated with clinical status or the pathological grade of the tumors. In analyses adjusted for confounding factors, patients carrying the GG allele at rs1823375 were at lower risk for developing clinically staged breast cancer. Interestingly, our previous research revealed that this variant rs1823375 increased the risk of colorectal cancer in a Chinese Han cohort20. A possible explanation for this difference in risk between different cancer types is that gender has disparate effects, but this requires further research.Based on blood samples from 539 healthy, cancer-free women and 464 women with malignant breast neoplasms, we found no significant between-group distribution frequencies for any of the five + disease. A recent study reported that stromal overexpression of the SNAIL transcription factor SNAI2 is linked to poor prognosis in patients with Luminal B HER2+ breast cancer, while the absence of SNAI2 in the stroma of Luminal B HER2+ breast tumor cells is associated with lower levels of plasma Ang232. Another study has indicated that ANGPT2 variants rs2515409 and rs13269021 are associated with pathological complete responses to bevacizumab treatment in breast cancer29. Accordingly, ANGPT2 mRNA levels and survival rates in women with breast cancer deserve more investigation in future clinical trials.We also found that the variant rs1823375 lowered the risk of developing lymph node metastasis in patients with HER233. Haplotype analyses can provide significant statistical power for clarifying the contribution of genes to disease susceptibility34. To analyze the common haplotypes, we used Haploview software and the PHASE program. As shown in Fig. ANGPT2 variants investigated in this study upon the risk of a malignant breast neoplasm, we found that the TTCAT haplotype increased the risk. It is possible that the ANGPT2 TTCAT haplotype is in LD with other functional polymorphisms that increase the susceptibility for a malignant breast neoplasm.LD in the human genome is critical for genetic variation and features in the detection and treatment of diseaseANGPT2 SNPs and susceptibility to malignant breast neoplasms in our study population. Potential limitations include the possibility that the study observations merely reflect a cross-sectional relationship instead of actual causality. Moreover, the study participants were all enrolled from only one hospital, which gives rise to possible selection bias. Lastly, our modest sample size requires a larger, independent cohort study to confirm our findings.The main strength of our study is its systematic analysis of ANGPT2 gene variants and susceptibility for a malignant breast neoplasm and its progression among Chinese Han women. In this study, the ANGPT2 rs1823375 polymorphism appeared to be protective against clinically staged breast cancer and also lymph node disease, while the T-T-C-A-T ANGPT2 haplotype appeared to significantly increase the risk for developing a malignant breast neoplasm. These findings suggest that the rs1823375 polymorphism can serve as a diagnostic marker for malignant breast neoplasms.In conclusion, our systematic genotyping results demonstrate an association between


Breast tissue enhances on contrast MRI and is called background parenchymal enhancement (BPE). Having high BPE has been associated with an increased risk of breast cancer. We examined the relationship between BPE and the amount of fibroglandular tissue on MRI (MRI-FGT) and breast cancer risk factors. This was a cross-sectional study of 415 women without breast cancer undergoing contrast-enhanced breast MRI at Memorial Sloan Kettering Cancer Center. All women completed a questionnaire assessing exposures at the time of MRI. Prevalence ratios (PR) and 95% confidence intervals (CI) describing the relationship between breast cancer risk factors and BPE and MRI-FGT were generated using modified Poisson regression. In multivariable-adjusted models a positive association between body mass index (BMI) and BPE was observed, with a 5-unit increase in BMI associated with a 14% and 44% increase in prevalence of high BPE in pre- and post-menopausal women, respectively. Conversely, a strong inverse relationship between BMI and MRI-FGT was observed in both pre-  and post-menopausal  women. Use of preventive medication  was associated with having low BPE, while no association was observed for MRI-FGT. BPE is an imaging marker available from standard contrast-enhanced MRI, that is influenced by endogenous and exogenous hormonal exposures in both pre- and post-menopausal women. While MPD is considered to be one of the strongest, established risk factors for breast cancer3. The amount of fibroglandular tissue in the breast can be assessed volumetrically on MRI (MRI-FGT) and is known to be correlated with MPD5. Much like MPD, MRI-FGT has been shown to be associated with breast cancer risk6, and sensitive to endogenous  and exogenous  hormonal exposures9. Like mammogram, there are other image features from MRI that may be associated with breast cancer risk.In the United States women at a high risk of breast cancer  are recommended to undergo annual screening with contrast-enhanced magnetic resonance imaging (MRI) in addition to mammography11. The MRI signal from normal FGT also enhances to varying degrees and is called background parenchymal enhancement (BPE). BPE is recorded as the proportion of FGT in the breast that enhances. Having high BPE has been associated with an increased risk of breast cancer in some17, but not all19 studies. Notably, this association is thought to be independent of MRI-FGT16. BPE has been shown to be highly influenced by both endogenous  and exogenous  hormonal exposures. However, many of these studies have been small or did not consider relevant confounders.Contrast-enhanced MRI uses an intravenously injected contrast agent, to help visualize tumors through the identification of distinct patterns of contrast dispersionThe objective of this study was to contribute to our understanding of BPE and MRI-FGT as imaging markers of breast cancer risk by examining their relationship with established breast cancer risk factors.P < 0.0001 for both) . The distribution of different breast cancer risk factors in the study population are shown in Tables The median age at MRI was 49 years, 48% of women were postmenopausal, and 90% self-identified as White Table . Most woh) Table . WeighteBRCA mutations were less likely to have higher BPE than non-carriers . It was thought that this relationship could be explained by use of preventive medications  in this high-risk group. However, none of the women identified as premenopausal BRCA mutation carriers reported use of preventive medications at the time of MRI. In multivariable-adjusted models of MRI-FGT in premenopausal women, BMI was significantly associated with MRI-FGT, with increasing BMI associated with a lower prevalence of high MRI-FGT . We also found a significant positive association between having a personal history of LCIS and the prevalence of high MRI-FGT .Table In postmenopausal women Table , BPE tenSensitivity analyses were conducted restricting to women who self-reported White/Caucasian or reported having an MRI for high-risk screening purposes and the results did not differ (results not shown).p = 0.07 in premenopausal women and p = 0.05 in postmenopausal women). We therefore could not include these variables in the multivariable models for BPE due to small (zero) cell counts. No association between current use of preventive medications and MRI-FGT was observed (p > 0.05)  Table .Table 6D16. To better understand these relationships and how they could be used to inform recommendations for screening and prevention, it is necessary to understand the factors that impact these imaging markers. The results of the current study show that BPE is highly dependent on hormonal exposures, with a positive association observed between BMI  and a strong inverse association with use of preventive medications .BPE and MRI-FGT are characteristics of normal breast tissue that are routinely assessed by radiologists from standard contrast-enhanced MRI. Prior studies have shown these markers to be independently associated with breast cancer risk, contributing distinct information about a woman’s risk21 found that women with obesity (BMI > 30 kg/m2) had an almost 5-fold higher odds  of having high versus low BPE compared to women with a BMI < 25 kg/m2. A second study found an association between BMI and BPE in unadjusted analyses22. Ours is the largest multivariable-adjusted study to-date, able to also examine this relationship stratified by menopausal status. Consideration of menopausal status is important given the complex relationship between BMI, menopausal status, and breast cancer risk.BPE was found to be positively associated with BMI in both pre-and post-menopausal women. This relationship was most clear  for postmenopausal women where for every 5-unit increase in BMI the prevalence of high BPE increases by about 40%. While a positive association was also observed in premenopausal women, this association did not reach statistical significance. These results are consistent with those of two prior studies observing a positive association between BMI and BPE. In a small study of 214 women, Hellgren et al.27. This relationship is likely explained in part by the relationship between BMI and hormones 28, where in postmenopausal women, adipose tissue becomes the primary source of circulating estrogens29. There is a growing body of evidence showing BPE to be associated with both endogenous and exogenous hormonal exposures. BPE has been shown to increase with the use of MHT24 and to decrease with menopause7 and oophorectomy30 and in response to treatment with tamoxifen25, or aromatase inhibitors26. Recently we also showed that BPE is significantly positively associated with serum estradiol levels in postmenopausal women20. Together this suggests a plausible mechanism through which BMI could be impacting BPE in postmenopausal women. Further, there is some indication that the relationship between BPE and breast cancer risk may be modified by BMI, however, this requires further investigation16.BMI is positively associated with breast cancer risk in postmenopausal women and inversely associated with risk in premenopausal women32. These results support the hypothesis that BPE is a reflection of current/recent hormonal exposures (endogenous and exogenous) experienced in the breast, however further investigation of the influence of oral contraceptive use on BPE is warranted.In the current study, we found a strong relationship between the use of hormonal medications at the time of MRI and BPE. Specifically, the use of preventive medications  was so strongly associated with low BPE in both pre- and postmenopausal women, that all women using these medications had low BPE. We also found that use of oral contraceptives at the time of MRI was associated with a higher prevalence of high BPE, however, this association did not reach statistical significance. Prior work has shown that current or recent use of oral contraceptives is associated with increased breast cancer risk24. We found that use of MHT at the time of MRI was associated with a non-significant increase in the prevalence of high BPE. This is likely due to the small number of women reporting use of MHT, and the high proportion of those reporting use of local therapy. Specifically, of the 33 women who reported MHT use at the time of MRI, 21 reported use of estrogen-only therapy and 16 of these women reported use of local therapy . We did not have the sample size to conduct analyses further stratified by subtype, but since it is thought that BPE may be an indicator of local and systemic hormonal exposures this could have important implications for the use of local estrogen therapy in women undergoing treatment for breast cancer with aromatase inhibitors33. Notably we did not see similar associations with MRI-FGT.Prior work has shown a positive association between BPE and MHT36, and increasing BMI34. MPD has also been shown to be influenced by hormonal exposures, decreasing with menopause, and with tamoxifen use in postmenopausal women37, and increasing with administration of combined estrogen and progestin MHT 38. Similarly, we observed an inverse relationship between MRI-FGT and BMI. This was expected given that MRI-FGT is a volumetric measure of the amount of fibroglandular tissue in the breast that has been shown to correlate with MPD39. Other factors  previously associated with MPD were not associated with MRI-FGT in this study. We hypothesize that this is because the current analysis is focused on exposure status at the time of MRI. Prior work by our group has shown that BPE is highly dynamic and responsive to the hormonal environment of the breast, whereas changes in MRI-FGT take longer to be observed on MRI9. This supports the idea that BPE may be an imaging biomarker of current hormonal exposures in the breast and could be used as an indicator of response to hormonal medications40. One finding that deserves further consideration is the relationship between LCIS and the prevalence of high MRI-FGT. To our knowledge, this association has not been shown before, however breast density has been shown to play an important role in breast cancer risk among women with LCIS41.MPD has been studied extensively, and it is known to be highly variable across the population. Overall it has been shown to decrease with increasing age, increasing the number of birthsBRCA mutation carrier status was inversely associated with BPE in premenopausal women such that women carrying a BRCA mutation were 60% less likely to have high BPE, compared to non-carriers. It was thought that this association could be related to use of preventive medications (prescribed as chemoprevention in this high-risk population), however, none of the premenopausal BRCA mutation carriers reported use of these medications. Further, because this association is only observed in premenopausal women, we know that the lower BPE is also not due to prophylactic oophorectomy.One unexpected finding was that BRCA mutation carriers to have lower BPE than non-carriers in unadjusted analyses42. However, the results of this study (while consistent with our findings) are hard to interpret given that it is not clear if this association is due to other differences between carriers and non-carriers . To date no studies have specifically addressed the relationship between BPE and breast cancer risk in BRCA mutation carriers. However, the few studies that have examined the association between BPE and breast cancer risk, suggest that BPE is also a risk factor for breast cancer in these women12.A small study conducted in Chinese women found A major strength of this study is the collection of data on multiple breast cancer risk factors from both a study questionnaire at the time of MRI, and patients’ medical records. This is particularly important for the assessment of the impact of hormonal medications and lifestyle factors , where in our study current use (at the time of MRI) was assessed. Inter-reader variability is an important consideration in studies involving the assessment of BPE and MRI-FGT, with many ongoing efforts to develop computer-assisted algorithms for image assessment to reduce potential variability. Here we used a single experienced reader, with repeat BPE and MRI-FGT reads showing very high concordance . Although the use of a single reader could potentially limit the generalizability of the study, the high degree of reproducibility of repeat reads by the study radiologist shows strong internal validity. Further, by dichotomizing BPE as low (min/mild) and high (moderate/marked), external validity is increased by reducing the potential for discordance.43. Information on menstrual cycle week was not consistently available for study participants and so is not part of the current analysis. The impact of this is likely negligible as recent papers have found no association between menstrual cycle week and BPE45. Finally, we did not have information on all breast cancer risk factors. Of particular interest could be the relationship between physical activity and BPE. Physical activity is a potentially modifiable risk factor that has been shown to be associated with both circulating hormone levels and body composition47.Further limitations include the lack of racial diversity in the study population, with 89% of women self-identifying as White, limiting our ability to examine the impact of race on BPE or MRI-FGT. We also lacked information on the timing of MRI with respect to week of the menstrual cycle for pre-menopausal women. The American College of Radiology recommends that MRIs be performed in week 2 of the menstrual cycle when BPE is thought to be at its lowest, thereby maximizing the sensitivity of the MRI for cancer detection16. The development of abbreviated MRI screening protocols likely means that MRI will increasingly be used to screen women that do not meet the high-risk criteria. This could include women with dense breasts48 or those at higher than average (elevated) risk49. This highlights the need to understand the factors that influence BPE. Here we show that BPE is significantly positively associated with BMI in postmenopausal women. Further, use of preventive medications led to an almost complete reduction in BPE. The hormonally responsive nature of BPE, supported by this and prior studies, suggests that BPE could be an imaging biomarker of hormonal exposures in the breast, potentially used as an indicator of response to hormonal medications, or to further stratify women at high risk of breast cancer undergoing MRI screening.Prior work has found BPE to be a promising new marker of breast cancer risk providing information beyond that provided by assessment of breast densityThis study was reviewed and approved by the Memorial Sloan Kettering Cancer Center (MSK) Institutional Review Board, and written informed consent was obtained at the time of recruitment from all study participants.20. Briefly, women (N = 504) who had no prior history of any cancer  as noted in their medical record were approached in the MRI screening clinic at MSK between August 2012 and March 2014. Of the 449 women (88.9%) who volunteered to participate in the study, 30 were ultimately determined to be ineligible. Reasons for exclusion included insufficient proficiency in English (n = 2), prior personal history of cancer not previously identified during medical record review (n = 14), incomplete study questionnaire (n = 2) and diagnosis of breast cancer within the six months following MRI (n = 12). Individuals missing information on any covariates were also excluded . This left a study population of 415 women for the current analysis.Patient recruitment and data collection have been published previouslyAll women completed a self-administered questionnaire at the time of their MRI capturing information related to reproductive history, use of hormonal medications, family history of breast cancer and other risk factors. These included: age at menarche and menopause, parity , use of hormonal medications at the time of MRI , weight and height at the time of MRI, family history of breast cancer, and history of oophorectomy. Data from questionnaires was confirmed, when possible, through review of medical records.20. BPE and MRI-FGT were assess by a single reader using the proposed American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) criteria51. As such, BPE was classified as: minimal, mild, moderate or marked, and MRI-FGT as: a. almost entirely fatty, b. scattered fibroglandular tissue, c. heterogeneous fibroglandular tissue, or d. extreme fibroglandular tissue. The radiologist was blinded to all clinical characteristics of the patients.Breast MRIs were conducted using standard imaging protocols as described previously11. To confirm this, readings were conducted in both breasts and were only found to be discordant in one individual. In this instance, the higher value of the two breasts was assigned. Finally, to assess agreement between repeat reads, a set of MRIs (n = 19) were randomly selected to be re-read for both BPE and MRI-FGT.BPE and MRI-FGT are usually similar between breastsThis was a cross-sectional study examining the relationship between BPE, MRI-FGT and breast cancer risk factors. BI-RADS categories of BPE and MRI-FGT were collapsed to create dichotomous variables categorizing BPE as minimal/mild and moderate/marked, and MRI-FGT as predominantly fatty/scattered and heterogeneous/extreme.BRCA1/2 mutation status categories were collapsed ], untested [Table Breast cancer risk factors considered included: age at MRI (continuous), menopausal status (see below), current BMI (continuous), first-degree family history of breast cancer , personal history of breast biopsy , history of high-risk benign lesions , lobular carcinoma in situ (LCIS), age at menarche , parous (yes/no), number of full-term pregnancies , and age at first full-term pregnancy . n = 2) or had a period between 6 and 12 months of enrollment (n = 3). Eleven women, ranging in age from 44 to 64 years reported having had a simple hysterectomy, making it challenging to determine their menopausal status. For these groups of women, a prior analysis in this study population that included serum measurements of estradiol and estrone found that all had hormone levels were within the postmenopausal range. This indicated that they were indeed postmenopausal at the time of MRI20.If a woman reported that she had not had a menstrual period in the previous 12 months or had a personal history of a bilateral oophorectomy she was considered postmenopausal at the time of MRI. Five women were either missing information on age at the last menstrual period (52. Models did not include an adjustment for MRI-FGT because there was no association between BPE and MRI-FGT in our data (thus it did not meet the requirement of a confounder). Further, for analyses related to BMI, there was concern about over-adjustment given the strong relationship between BMI and MRI-FGT. All analyses were conducted stratified by menopausal status. Analyses were also conducted restricting to women who were having an MRI for high-risk screening purposes  and then again in those that self-reported White/Caucasian race/ethnicity (N = 369).Mutually adjusted prevalence ratios (PR) and 95% confidence intervals (CI) were estimated using modified Poisson regression p values are 2-sided.Concordance between repeat BPE and MRI-FGT reads was assessed using Cohen’s kappa coefficients. All statistical analyses were conducted using SAS 9.4  and all