For patients with newly diagnosed breast cancer, information regarding hereditary predisposition can influence treatment decisions. From a surgical standpoint, patients with known germline mutations may alter decisions of local therapy to reduce the risk of second breast primaries. This information may also be considered in the choice of adjuvant therapies or eligibility for clinical trials. In recent years, the criteria for the consideration of germline testing in patients with breast cancer has expanded. Additionally, studies have shown a similar prevalence of pathogenic mutations in those patients outside of these traditional criteria, prompting calls for genetic testing for all patients with a history of breast cancer. While data confirms the benefit of counseling by certified genetics professionals, the capacity of genetic counselors may no longer meet the needs of these growing numbers of patients. National societies assert that counseling and testing can be performed by providers with training and experience in genetics. Breast surgeons are well positioned to offer this service, as they receive formal genetics training during their fellowship, manage these patients daily in their practices, and are often the first providers to see patients after their cancer diagnosis. Approximately 10% of breast cancers are associated with a pathogenic germline mutation .,6.BRCA mBRCA mutation, no other factors were associated with other genes [Using the Georgia-California SEER Genetic Testing Linkage Initiative, Kurian and colleagues evaluated the test results from 77,085 patients with breast cancer, as tested by 4 separate laboratories. In their cohort, the prevalence of PV or LPV was 7.8%, and the distribution of mutations was similar to the above studies [er genes ,8.BRCA2 being the most common [BRCA1 can be identified, but less frequently than in BRCA2. In those who test negative for PVs in BRCA, the next most common mutations were CHEK2 and PALB2, demonstrating the need for multi-gene panel testing  [p = 0.42). Not surprisingly both studies demonstrated fewer BRCA mutations in patients outside of the criteria, as the NCCN guidelines were originally established to identify BRCA mutations [p < 0.001), but they also noted that 29.9% of women with pathogenic mutations identified in a 9-gene panel would not have qualified for testing per the NCCN. Younger age at diagnosis improved the sensitivity of testing, so the authors proposed a hybrid testing model that utilizes the NCCN guidelines for women over 65 and the consideration of testing for all women with breast cancer under the age of 65 [It is not uncommon for women with breast cancer who are outside the traditional criteria to request testing. While it is feasible, the cost of testing may not be reimbursed by insurance if they do not meet the criteria. Two industry-sponsored studies evaluated the presence of PV or LPV in women with breast cancer outside of the NCCN guidelines. In a cohort of 4196 Medicare patients who underwent comprehensive panel testing by a sole laboratory, similar rates of PV or LPV were identified, whether patients met the criteria or not  . Comparautations . These sutations . A thirdge of 65 .Should women with known PV or LPV avoid breast conservation therapy (BCT) when diagnosed with breast cancer? There are no randomized trials to address this question. Since these pathogenic variants are rare, data evaluating the risk of local recurrence (LR) after BCT in germline mutation carriers are limited and observational.BRCA. As BRCA1 and BRCA2 were the first genes identified in hereditary breast cancer syndromes, outcomes in these patients are most reported. A meta-analysis of 10 studies comparing BCT in BRCA carriers to sporadic controls demonstrated a slight increase in LR , but this was not statistically significant. The authors concluded it was likely a result of new primaries rather than true LR, as in those studies with a longer follow-up (>7 years), there was a significant increase [BRCA carriers reported a higher LR at 5, 10, and 15-year follow-ups. However, in the BCT group, the risk of LR consistently increased over time, while in the mastectomy group, the risk of LR did not appear to increase after 5 years, again suggesting this was a result of second breast primaries [BRCA carriers receiving definitive radiation for their index breast cancer. Therefore, one can conclude that BRCA carriers should be considered for BCT if otherwise eligible, but counseling regarding the risk of second breast primaries and enhanced surveillance with annual mammography and breast MRI should be performed [increase . A separrimaries . FurtherTP53. Breast cancer is one of the most common cancers associated with TP53 mutations (aka Li-Fraumeni Syndrome or LFS), with 85% of women developing cancer before age 60. This mutation is extremely rare, with <1% prevalence on multi-gene panel testing in women with breast cancers [TP53 carriers when compared to sporadic controls  with no associated increase after mastectomy. Looking specifically at the TP53 carriers, the risk of recurrence was higher after BCT when compared to mastectomy  [p = 0.001), and a non-significant increase in sarcomas  after radiation for breast cancer in patients with LFS. The authors concluded that the risk of radiation-induced cancers may not be as high as previously reported, but decisions regarding the use of radiotherapy should be individualized [ cancers . Few stu= 0.038) . In addi= 0.038) ,21. The Moderate penetrance genes. Data regarding clinical outcomes are lacking in moderate penetrance genes such as ATM, PALB2, or CHEK2. Small cohort studies demonstrate no difference in LR or second breast primaries after BCT when compared to women without these mutations [BRCA carriers, there is no increase in toxicity or CBC after definitive radiation in these patients [utations . Additiopatients ,25. Therpatients . Therefopatients .BRCA1, BRCA2, and CHEK2 mutations (p < 0.05). Hazard ratios were as follows: BRCA1 2.7, BRCA2 3.0, and CHEK2 1.9. There was no overall increase in CBC in women with PALB2 or ATM mutations; however, a significant increase was seen in PALB2 carriers with ER-negative tumors . In all groups, the age at diagnosis was the strongest predictor, with an increased risk of CBC after menopause only seen in BRCA2 carriers  [Multiple studies have suggested that women with germline PV or LPV are at an increased risk of CBC, but like studies evaluating LR, data regarding CBC is limited. A recent publication by Yadav et al estimated the risk of CBC in PV carriers as compared to sporadic controls as a part of the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. In this prospective review of 15,104 women with breast cancer with 11-year median follow-up, CBC was seen in 5.3%, with a significant increase in women with < 0.001) . These f< 0.001) ,30,31,32< 0.001) .BRCA carriers with a personal history of invasive breast cancer. At mean the 5-year follow-up, CPM reduced the risk of a CBC by 91%, although there were no statistically significant differences in the overall survival between the CPM and surveillance groups [Knowledge regarding the risk of CBC allows women to consider contralateral prophylactic mastectomy (CPM) for risk reduction and the avoidance of imaging surveillance. Van Sprundel et al investigated the effect of CPM in e groups . These re groups . More dae groups .BRCA carriers, 42.5% with other gene mutations, and 24.3% of women with negative testing results [p < 0.001). Furthermore, of those identified to be carriers after surgery was complete, 59% elected to undergo delayed bilateral mastectomies [For women with newly diagnosed breast cancer, testing prior to surgery is beneficial as it provides the opportunity to assess the risk of local recurrence and additional breast primaries when making decisions about surgery. Multiple studies have shown that knowledge of the PV or LPV status is associated with bilateral mastectomy rates, and for those who test negative, reassurance can be provided. Kurian et al reported the use of bilateral mastectomies in 61.7% of  results . Chiba aectomies .p < 0.0001) and overall survival , prompting the Food and Drug Administration to approve it for use in this setting in March 2022 [The identification of germline mutations may allow for additional options for systemic therapy, such as molecularly targeted agents. For women with metastatic disease, two large, randomized, open-label, phase 3 trials (OlympiAD and EMBRACA) demonstrated significant benefits in progression-free survival and improved the quality of life with poly (ADP-ribose) polymerase (PARP) inhibitors  in BRCA carriers ,38,39. Irch 2022 . The finrch 2022 .For the reasons listed above, testing for germline mutations has become a key component of breast cancer treatment decisions. One of the most important aspects of this algorithm includes the pre- and post-test counseling and documentation of this may be mandated for insurance coverage. These discussions should aim to reduce distress and help the patient understand the benefit of testing as a vehicle to obtain information about personal risk, empowering the patient to consider interventions to manage or reduce that risk . A PolisPost-test counseling primarily focuses on the interpretation and delivery of test results, either in person, by phone, or virtually. For patients with negative results or VUS, it is recommended that medical decisions should be made based on treatment-related factors and personal and family histories of cancer . For thoThe gold standard would be for counseling to be provided by an expert in cancer genetics . Stenehjp < 0.001) [Alternative models have been investigated to improve access to CGCs. Since the need for physical examination is limited, genetic counseling is well-suited for remote delivery by telephone or videoconference, removing the barriers of travel, time off work, and the need for childcare. A meta-analysis of 3 randomized studies of 2753 patients undergoing BRCA testing showed that telephone counseling was not inferior to in-person visits in patient-reported cancer-specific distress or genetics knowledge, and the authors concluded that telephone consults may be considered as an alternative method to improve access . However< 0.001) . A syste< 0.001) . While tTelehealth and phone consultations avoid the need for in-person appointments, but the inconvenience of another appointment to meet with a CGC could adversely result in delays in definitive treatment or the failure to have testing at all. Ochoa et al performed a retrospective review of the referral process for genetic counseling in women under treatment for breast cancer at their institution. Of the 392 women referred, 20.9% did not pursue scheduling a consultation, and another 19% either cancelled or failed to show up for the appointment. For those whose results would impact treatment plans, the time from referral to consultation was an average of 1.7 months, delaying definitive surgical therapy decisions . Others p < 0.0001) [Point-of-care testing in the context of existing appointments can improve access. Culver and colleagues reported 95% acceptance of counseling and 93% completion of testing when all patients seen in a multidisciplinary breast cancer clinic were offered an immediate consult with a CGC . These f 0.0001) .This is where breast surgeons can serve an important role. Breast surgeons receive a formal education regarding cancer genetics during fellowship training, and routinely manage carriers of mutations as a part of daily practice. A 2014 survey of practicing breast surgeons reported that the majority routinely performed the key components of counseling and testing—obtaining a 3-generation family pedigree, counseling of risks and benefits of testing, and interpreting and discussing results . They arSeveral educational programs have been developed to educate surgeons and non-genetic healthcare providers with an interest in genetic counseling and testing. Societies such as ASCO and the ASBrS have developed courses at the time of annual meetings for providers seeking additional education ,60. OtheThe role of germline testing in newly diagnosed breast cancer patients continues to evolve. The number of patients who are candidates for testing continues to expand, with some calling for testing in all women with breast cancer. While the benefits of counseling by a certified genetics professional are well-established, unfortunately, there is an inadequate workforce to accommodate this need. Breast surgeons can help bridge this gap. To provide adequate genetic counseling, however, it is important for surgeons to have experience in identifying patients who are candidates for testing, perform informed consent and pretest counseling, provide post-test counseling with a discussion of management strategies, and refer family members for cascade testing when appropriate. There are various tools that can assist in calculating risk as well as management strategies for surveillance and risk reduction.


The selected DMPs mediated the micronutrient breast cancer associations with an average mediation proportion of 36.43%. This study depicted comprehensive associations between circulating one-carbon metabolism-related micronutrients and breast cancer risk mediated by DNA methylation.Findings of epidemiologic studies focusing on the association between one-carbon metabolism-related micronutrients and breast cancer risk, along with the involvement of DNA methylation, have been inconsistent and incomprehensive. We conducted a case–control study in China including 107 paired participants and comprehensively detected 12 plasma one-carbon metabolism-related micronutrients. Genomic DNA methylation was measured using an 850 K chip and differential methylation probes (DMPs) were identified. Multivariate logistic regression was performed to estimate the associations between plasma micronutrients and the odds of breast cancer. The mediation of selected DMPs in micronutrient breast cancer associations was examined using mediation analyses. An inverse association of plasma folate, methionine cycling-related micronutrients , and all micronutrients in the choline metabolism and enzymatic factor groups, and a positive association of methionine cycling-related cysteine with breast cancer risk were observed. Nine micronutrients (methionine, cysteine, SAM, folate, choline, betaine, P5P, vitamins B Breast cancer is a serious threat to global women’s health. In 2020, approximately 2.26 million new cases and 680 thousand new deaths from breast cancer occurred worldwide . Due to Dietary factors and nutritional status play an important role in the occurrence and development of breast cancer. Epidemiological studies have shown that the intake of dietary micronutrients involved in the one-carbon metabolism pathway influenced the onset and progression of breast cancer ,7,8,9,10DNA methylation is the most common and important form of epigenetic modification in breast cancer. The epigenome-wide association (EWAS) studies have shown a hypomethylation pattern of peripheral blood genomic DNA existing in breast cancer patients ,24. The Herein, we aimed to conduct a hospital-based case–control study among Chinese women to examine the association of multiple plasma one-carbon metabolism-related micronutrients with the risk of breast cancer and DNA methylation, and further explore the mediation of DNA methylation in these biochemically-related micronutrients-breast cancer associations.The study population consisted of 107 paired breast cancer patients and controls, simply randomly extracted from a hospital-based case–control study we set up . As descAll participants enrolled in this study were of Chinese Han ethnicity. The Ethics Committee of Tianjin Medical University Cancer Institute and Hospital approved the study protocol (Ek2022212), and written informed consent was obtained from all patients and controls to participate in this study.Information of each subject about demographics , menstrual and reproductive history , environmental exposures (passive smoking and negative events), lifestyles , and family history of cancer in first-degree relatives was obtained from a structured questionnaire. Regarding negative events, participants were questioned, “Have you ever suffered from a negative life event  within the last year that caused a pronounced and lasting negative emotional experience” in the questionnaire, and asked to answer “yes” or “no” according to their own experiences and feelings. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m). Information on breast density was obtained from imaging examinations.Five to 10 mL of fasting peripheral blood samples were collected from all subjects. After quiescence for 1–2 h, the blood samples were centrifuged at 3000 rpm for 15 min. Genomic DNA from leukocytes was isolated by the standard phenol–chloroform extraction. The separated plasma and extracted genomic DNA stock solution were stored in the refrigerator at −80 °C for subsequent use.6), vitamin B2, and vitamin B12.The one-carbon metabolism included two major pathways, i.e., folate cycle and methionine cycle, involving choline metabolism and some enzymatic factors . Therefo®  [Targeted metabolomic analysis of one-carbon metabolism-related micronutrients in plasma samples was performed using validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods ,29. SampMA, USA) . Mass spThe pattern and extent of DNA methylation in the samples were determined using an Illumina Infinium Methylation EPIC BeadChip Kit (850K chip). DNA samples were processed by a series of steps according to the manufacturer’s protocols, i.e., DNA denaturation, whole genome amplification, fragmentation, precipitation, resuspension, hybridization, washing, elongation, staining, and scanning processes, to obtain methylation signals. The extent of methylation was determined by the β value, which was calculated as β = M/(M + U + 100), where M and U represented the signal strength of methylation and unmethylation, respectively. The β values ranged from 0–1, indicating completely unmethylated to totally methylated DNA . The glop-value above 0.01, 6957 probes with a bead count < 3 in more than 10 samples, 2882 probes with non-CpG sites, 94,837 probes with single nucleotide polymorphisms, 11 probes that aligned to multiple locations, and 16,694 probes located on the X and Y chromosomes. The remaining 735,045 probes were used for further analysis. Furthermore, the beta-mixture quantile (BMIQ) normalization method was used to adjust the intensity distribution of the Infinium II probes to fit that of the Infinium I probes [After quality control, we retained 98 cases and 102 controls for subsequent methylation analysis. The raw data of DNA methylation intensity were analyzed using the “ChAMP” package (version 2.21.1) . We readI probes , and theI probes . We usedI probes .p-value less than 0.05 was defined as a differentially methylated probe (DMP). The heatmap with unsupervised clustering was performed to evaluate the differentiating capacity of DMPs.Array-wide differential methylation analysis was carried out using the “limma” package implemented by “champ.DMP” function. A CpG site with |Δβ| > 0.2 (case vs. control) and an adjusted We subsequently estimated candidate differentially methylated regions (DMRs) using the “Bumphunter” algorithm , where cp < 0.05.To identify the potential biological pathways that DMPs and DMRs are involved in, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed with the “RclusterProfiler” package (Version 4.4.4.) . The sigt-test and categorical variables were compared using the Chi-square test. Twelve one-carbon metabolism-related micronutrients were converted to Z scores and then compared by rank-sum tests. A logistic regression model was applied to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between one-carbon metabolism-related micronutrients and breast cancer risk. Combining the results of the distribution of basic characteristics with those well-known risk factors for breast cancer reported in the literature, the model was adjusted for per capita monthly household income, education, body mass index (BMI), negative events, benign breast disease, family history of cancer, age of menarche, menopausal status, number of pregnancies, number of live births, breastfeeding months, and abortion as covariates. We further examined the association between these micronutrients and breast cancer risk stratified by menopausal status.Continuous variables were compared using the student’s p-values corrected by FDR and Bonferroni methods. To ascertain if DNA methylation mediated the association between one-carbon metabolism-related micronutrients and breast cancer, we carried out a mediation analysis using the “mediator” package with adjustment for the same covariates previously identified to evaluate the direct effects, indirect effects, and proportion of mediation by the selected DMPs.We investigated correlations of one-carbon metabolism-related micronutrients with array-wide mean methylation levels and selected DMPs , with the threshold of <0.05 for http://www.r-project.org, accessed on 1 June 2023, version 4.2.3). A level of <0.05 for two-sided p-values was considered statistically significant.All analyses were performed using SAS version 9.4  and R software , with the case group presenting lower levels of methionine, SAM and SAH in the methionine cycle group, folate, and all micronutrients in the enzymatic factor group and choline metabolism group, but a higher level of methionine cycling-related cysteine.As shown in 2, 0.01 (0.001–0.06) for vitamin B12, 0.43 (0.25–0.73) for choline, 0.36 (0.17–0.75) for betaine, and 1.79 (1.08–2.97) for cysteine, respectively.The univariate logistic regression analysis showed that 9 one-carbon metabolism-related micronutrients, i.e., methionine, SAM and SAH in the methionine cycle group, folate, and all micronutrients in the enzymatic factor group and choline metabolism group, were associated with a decreased risk of breast cancer, while a higher level of cysteine contributed to an increased breast cancer risk . These s2 had a similar trend of association with breast cancer risk, regardless of menopausal status. However, methionine was only associated with the risk of premenopausal breast cancer, but SAM, folate, vitamin B12, and choline were only linked to the risk of postmenopausal breast cancer.Stratified analyses performed according to menopausal status are shown in p = 2.2 × 10−16; p-value of <0.05 by a two-group comparison and identified a total of 524 DMPs  can almost completely distinguish between cases and controls  with areBased on DMPs that were highly correlated with one-carbon metabolism-related micronutrients, the mediation analysis was conducted to examine the mediation of DMPs in the associations between one-carbon metabolism-related micronutrients and breast cancer risk . We obse2 and B12), and micronutrients involved in the methionine cycle  and the choline metabolism (choline and betaine) were associated with a decreased risk of breast cancer, but cysteine level was positively associated with breast cancer risk. Most micronutrients were related to overall or probe-specific methylation levels. Moreover, DNA methylation to a larger extent mediated the micronutrient-breast cancer associations.This case–control study among Chinese women suggested that higher plasma levels of B vitamins  gene C677T (rs1081133) and A1298C (rs1801131) variants were reported to be factors predisposing breast cancer in Asians [The methionine cycle is a major pathway of one-carbon metabolism, accompanied by the folate cycle and choline metabolism which are involved in homocysteine remethylation. The association between plasma homocysteine and the risk of breast cancer has been reported to be null in Western countries ,16,17,18n Asians , but notn Asians . They man Asians . In the 2, B6, and B12, are also key cofactors for one-carbon metabolism. The latest pooled analysis reported that a higher intake of dietary vitamin B2 might reduce the risk of breast cancer, but vitamins B6 and B12 do not [2 and B12 had no effects on breast cancer [2 and B12 with breast cancer risk in Chinese women. The effects of P5P and vitamin B2 were among both premenopausal and postmenopausal women and that of vitamin B12 was only among postmenopausal women. Nevertheless, more prospective studies and large-scale populations are warranted to support our results.Some other B vitamins, such as vitamins B2 do not . A smallt cancer . HoweverHypermethylation of the promoter in cancer suppressor genes, accompanied by global hypomethylation of the genome, is a common feature of tumor cells . Our resKIFC2, widely mediated the associations between almost all micronutrients and breast cancer in our study, although no report about the relationship between KIFC2 and breast cancer has been found so far. Another interesting finding was the association of choline with a decreased risk of breast cancer only mediated by the hypomethylation of cg21697381, located in the open sea region of the SLFN12 promoter. The over-expression of SLFN12 can sensitize triple-negative breast cancer cells to chemotherapy drugs and radiotherapy [SLFN12 gene is related to a reduced risk of breast cancer conferred by choline needs to be further investigated. Together, our findings make it interesting to systematically evaluate the role of DNA methylation modulation by one-carbon metabolism-related micronutrients in breast cancer in future studies.The hypomethylated probe cg04794268, located in the promoter of To our knowledge, this was the first study to systematically consider one-carbon metabolism-related micronutrients as functional groups  and comprehensively evaluate the potential role of plasma levels of these micronutrients in breast cancer and the involvement of DNA methylation in a Chinese population. Moreover, the whole genome methylation levels were first detected by an 850 K chip in a breast cancer study, providing wider coverage, higher data quality, and higher reproducibility. However, several limitations existing in the present study merited special consideration. Firstly, our study had the inherent limitations of a case–control study, such as recall bias and selection bias. Secondly, the main population in this study was citizens of Tianjin (a city in northern China), which may not be representative of the entire Chinese population. Thirdly, even though we had controlled the majority of confounders, the residual confounding from unmeasured or unknown factors might remain. Finally, due to the relatively small sample size of this study, the current analysis may be underpowered and the conclusions need to be verified by large-scale prospective data.2 and B12) and a positive association of methionine cycling-related cysteine with breast cancer risk in a Chinese population. Certain one-carbon metabolism-related micronutrients were related to array-wide and probe-specific methylation levels. Furthermore, differentially methylated CpGs partially or completely mediated the micronutrient-breast cancer associations. The above findings enrich the theoretical basis for the relationship between one-carbon metabolism-related micronutrients and individual methylation sites and provide evidence that one-carbon metabolism-related micronutrients may specifically affect breast cancer risk through different methylation sites. Meanwhile, one-carbon metabolism-related micronutrients may serve as a potential epigenetic drug to reverse abnormal methylation patterns in breast cancer, contributing to the development of targeted prevention and control measures for breast cancer. More prospective studies are needed in the future to clarify those associations, as well as to be motivated to uncover the specific mechanisms of action.Our findings provided the first comprehensive depiction of an inverse association of plasma folate, micronutrients involved in the methionine cycle  and choline metabolism (choline and betaine) and enzymatic factors in one-carbon metabolism (P5P, vitamins B


In August 2019, the safety of menopausal hormone therapy (MHT) returned to the scene again. Once more, its association with breast cancer risk came up, this time in an article published in the prestigious The Lancet (online in August and printed in September/2019). The subject is not new, and authors of the article are not newcomers either. By representing the Collaborative Group on Hormonal Factors in Breast Cancer, they brought a reanalysis of data from studies on the subject published so far.In summary, they evaluated data from 58 studies, out of which 24 were prospective and 34 were retrospective studies, covering almost 144 thousand postmenopausal women with breast cancer (cases) and close to 425 thousand without the disease (controls). A higher risk for developing breast cancer was found among MHT users. Women taking combined MHT for 1 to 4 years had a relative risk (RR) of 1.60 with a 95% confidence interval (CI) from 1.52 to 1.69, and for estrogen alone, it was observed a RR of 1.17 (95%CI: 1.10–1.26). For more prolonged use (5 to 14 years), RRs were 2.08 and 1.33, respectively.The first important point when evaluating this study is the fact that it is a reanalysis of data from other studies. In other words, data from other 58 studies were obtained and compiled, a total database was generated, and then analyzed. This was not a meta-analysis or systematic review, neither were data obtained from a same population at the same time or using the same method.Soon after publication, the International Menopause Society (IMS) came public with their interpretationIn their comments, the IMS mentioned that much information brought in the recent article is not new.The Million Women Study also found similar values. The RR for breast cancer in MHT users was 1.66, in combined MHT users it was 2.00, and in users of estrogen MHT alone the RR was 1.30.What differs in the study published in The Lancet in 2019 regards the use of estrogen alone, because in this study, the use of estrogen alone presented higher risk, as well as the observational studies previously mentioned. However, in the Women's Health Initiative (WHI), the only large randomized study that assessed MHT effects on the risk for breast cancer, this effect was not observed. In the WHI, the RR for invasive breast cancer in users of estrogen MHT alone compared with placebo was 0.80 95%CI: 0.62–1.04).2–1.04.6 On the other hand, although this article did not bring much novelty in terms of MHT-associated breast cancer risk, there is a problem that may seem more relevant from the IMS perspective: most of the MHT assessed does not represent the most common current practices for this type of therapy. This is a result of the fact that in the Collaborative Group reanalysis, the median year of diagnosis of breast cancer cases for the entire database was 2002, whereas for retrospective studies, the median was year 1995. For American prospective studies, the median of the year of breast cancer diagnosis was 1999, and for Europeans it was 2007. Furthermore, in prospective studies, the average time of using MHT was 10 years in users diagnosed while using the therapy, and 7 years in former users.Another relevant criticism of this reanalysis involves the context of women who started MHT before the age of 45. In the presentation of results, the effect of MHT in this context was compared with women in the same age group that were not using MHT despite ovarian failure before the usual age, which led to the conclusion of a higher risk for breast cancer associated with MHT in these younger women. The correct thing would have been to compare the effects of MHT in women in the same age group while still in premenopause, because the most common in this age group is women still having ovarian hormone production and not the other way around.However, the study in question has brought an important warning: obesity and overweight are associated with a higher risk for breast cancer, and this risk does not differ substantially from the risk associated with estrogen MHT alone in this same publication.Finally, it is important to analyze the global effects of MHT and not just the effects on risk for breast cancer. The decision on whether or not to use this therapy should not fall solely on this issue. As an example, it is sufficient to retrieve information from the WHI study itself. Although it revealed a higher risk for breast cancer associated with MHT, neither a higher overall risk for all types of cancer together nor for mortality from these cancers were observed.The postintervention WHI data with 18 years of follow-up of participants showed no increase in the mortality rate from cancer in general or from cardiovascular causes.In conclusion, the publication of the Collaborative Group in The Lancet (2019) did not bring significant novelty regarding the risk for breast cancer in MHT users. Moreover, its results possibly do not reflect directly the real effects of the most current practices in MHT. In spite of all this, the decision to use MHT or not should always be made individually by taking into account the characteristics of each patient, the indications and absence of contraindications, the time since menopause (window of opportunity concept), the presence of comorbidities, as well as the values and opinions of the patient after due clarification.


This study aimed to investigate the contemporary characteristics of sedentary behavior and physical activity levels in breast cancer survivors. The cross-sectional data of 10,073 community-dwelling Korean women aged ≥50 years in the Korea National Health and Nutrition Examination Survey were analyzed. The differences in sedentary behavior, walking activity, and moderate-to-vigorous physical activity (MVPA) levels between breast cancer survivors, other cancer survivors, and women with no history of cancer were compared by complex-sample general linear models. Breast cancer survivors spent significantly less mean time in sedentary behavior than other cancer survivors and women with no history of cancer; however, among them, 48.34% spent a long sedentary time of ≥420 min/day. Breast cancer survivors had a significantly higher level of walking activity and similar total MVPA levels compared to women with no history of cancer. When comparing domain-specific MVPA levels, breast cancer survivors showed significantly lower work-related MVPA levels than women with no history of cancer. In recent years, community-dwelling Korean breast cancer survivors were less sedentary, walked more, and had equivalent MVPA levels compared with women with no history of cancer. Considering the growing emphasis on healthy lifestyles, our results may reflect more contemporary behavior trends of breast cancer survivors. Physical activity is defined as any bodily movement produced by skeletal muscles that requires energy expenditure, either for leisure, transportation, or work . PhysicaThe benefits of physical activity in patients with cancer and in the general population have been well established by many previous studies . RegularMany breast cancer survivors suffer from impairments of the upper extremities, depression, or cognitive decline after treatment, which leads to limitations in activities of daily living and participation in work, sports, and leisure activities ,8. TheseConsidering the increasing incidence and survival rate of patients with breast cancer, the role of physical activity among breast cancer survivors in leading a healthy life has been increasingly emphasized . Neverthhttps://knhanes.kdca.go.kr (accessed on 29 November 2022)). All participants of the KNHANES provided informed consent before participation, and the requirement for ethical approval was exempted by the Institutional Review Board of our hospital because the current study uses the publicly available data of the KNHANES.This cross-sectional study utilized the data from the Korea National Health and Nutrition Examination Survey (KNHANES) VI, VII, and VIII . The Korn = 1102) and with double primary cancer in the breast and other organs (n = 12), 10,073 female participants were finally included in the current study. Women who had ever been diagnosed with cancer by a doctor were defined as cancer survivors [n = 193), survivors of cancers other than breast cancer (n = 644), and those without a history of cancer (9236) [A total of 47,309 participants  were recruited for the KNHANES between 2014 and 2019. Among the total participants, 20,546 participants  were aged 50 years or older (43.43%). After excluding people with a missing history of cancer (urvivors . In the r (9236) . BecauseSedentary behavior and moderate-to-vigorous physical activity were evaluated using a validated Korean version of the World Health Organization (WHO) Global Physical Activity Questionnaire (GPAQ) . The GPABecause the information on walking and resistance exercise is not obtainable via the GPAQ, walking activity and resistance exercise were separately surveyed . Walking2). Information on education level (>9 years or ≤9 years) and residence area  was obtained. Those who worked for more than 1 h in the past week with the purpose of earning income or worked as unpaid family workers for more than 18 h were considered to have an occupation (employed state). Individuals who had never consumed alcohol or had not consumed alcohol at all in the last year were classified as non-drinkers.Height was measured with the minimum requirement that the heels and buttocks touched the vertical board while standing. Weight was measured in a state of exhaling breath, wearing light clothing only. Body mass index was calculated using measured weight (kg) divided by height squared , as appropriate. All statistics were calculated using the Statistical Package for the Social Sciences, version 22 . p-values < 0.05 were considered statistically significant.The characteristics of participants by cancer status  were compared using the complex-sample Student’s Among the 10,073 women aged 50 years or older, the prevalence of breast cancer survivors, other cancer survivors, and individuals with no history of cancer was 1.88%, 6.65%, and 91.47%, respectively. Characteristics of participants are compared by cancer status in Meanwhile, the levels of total moderate-to-vigorous physical activity and resistance exercise were not significantly different among breast cancer survivors, other cancer survivors, and participants with no history of cancer . The meaThe current study presents the contemporary sedentary behavior and physical activity patterns in community-dwelling Korean breast cancer survivors aged 50 years or older. Breast cancer survivors spent less sedentary time than other cancer survivors and participants with no history of cancer. Furthermore, breast cancer survivors walked significantly more than females without a history of cancer. However, total moderate-to-vigorous physical activity levels were similar between survivors of breast cancer, survivors of cancers other than breast cancer, and those without a history of cancer. With regard to domain-specific moderate-to-vigorous physical activity, travel- and recreation-related moderate-to-vigorous physical activity were not significantly different across the three groups, but work-related moderate-to-vigorous physical activity was significantly lower in the survivors of breast and other cancers than in the participants without a history of cancer.Regarding our findings that Korean breast cancer survivors spent less sedentary time than the non-cancer controls and other cancer survivors, the results of our study differed from earlier studies reporting that breast cancer survivors are more sedentary than women who did not have cancer ,24,25. HWhile breast cancer survivors were less sedentary than females without a history of cancer and survivors of other cancers, approximately half of them still spent a relatively long time in sedentary behavior—over 7 h per day. Given that the prevalence of sedentary individuals is still high among breast cancer survivors, community-based tailored physical activity-promoting programs, incorporating moderate-to-vigorous physical activity as well as simple walking, are necessary. Recent studies suggest that sedentary behavior has a negative impact on health outcomes that are independent of the overall amount of physical activity, and that spending more time in physical activity cannot reduce the detrimental effect of prolonged sedentary behavior on health outcomes . The WHOThe results of our study indicated that community-dwelling breast cancer survivors walked significantly more than women without a history of cancer. This notable result is encouraging for public health, given that walking is the most easily accessible and a relatively light form of physical activity . To our Inconsistency persists regarding the moderate-to-vigorous physical activity levels in breast cancer survivors compared with controls ,24,26. TThe results of our study that breast cancer survivors were sedentary, walked more, and performed similar moderate-to-vigorous physical activity compared to controls may reflect the physical modality preference of breast cancer survivors. A pilot randomized controlled trial found that reductions in sedentary time were greater in participants randomized to the lower-intensity physical activity group than in those randomized to the higher-intensity physical activity group and control group . A crossAs with the previous literature reporting reduced work engagement and work ability in breast cancer survivors , our stuThe strength of our study is that it presents contemporary real-world data from breast cancer survivors living in the Korean community, rather than hospitalized patients under treatment for breast cancer. Since research on the physical activity and sedentary behavior of Asian breast cancer survivors is lacking, our study provides valuable insight into the behavioral patterns of middle-aged and older Asian female breast cancer survivors. Therefore, the results of this study may suggest the future direction for interventions to reduce sedentary behavior and promote physical activity in breast cancer survivors living in the community. The limitations of our study stem from the cross-sectional design of the KNHANES, which cannot reveal the causal relationships between variables, such as the association between physical activity and breast cancer. Second, the self-reported surveys of physical activity and sedentary behavior could confer recall bias. In addition, the data obtained by self-reported questionnaires and objective physical activity measures may show different results. Third, because there are no detailed cancer-related data in the KNHANES, such as the stage and treatment status, their effects are unknown. Moreover, since the KNHANES does not include information on participants prior to cancer diagnosis, it was not possible to adjust for pre-cancer factors during the analyses. Finally, considering the differences in demographic and cancer-related factors across the various countries, the results of our study may not be generalizable to other populations.Community-dwelling Korean breast cancer survivors aged 50 years or older were less sedentary and walked more than women without a history of cancer. However, moderate-to-vigorous physical activity levels were similar between breast cancer survivors, other cancer survivors, and women with no history of cancer. Community-dwelling breast cancer survivors may prefer walking as a mode of physical activity in order to be less sedentary. Therefore, future prospective studies and randomized controlled trials are needed to examine the factors associated with the types of physical activity chosen by breast cancer survivors to reduce sedentary behavior. By synthesizing the findings of our study and future studies, personalized programs can be developed to convert sedentary time into physical activity in community-dwelling breast cancer survivors. In addition, healthcare professionals should regularly recommend increasing physical activity, assuming that half of the breast cancer survivors spend a long time being sedentary.


Radiation-induced secondary tumors constitute a rare complication of radiationtherapy and typically occur in or near the irradiated area. Women who undergothoracic radiotherapy before 30 years of age have a significantly greaterlifetime risk of developing breast cancer than do those in the generalpopulation. It is recommended that a patient who has previously receivedthoracic radiotherapy with a radiation dose ≥ 10 Gy subsequently undergoannual screening with mammography and magnetic resonance imaging, beginningeight years after the initial treatment or when the patient has reached 25 yearsof age (whichever comes later). The treatment of secondary breast cancer in thispopulation should be individualized and should be discussed with amultidisciplinary team to avoid toxicity related to the treatment of the primarycancer. Radiation-induced tumors are rare, being observed in less than 1% of patientsundergoing radiotherapy. The main risk factor for the development of aradiation-induced secondary tumor is the age at which the primary tumor was treated,younger age at the initial treatment correlating with greater risk. Children arethree to six times more susceptible to the carcinogenic effect of ionizing radiationthan are adults.,2: those thatare sporadic; and those related to hereditary syndromes that increase the risk ofcancer. Sporadic radiation-induced tumors are identified on the basis of Cahan’scriteria: occurring inthe previous radiation field but not present on the images acquired at the beginningof radiotherapy; a mean latency period of 10 years between exposure to radiation and the development of the secondary tumor; beinghistologically different from the primary tumor; and occurring in patient with nogenetic syndrome that predisposes to cancer. Radiation-induced tumors related togenetic syndromes are mainly related to pathogenic mutation of TP53, which leads toLi-Fraumeni syndrome. The latency period can be shorter for such tumors than forsporadic tumors,2.Radiation-induced tumors can be divided into two groups. However, theradiotherapy increases the risk of secondary cancer, especially breastcancer-10. This reaffirms the concept that breast tissue isone of most radiosensitive organs in the human body. Secondary cancer is also themain cause of death among primary cancer survivors.Thoracic radiotherapy has been successful for the treatment of primary cancers inchildhood and adolescence, with a significant increase in relative survival, theten-year survival rate among such cases having been reported to be approximately95%The aim of this study was to review aspects related to the risk of developingsecondary breast cancer in young patients undergoing thoracic radiotherapy, as wellas current screening recommendations, tumor characteristics, and the peculiaritiesof cancer treatment in this population.. Among such women, the risk of developing breast cancerincreases five to nine years after the initial treatment, peaking betweenpost-treatment years 15 and 19 and declining thereafter, although the risk remainshigh until 30-40 years after the initial treatment. Horst et al. found that 34% of patients who were ≤ 30 years ofage when they were treated for Hodgkin lymphoma (HL) later developed breast cancer,with a median latency period of 21 years  and a median age atbreast cancer diagnosis of 43 years . The authors also foundthat, among the patients who were > 30 years of age when they were treated forHL, only 19% later developed breast cancer, with a median latency period of 18 years and a median age at breast cancer diagnosis of 53 years .Women undergoing thoracic radiotherapy when they are under 30 years of age are up toeight times more likely to develop breast cancer during their lifetime than arethose in the general population demonstrated thatthe incidence of secondary breast cancer was higher among the women with a familyhistory of breast cancer or thyroid disease and was lower among those exposed toradiation of the pelvis (compared with those exposed to radiation of the thorax).The risk has also been shown to be greater among women who received radiation atyounger ages and to increase cumulatively with age,12,15. Another factor that has beenshown to increase the risk of breast cancer after radiotherapy is the concomitantuse of chemotherapy with anthracycline during the treatment of the primarycancer,17.In a retrospective cohort study designed to identify risk factors for breast cancerin female survivors of primary childhood cancer, including 6,068 women, Kenney etal.. In addition,fiveand ten-year survival rates remain the same, regardless of the radiation dose orthe area irradiated. Moskowitz et al. showed that the risk remains high even if lower radiation doses(10-19 Gy) were used, justifying breast cancer screening in patients receiving suchdoses, despite the fact that 20 Gy is the cutoff point previously established forbreast cancer screening in women having undergone thoracic radiotherapy. It isnoteworthy that although the induction of secondary neoplasms is a stochastic event, low doses and small volumes do not completely eliminate therisk. Thoracic radiotherapy for lymphoma, for example, currently uses lower dosesand volumes than previously standardized, which could make the risk ofradiation-induced tumors lower than that observed in historical series.Regarding previous thoracic radiotherapy, the risk of breast cancer has been found toshow a linear relationship with the radiation dose, although the risk is lower whenthere is less breast tissue involved, even when the radiation dose is applied to theentire thorax-22. The American College of Radiology. and the Brazilian College ofRadiology and Diagnostic Imaging, together with the Brazilian Breast Disease Societyand the Brazilian Federation of Gynecology and Obstetrics Associations, recommend that such women bescreened annually with mammography and MRI.Because women who have undergone thoracic radiotherapy in childhood and adolescenceare at an increased risk of developing breast cancer before entering the age rangeusually indicated for screening, the recommendations for such women should bedifferent from those applied in the general population. Mammography, the most widelyused method of screening for breast cancer, is less sensitive in young women becausebreast density is greater in that population. As detailed in . The recommendations include annual screening forbreast cancer, starting at age 25 or eight years after radiotherapy (whichever comeslater), for patients undergoing thoracic radiotherapy at a dose ≥ 10 Gybefore 30 years of age and the continuation of such screening until at least 60years of age. An additional recommendation is that screening for breast cancershould also be considered in patients who underwent radiotherapy only of the upperabdomen. Those practices would allow early detection of the disease, improving theprognosis, given the fact that the therapeutic options are often limited, becausesuch women have already been submitted to chemotherapy and radiotherapy during thetreatment of the primary tumor.In 2019, the International Late Effects of Childhood Cancer Guideline HarmonizationGroup published updated recommendations for breast cancer screening in women treatedfor cancer in childhood, adolescence, or young adulthood,27. Those modelsdemonstrated that early screening with mammography and MRI would reduce the absoluterisk of death from breast cancer in this population by as much as half. Theadditional benefit of mammography over MRI was very small in those studies. However,the models used did not consider ductal carcinoma in situ (DCIS) aspart of the natural history of breast cancer, assuming that it would not contributeto mortality. That omission could have interfered with the results of mammographicscreening. In both studies, a higher number of false-positive screening results wereobserved when MRI was included, although the values were considered to beacceptable.Because of the difficulty in gathering a considerable number of women who fit theprofile for studies designed to validate these screening indications, some authorshave developed mathematical models to assess the benefit of early screening in HLsurvivors from the age of 25 onward and express hormone receptors. Inone study of secondary breast tumors in women who had received radiotherapy inchildhood or young adulthood, Demoor-Goldschmidt et al. found that 70% of the secondary tumors hadestrogen receptors and 64% had progesterone receptors. However, compared with casesof breast cancer in the general population, cases of such radiation-inducedsecondary tumors have been shown to have a worse prognosis, with higher rates ofbilaterality and a higher grade, as well as being less likely to express hormonereceptors and more likely to present the triple-negative subtype,30. Horst et al. found that 39% of patients with breast cancer who hadundergone thoracic radiotherapy presented the triple-negative subtype, compared withonly 14% of the patients with sporadic breast cancer.The most common malignant breast neoplasms after chest radiotherapy are invasivecarcinoma not otherwise specified  andDCIS. In this population, most tumors are diagnosed at an earlier stagedemonstrated that most radiation-induced tumors were diagnosed during screening. Inanother multicenter study, carried out in France, Demoor-Goldschmidt etal. found that mostsuch tumors were diagnosed in the symptomatic phase. In general, patients diagnosedduring the screening process tend to have smaller, earlier stage tumors are at increased risk of developing breast cancer during their lifetime. Such womenshould undergo annual screening with mammography and MRI starting eight years aftertreatment, assuming that they are at least 25 years of age at that time. Screeningallows early detection of the disease, improving the prognosis, given that previousradiotherapy limits the therapeutic options.


Despite the known increasing incidence of breast cancer in China, evidence on the spatial pattern of hospitalization for breast cancer is scarce. This study aimed to describe the disparity of breast cancer hospitalization in the rural population of Southeast China and to explore the impacts of socioeconomic factors and heavy metal pollution in soil.This study was conducted using the New Rural Cooperative Medical Scheme (NRCMS) claims data covering 20.9 million rural residents from 73 counties in Southeast China during 2015–2016. The associations between breast cancer hospitalization and socioeconomic factors and soil heavy metal pollutants were evaluated with quasi-Poisson regression models and geographically weighted Poisson regressions (GWPR).P = 0.02), urbanization  and soil cadmium (Cd) pollution . In the GWPR model, a stronger spatial association of Cd, road density and breast cancer hospitalization was found in the northeast regions of the study area while breast cancer hospitalization was mainly related to urbanization in the western regions.The annual hospitalization rate for breast cancer was 101.40/100,000 in the studied area and the rate varied across different counties. Overall, hospitalization for breast cancer was associated with road density (β = 0.43, Soil Cd pollution, road density, and urbanization were associated with breast cancer hospitalization in different regions. Findings in this study might provide valuable information for healthcare policies and intervention strategies for breast cancer.The online version contains supplementary material available at 10.1186/s12905-023-02336-w. Female breast cancer is a leading cause of cancer in the world and in China . NowadaySocioeconomic factors could influence women’s lifestyle , includiMoreover, special attention should be paid to the impact of environmental exposures, especially soil heavy metal pollution, considering the biological , 19 carcAssessment of the spatial pattern and associated factors for breast cancer hospitalization is important for the planning of cancer-related health resources and identifying priority regions for possible prophylactic interventions. In this study, we focus on the spatial autocorrelation of breast cancer hospitalization in the rural population of Southeast China and explore the association between socioeconomic factors, soil heavy metals and breast cancer hospitalization by using general spatial autocorrelation. We further used the geographically weighted Poisson regression (GWPR) model to explore spatial variations of the associations between socioeconomic factors, soil heavy metals and breast cancer.2, with a total population of 37.2 million in 2015, of which 20.9 million were rural. By the end of 2014, 98.9% of the rural population (https://data.cnki.net/yearBook/single?id=N2015110123) participated in the NRCMS. Therefore, we extracted medical insurance claims data of hospitalized female breast cancer patients within the NRCMS from January 1, 2015, to December 31, 2016. Due to the small number of rural residents in Taijiang County, Gulou County, Licheng County, Fengze County, Cangshan County, and Xiamen City, people in these counties were covered by the Urban Basic Medical Insurance and were excluded from the analysis, leaving 73 counties covering about 98% of the rural population in the study area.This study used data from the New Rural Cooperative Medical Scheme (NRCMS) in Fujian Province, which is located in the southeast of China (ranging from 23°33′ ~ 28°20′ N to 115°50′~ 120°40′ E). It covers an area of about 124,000 km https://data.cnki.net/yearBook/single?id=N2017020245). All data were aggregated at the county level. The rate of breast cancer hospitalization was then calculated as the number of female breast cancer hospitalizations divided by female rural population in 73 counties.Breast cancer hospitalization was identified using the International Classification of Diseases (ICD) 10 code C50. The hospitalization data consisted of age, sex, county of registered residence, year of hospitalization, and cause of hospitalization. Cases were selected based on the county of registered residence rather than hospital attended, which ensures a better representation of the spatial distribution of the exposed population to the environmental and socioeconomic factors. The rural female population data was obtained from the Fujian Statistical Yearbook . S2 is the variance of the whole grid. I* is the local Moran’s I index; Wpq is the standardized spatial weight matrix; and Zp and Zq represent standardized values of grid p and q.In the formulation, I represents the global Moran’s I index; k represents the number of grids. XQuasi Poisson regression model was used to evaluate the overall association between the socioeconomic variables  and breast cancer hospitalization in women. In the univariate model, we tested the association with each of these variables, while the multivariable model mutually adjusted for the statistically significant variables identified in the univariate model.Then, we selected statistically significant socioeconomic variables in the multivariable model, and incorporated each soli heavy metal pollutant into the model, separately . This imIn the next step, geographically weighted Poisson regression was used to identify the factors associated with breast cancer hospitalization. The geographical weight regression model allows the association between two factors to vary spatially, which has been used in several previous environmental studies –35. The i, ui, xk, i and Ni are, respectively, dependent variable , the linear predictor, kth independent variable including the constant term, and the offset variable corresponding to population size at risk  at the location i. It should be noted that the estimated risk of hospitalization for breast cancer at location i is given by the term of exp(ui).  is the x-y coordinate of the ith location; and coefficients βk are assumed to be smoothly varying conditional on the location.where yThe estimates of the local coefficients at the location i are obtained by fitting a usual Poisson regression model to the data subset around the regression point i with a geographical weighting function. The standard errors of estimated local coefficients can be derived using local regression theory. A descriptive measure of goodness-of-fit for Poisson regression is the percent of deviance explained:The data were screened and cleaned using exploratory data analysis using SPSS26.0 and Microsoft Excel. Global Moran’s I, LISA values, were measured using ArcMap software (version 10.6). We used GWR software (version 4.0.80) to implement a GWPR to explore spatial non-stationarity in our data. All vector maps were created using ArcMap software (version 10.6). The study was approved by the ethical committee at Fujian Medical University (committee’s reference number 2019-27).5. The spatial distribution map , which suggested significant clustering. We further employed local Moran statistics to observe the local aggregation of breast cancer hospitalization rates. According to the result of local Moran statistics, two ‘high-high’ cluster regions, two ‘low-low’ cluster regions, as well as one ‘low-high’ cluster region were detected as statistically significant clusters  and road density  were significantly associated with breast cancer hospitalizations. However, medical institutions, health workers and per capita GDP were not significantly associated with breast cancer hospitalization rate at the 0.05 level.Table In this study, ArcMap software was used to extract the polluted areas of arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), nickel (Ni), lead (Pb), and zinc(Zn) in these 73 counties. Cd was the most serious pollutant covering 54.27% of the total area, followed by Hg, As, and Pb. To eliminate the influence of the area factor of each county, the polluted area of each county was converted into the percentage of soil polluted area of each county. Distribution of percentage of polluted areas in 73 counties of Fujian province was visualized by color in Fig. P = 0.016; Table After adjustment for urbanization and road density, Cd was the only heavy metal significantly associated with the hospitalization rate of breast cancer , two low clusters , and one high-low cluster(L) for the hospitalization of breast cancer. This spatial distribution may be partly because of the uneven distribution of medical resources for the rural population in Fujian province, with most provincial and high-quality hospitals located in relatively developed coastal cities. However, it’s worth noting that the developing area (C) had a high hospitalization rate, suggesting stronger demand for medical resources and unequal resource distribution in this area. Recently, due to the rapid economic development in China , even peIn this study, we found a positive association between urbanization and breast cancer hospitalization in the majority of the counties, which was consistent with the previously reported association between urbanization and breast cancer risk –43. In r2 might be associated with a higher risk of breast cancer [Together with the increase of urbanization, road density is also increasing in China recently. Positive association between road density and breast cancer hospitalization was found in many counties, possibly due to several reasons. First, higher road density means that there may be more traffic pollution. Studies on traffic-related pollutants have suggested that NOt cancer , 48. PAHt cancer . What’s t cancer . Second,t cancer , which wWe observed substantial geographic heterogeneity in the association between Cd and breast cancer hospitalization, with the strongest association observed among women in the northeast region (region D). Cd has been classified as a known carcinogen . The incConsidering the geographical disparity of risk factors for breast cancer hospitalization, different measures should be taken to improve women’s health. In western areas, which are in the rapid development stage, urbanization is the main risk factor for breast cancer and women have more demand for high quality medical resources. Health education to increase awareness of socioeconomic and lifestyle risk factors might reduce their future risk of breast cancer. In addition, regular screening services could be provided to detect breast cancer earlier and avoid hospitalizations caused by severe diseases. What’s more, for those coastal east areas, road density and Cd are the main risk factors. It is therefore vital to strengthen environmental governance, such as limiting the discharge of industrial heavy metals, especially Cd, and promoting the use of electric vehicles.The major strength of our study is the use of geographically weighted regression models, which are able to detect the spatially varied magnitude of the associations and provide insight into priority regions for health resource planning and allocation. Moreover, we had access to a variety of data on socioeconomic factors and soil heavy metals, allowing us to explore the potential influencing factors.Despite these, our findings should be interpreted in the context of several limitations. First, the design of ecological studies limits the ability to prove causality. The observed associations may be influenced by many unobserved confounding factors, such as other cultural factors, policy factors, and other natural factors. Second, the research unit of this paper is the county level divided by administrative regions. However, the distribution of environmental factors may be related to the natural geographical environment, and the corresponding effect might be attenuated. Subsequent studies are, therefore, needed to confirm the relationship between Cd and breast cancer using regions divided by the natural environment.Soil Cd pollution, road density, and urbanization were associated with breast cancer hospitalization in southeast China. The findings in this paper will help to understand the regional impact of Cd, road density and urbanization on the hospitalization rate of breast cancer, and provide valuable reference for the prevention strategy for breast cancer in southeast China and similar regions.Below is the link to the electronic supplementary material.Supplementary Table 1 source of the used dataset 2) Supplementary Table 2 contaminated area of soil metal elements (kmSupplementary Table 3 Summary of local parameters in the GWPR Supplementary Data 1 Socioeconomic data used in the analysis