Unfortunately, long-term survival comes at a cost to the survivor in the form of long-term health consequences. Subsequent malignancies, the most common of which is breast cancer among women, are associated with significant morbidity and mortality.This primer provides clinical cases focusing on the challenges associated with treating breast cancer after surviving childhood cancer.2 and blood pressure is 145/80 mm Hg. Medications include carvedilol, metformin, aspirin 81 mg/d. Treatment with 4 cycles of neoadjuvant doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) given intravenously every 2 weeks followed by paclitaxel (80 mg/m2) intravenously for 12 weeks is prescribed. Baseline 2-dimensional echocardiography reveals a left ventricular ejection fraction (LVEF) of 50%. Baseline electrocardiography shows normal sinus rhythm with mild left ventricular (LV) hypertrophy.A 50-year-old woman with a history of hypertension and diabetes presents with a T2N0M0 triple-negative  breast cancer of the left breast. She was treated at 4 years of age for Wilms’ tumor with right nephrectomy, flank and bilateral whole-lung radiation, and multiagent nonanthracycline chemotherapy. Body mass index is >30 kg/mThis patient is at high risk for incident breast cancer and cardiovascular (CV) complications from her prior radiation. Current guidelines recommend screening mammography and breast magnetic resonance imaging annually beginning 8 years after radiation or at the age of 25 years, whichever comes last.Triple-negative breast cancer is a biologically aggressive cancer in which combination chemotherapy with an anthracycline and taxane with or without carboplatin and immunotherapy is recommended and is generally well tolerated.2, medium risk (1 point); the total risk score is 5 points. Patients with scores ≥ 5 points are deemed at high risk, and referral for cardio-oncologic assessment is recommended. Patients at low to medium risk can be followed closely, with less vigorous cardiac monitoring, per current guidelines. Although validation studies are needed, this is an important contribution to personalizing CV risk assessment in patients with cancer.Cardiology and oncology professional society guidelines recommend baseline CV risk assessment for all patients with cancer prescribed potentially cardiotoxic therapy, but guidance is limited on how to define CV risk for individual patients. Risk is a continuous variable, and multiple factors may coexist. Weighing both patient comorbidities and treatment-related CV risk factors should be considered, and expert-consensus based calculators including those developed by the Cardio-Oncology Study Group from the Heart Failure Association of the European Society of Cardiology could be considered.Recognizing the extremely high risk for an asynchronous breast cancer and the high mortality after breast cancer diagnosis (50% by 15 years after diagnosis), and given the wide and bilateral field of radiation for Wilms’ tumor, a bilateral mastectomy (prophylactic right) should be recommended. Breast conservation, however, is not entirely contraindicated. A dose of 40 to 42.5 Gy over 15 to 16 fractions to the whole breast is generally considered safe following remote treatment with 12 Gy to the lung. Cardiac-sparing techniques such as deep-inspiration breath hold or prone positioning should be used. The risk for secondary malignancies and radiation-induced pulmonary and cardiotoxicities should be considered.Given the accelerated aging of childhood cancer survivors and the impact of cancer therapy on exercise tolerance, referral to a cancer rehabilitation program is highly recommended.2 anthracycline and developed premature menopause with her prior therapy. Genetics referral is provided.A 39-year-old postmenopausal woman with a history of hypertension presents with 2-cm, node-negative, ER+/HER2− left-sided breast cancer. The Oncotype DX score was 15. She was treated at 15 years of age for sarcoma with “red chemotherapy and multiple other drugs.” After reviewing records, it was found that she received 400 mg/mThe standard surgical approach for early-stage hormone-positive breast cancer is treatment with lumpectomy, sentinel lymph node biopsy, and adjuvant radiation therapy. Mastectomy with sentinel lymph node biopsy results in equivalent breast cancer recurrence outcomes and no improvement in overall survival.Cancer survivors often cannot recall the names of chemotherapies they received, and obtaining records from decades prior is difficult. On the basis of CV risk calculators developed and validated by the Childhood Cancer Survivor Study, this patient’s risk for heart failure by 50 years of age is 9.7%, a 31-fold higher risk compared with a sibling control without cancer.Adjuvant endocrine therapy with tamoxifen or an AI reduces the risk for recurrence by approximately one-third. In postmenopausal women, an AI would be recommended given superiority in reduction of risk for breast cancer recurrence. Large clinical studies have reported higher rates of hypertension, hypercholesterolemia, and ischemic CV disease in postmenopausal breast cancer survivors receiving AIs. This patient’s prior anthracycline exposure, premature menopause, and use of AIs necessitate aggressive CV risk factor management with risk-reducing medications and exercise under the direction of a cardio-oncologist or primary care provider.2, bleomycin, vinblastine, and dacarbazine) and mantle radiation at 19 years of age presents with a stage IIB (T2N1) lymph node–positive ER−/HER2+ breast cancer. Neoadjuvant chemotherapy with a non-anthracycline-based regimen with trastuzumab and pertuzumab (HP) is recommended.A 40-year-old woman with a history of Hodgkin lymphoma treated with ABVD chemotherapy  would be considered optimal.This patient is at increased risk for cancer therapy–related cardiac dysfunction, defined as a decrease in LVEF of >10% to a value less than the lower limit of normal. A baseline comprehensive CV assessment including 3-dimensional echocardiography with global longitudinal strain and consideration for prophylactic cardioprotective medications is recommended prior to treatment.As previously discussed, bilateral mastectomy would be recommended given the patient’s elevated risk for additional future de novo breast cancers. Adjuvant radiation therapy may still need to be considered given the elevated risk for locoregional recurrence. Although retrospective data are reassuring, reporting a low risk for grade 3 toxicity,The patient completes docetaxel, carboplatin, trastuzumab, and pertuzumab and undergoes surgery with a full axillary node dissection. She has pCR. Cancer treatment with 1 year of postoperative HP is recommended. Follow-up echocardiography after the first cycle of HP demonstrates a decline in LVEF to 44%.In the adjuvant setting, trastuzumab with or without pertuzumab is recommended every 3 weeks to complete 12 months of therapy. Trastuzumab emtansine can be offered in the adjuvant setting for those who do not achieve pCRIn an individual with prior exposure to anthracyclines and chest radiation, this decline in LVEF is suggestive of cancer therapy–related cardiac dysfunction related to HER2 therapy. Other causes, including metabolic and ischemic etiologies (particularly given prior chest radiation), must be excluded.+ Breast Cancer) trial, which enrolled HER2-positive patients with asymptomatic LV dysfunction (LVEF 40%-49%) who were candidates for trastuzumab, pertuzumab, or trastuzumab emtansine,The SAFE-HeaRt (Cardiac Safety Study in Patients With HER2Individuals who develop metastatic HER2-positive breast cancer will be exposed to sequential HER2-based therapies. For these patients, there is no clear guidance on the frequency of cardiac monitoring. If LVEF is stable for 12 months, the patient remains asymptomatic, and natriuretic peptide biomarkers remain stable, it may be reasonable to consider reducing the interval of echocardiography frequency to 6 months or more. This modification should be made on an individual basis, weighing prior cardiotoxic exposures and comorbid risk factors.Care for childhood cancer survivors who develop breast cancer requires careful consideration of prior cancer treatments, as well as comorbidities that frequently develop in the decades following childhood cancer diagnosis. Aggressive management of CV risk factors in collaboration with cardiologists, oncologists, primary care providers, and allied health care providers is needed to provide the best cancer treatment while optimizing CV health.This work was supported by NIH grant K08 CA234232 to Dr Turcotte. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.


This cohort study evaluates the risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment among premenopausal Korean women with breast cancer. Is the use of tamoxifen as an adjuvant hormone therapy for breast cancer associated with increased risk of uterine diseases among premenopausal Korean women?This cohort study of 78 320 participants revealed that tamoxifen use in premenopausal women with breast cancer was independently associated with an increased risk of endometrial polyps, hyperplasia, carcinoma, and other uterine cancers.These findings suggest that awareness about the absolute risks of uterine diseases with long-term follow-up is essential for the daily management of premenopausal breast cancer survivors receiving tamoxifen and that the risk of uterine diseases in tamoxifen users, specifically in premenopausal women, should be considered. The association of tamoxifen use with the risk of uterine diseases, such as endometrial cancer, in premenopausal women with breast cancer remains controversial. However, many studies have reported an increased risk of uterine disease among postmenopausal tamoxifen users.To investigate the association of tamoxifen use with the risk of endometrial cancer and other uterine diseases in premenopausal women with breast cancer.A nationwide, population-based, retrospective longitudinal cohort study with an 18-year study period was conducted using data obtained from the Korean National Health Insurance Service. Participants included premenopausal women aged 20 to 50 years with breast cancer diagnoses between January 2003 and December 2018. Data were analyzed from April to December 2021.Tamoxifen treatment.The incidence of uterine diseases, including endometrial cancer, hyperplasia, polyps, and other uterine cancers, was identified in the study cohort using insurance claim codes. The incidence of uterine diseases per 1000 person-years was compared between women receiving tamoxifen and those not treated with adjuvant hormone therapy. Multivariable Cox proportional hazard regression analysis was performed to determine the risk of each uterine disease.Among 78 320 female participants with a mean (SD) age of 42.1 (6.1) years, 34 637 (44.2%) were categorized into the tamoxifen group and 43 683 (55.8%) were categorized into the control group. Among tamoxifen users, during the mean (SD) follow-up duration of 6.13 (4.15) years, the incidence of newly diagnosed endometrial polyps was 20.13 cases per 1000 person-years, that of endometrial hyperplasia was 13.49 cases per 1000 person-years, that of endometrial cancer was 2.01 cases per 1000 person-years, and that of other uterine cancers was 0.45 cases per 1000 person-years. The risk of endometrial cancer was higher in the tamoxifen group than in the control group  after adjusting for age, body mass index, history of diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, gonadotropin-releasing hormone agonist treatment, and trastuzumab treatment.In this longitudinal cohort study, premenopausal Korean women with breast cancer who received tamoxifen as adjuvant hormone therapy had a significantly increased risk of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers compared with those who were not treated with adjuvant hormone therapy. These findings suggest that clinicians should consider the risk of uterine disease among tamoxifen users, including premenopausal women. It is assumed to have tumor-promoting activity, which is associated with serious adverse effects.4 Indeed, tamoxifen use has been reported to be associated with various uterine pathologies, such as endometrial polyps, hyperplasia, cancer, and other uterine cancers, in postmenopausal women.4 A meta-analysis5 of 55 randomized trials showed that the incidence of endometrial cancer increased, and the risk of mortality owing to endometrial cancer increased after the administration of adjuvant tamoxifen therapy in postmenopausal women with early breast cancer.Tamoxifen was the first selective estrogen receptor modulator approved by the US Food and Drug Administration as an adjuvant hormone therapy for women with breast cancer. Worldwide, breast cancer is the most common cancer in women.3 it remains unclear whether the use of tamoxifen in premenopausal women is associated with an increased risk of several uterine diseases, including endometrial cancer. Although many reports have described an increased risk of endometrial cancer in tamoxifen users, the risk group has typically been confined to postmenopausal women with breast cancer.6 Few retrospective or case-control studies have assessed endometrial pathology in premenopausal women treated with tamoxifen.11 Existing guidelines do not warn of the potential risk of gynecologic diseases with tamoxifen use, nor do they recommend routine screening for uterine diseases in premenopausal women receiving tamoxifen.13 Furthermore, Asian women are known to have an earlier peak age of occurrence of breast cancer than Western women, suggesting that the proportion of premenopausal women among tamoxifen users is higher in Asian women.14 However, extrapolation of the observations in postmenopausal Western women to relatively young premenopausal Asian women is debatable. Therefore, the objective of this cohort study was to use Korean nationwide cohort data to examine the risks of uterine pathologies, including endometrial hyperplasia, polyps, carcinoma, and other uterine cancers, in premenopausal Korean women with breast cancer who had been treated with tamoxifen.Although premenopausal women with breast cancer are usually treated with tamoxifen as first-line adjuvant hormone therapy,15 All medical institutions submit health care utilization–related data to ensure reimbursement, which are stored in the NHIS database. Established in January 2002, the NHIS database contains information from all hospitals, including admission and outpatient records . The NHIS includes an eligibility database , a medical treatment claims database , a health examination database , and a medical care institution database . This customized research database is available to medical researchers for policy development and academic research. The data used in this study comprised all the NHIS claims records from 2002 to 2019.We used data obtained from the Korean National Health Insurance Service (NHIS), a single medical insurer in the Republic of Korea. This national insurer is operated by the Ministry for Health, Welfare, and Family Affairs, and covers the majority of the Korean population (approximately 97%).STROBE) reporting guideline reporting guidelines for cohort studies. The requirement for informed consent was waived by the institutional review board because the data used were deidentified.Personal information in the Korean NHIS database was anonymized. Study protocols were approved by the official review committee of the Korean Government and the institutional review board of Korea University Anam Hospital and followed the Strengthening the Reporting of Observational Studies in Epidemiology , D05.X (carcinoma in situ of the breast), or D48.6 . The first date of diagnosis registration in the NHIS database was assumed to be the date of diagnosis. A 1-year washout period was used in this study, meaning that women with the first claim record from January 1, 2002, to December 31, 2002 (which might have included those with a diagnosis before 2002) and those with the first claim records from January 1, 2019, to December 31, 2019, and who had a follow-up period of less than 1 year, were not included. The exclusion criteria were as follows: (1) patients who reported being menopausal at the time of breast cancer diagnosis, (2) patients with any of the diagnostic codes related to postmenopausal status , (3) patients who had been treated with aromatase inhibitors  or toremifene as an adjuvant hormone therapy, (4) patients who died after the diagnosis of breast cancer and before the prescription of tamoxifen, (5) patients who had diagnoses of the following uterine diseases before breast cancer was diagnosed , (6) patients who had the aforementioned diagnosis of uterine diseases that occurred between the diagnosis of breast cancer and the first treatment of tamoxifen, (7) patients whose prescriptions were switched between tamoxifen and aromatase inhibitors, and (8) patients with no health checkup data. All participants who satisfied all the inclusion and exclusion criteria were included in the study , endometrial hyperplasia , endometrial cancer , other uterine malignant neoplasms , and the combined results . Other uterine malignant neoplasms were defined as malignant neoplasms of the uterus that did not originate from the endometrium, as follows: C54.0, malignant neoplasm of the isthmus of the uterus; C54.2, malignant neoplasm of the myometrium; C54.3, malignant neoplasm of the fundus of the uterus; C54.8, malignant neoplasm of the overlapping sites of corpus of the uterus; C54.9, malignant neoplasm of the corpus of the uterus; and C55, malignant neoplasm of the uterus, part unspecified. The following variables were compared between the 2 groups: age, body mass index (BMI), waist circumference, history of diabetes, hypertension, dyslipidemia, polycystic ovary syndrome (PCOS), household income level, physical exercise level, current smoking status, alcohol consumption, blood pressure, serum fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. Physical exercise level was categorized into 3 groups  according to the frequency of activity lasting at least 20 minutes per day.Medical histories of the participants were evaluated using t test and χ2 test were performed to compare the baseline characteristics of the groups, depending on the presence or absence of tamoxifen treatment. The incidence per 1000 person-years of each of the aforementioned uterine diseases was compared between the 2 groups using the Poisson regression model. Cox proportional hazard regression models were used to compare the risk of each disease outcome between the 2 groups. Multivariable Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs after adjusting for age, BMI, history of diabetes , hypertension, dyslipidemia, polycystic ovary syndrome, gonadotropin-releasing hormone (GnRH) agonist treatment, and trastuzumab treatment. For the subgroup analysis, the cumulative duration of tamoxifen use was used as a time-dependent covariate. All statistical analyses were performed using SAS statistical software version 9.4 (SAS Institute Inc). All P values provided were 2-sided, and P < .05 was considered significant. Data were analyzed from April to December 2021.The baseline demographic and clinical characteristics of the participants are summarized as mean (SD) for continuous variables and as numbers (percentages) for categorical variables. The Of the 78 320 premenopausal women with breast cancer , 34 637 (44.2%) were categorized as the tamoxifen group, and 43 683 (55.8%) as the control group. Compared with the women in the control group, those in the tamoxifen group had higher mean age, BMI, waist circumference, blood pressure, and fasting glucose levels; had poorer lipid profiles; were more likely to have a history of hypertension, diabetes, and dyslipidemia; had current smoking status; had treatment with GnRH agonist, trastuzumab, and metformin; had generally higher household income; and were less likely to have a history of PCOS . The totCox proportional hazard regression models were applied to compare the risk of each disease outcome and all composites between the 2 groups. The unadjusted HRs for endometrial hyperplasia and endometrial cancer were 5.55  and 3.725 , respectively. The results of multivariable Cox regression analysis are shown in Among the women in the tamoxifen group, 9378 (27.1%) had prolonged tamoxifen treatment beyond 5 years. The results of the multivariable Cox regression analyses for the risk of each uterine disease comparing tamoxifen treatment for the group treated 5 or less and the group treated more than 5 years with the control group are presented in We conducted a population-based, retrospective, longitudinal cohort study using a nationwide cohort data with long-term follow-up and found that premenopausal women with breast cancer who received tamoxifen as an adjuvant hormone therapy had significantly increased risks of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers compared with those who were not treated with adjuvant hormone therapy. Tamoxifen use was associated with an approximately 4-fold higher risk of developing endometrial cancer, even after controlling for several confounding factors, including age, BMI, diabetes, hypertension, dyslipidemia, PCOS, and GnRH agonist treatment.16 and the incidence was even higher than that in various age groups (0.26-1.38 cases per 1000 person-years) observed in another population-based cohort study in South Korea.17 A meta-analysis conducted 10 years earlier by the Early Breast Cancer Trialists’ Collaborative Group included 20 trials (21 457 participants) and reported that 5 years of tamoxifen use was associated with increased incidence of endometrial cancer only in women older than 55 years.18 Another systematic review conducted around the same time also found that only women older than 50 years who received tamoxifen, and not younger patients, had a higher risk of endometrial cancer than those who did not use tamoxifen.19 Unlike previous Western studies, recent studies conducted in East Asian populations showed contrasting results. A population-based cohort study20 with a 14-year study period included 39 216 women with nonmetastatic breast cancer in Taiwan. The study found that both older (aged ≥50 years) and younger (aged 40-49 years) patients treated with tamoxifen had a higher risk  of endometrial cancer than those who did not use tamoxifen.20 A recent retrospective cohort study17 using Health Insurance Review and Assessment Service claims data from South Korea included 60 545 women who had new diagnoses of breast cancer between 2010 and 2015. The study found that the use of tamoxifen was associated with an increased risk of endometrial cancer among women aged 40 to 49 years .17 However, these studies could not assess the menopausal status of women and did not control for some confounding factors in their analyses, such as BMI, although differences in baseline characteristics were observed between the tamoxifen and control groups.20In this study, the incidence of endometrial cancer was 2.01 cases per 1000 person-years in premenopausal women treated with tamoxifen and was comparable to that of tamoxifen-treated postmenopausal women with breast cancer (1.83/1000 person-years) observed in a previous multiethnic and multicenter cohort study in the US,12 Although these benign diseases are not life-threatening, they might be the most common endometrial pathologies occurring in tamoxifen users. These pathologies lead to additional medical costs or invasive procedures.11 The present study showed a greater risk of benign diseases in premenopausal tamoxifen users than those reported in previous clinical studies.21 Furthermore, we reaffirmed the increased risk of uterine cancers other than endometrial cancer such as sarcoma in premenopausal tamoxifen users.12 Tumor-promoting effects of tamoxifen on the uterus might be the mechanism that underlies those findings4; however, it is also possible that women who were treated with tamoxifen visited gynecologic clinics more frequently than women who did not, resulting in a higher detection rate of asymptomatic lesions.Tamoxifen is also associated with endometrial hyperplasia and polyp formation.12 These recommendations were based on previous studies23 that reported no associations between endometrial cancer and tamoxifen use among premenopausal women. However, most of these studies were outdated, with a small number of premenopausal women. These were hospital-based studies and conducted mostly in Western populations. Our findings clearly indicate that clinicians should consider the risks of endometrial cancer and other uterine malignant neoplasms among tamoxifen users, regardless of menopausal status. Furthermore, the median age at which East Asian women receive a breast cancer diagnosis is approximately 10 years lower than that of Western women.24 This makes it particularly important for clinicians to be aware of the risks of various uterine diseases in young premenopausal breast cancer survivors receiving adjuvant hormone therapies.The American College of Obstetricians and Gynecologists Committee advised that premenopausal women treated with tamoxifen have no known increased risk of uterine cancer and did not recommend any additional monitoring beyond routine gynecologic care.26 GnRH agonist treatment is associated with a higher risk of endometrial hyperplasia, although it has been shown that this treatment and the subsequently induced hypoestrogenism reduce the risk of endometrial diseases.27 This could be a consequence of the higher incidence of GnRH agonist use in the tamoxifen group. However, its suppressive effect on progesterone levels in premenopausal women, which has a protective role in the endometrium, should be considered.28 Interestingly, a history of trastuzumab treatment increased the risk of uterine cancers other than endometrial cancer, and the risk of endometrial polyps was reduced by approximately 50%. These findings should be investigated in future studies.Several expected factors associated with risk for endometrial cancer were reconfirmed in this study, including BMI, history of dyslipidemia, and PCOS; however, diabetes and hypertension were not confirmed.BRCA and MMR genes, were not available; further studies are needed to confirm the effect of genetic status on the association between tamoxifen use and the risk of uterine diseases. Fifth, owing to the retrospective nature of the study, we cannot exclude the possibility that the patients enrolled in the tamoxifen group had an undiagnosed uterine disease at the time of tamoxifen exposure. Diagnostic hysteroscopy immediately before beginning tamoxifen therapy in future prospective studies could overcome this limitation.Our study had limitations. First, considering that asymptomatic patients might be less likely to visit a gynecologic clinic, the incidence of uterine diseases might have been underestimated in the NHIS database. Furthermore, annual gynecologic screening is recommended in Korea for patients with breast cancer during the tamoxifen-treatment period and would help in diagnosing uterine diseases in patients more easily than in those who are not treated with tamoxifen. However, this limitation might be compensated by the high accessibility of health service in South Korea. Second, there was no information on clinical symptoms, histological findings, tumor stage, or tumor grade in the data. Therefore, we could not perform analyses according to the different types of breast cancer. Further studies are required to investigate whether these variables affect the association between tamoxifen and gynecologic diseases. Third, there were no data on whether the breast cancer in the patients was estrogen receptor–positive or estrogen receptor–negative. Although women with estrogen receptor–positive breast cancer who were not treated with tamoxifen would be the most appropriate control group for the tamoxifen group, such enrollment might be difficult considering the inherent limitation of using a claim-based database. Fourth, genetic variation data related to breast and endometrial cancers, such as In this longitudinal cohort study, premenopausal Korean women with breast cancer who received tamoxifen as adjuvant hormone therapy had a significantly higher risk of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers than those not treated with tamoxifen. Clinicians managing premenopausal tamoxifen users should consider the risks of these uterine diseases and counsel patients accordingly.


BRCA1/2 alterations increase females’ lifetime breast cancer risk to 40 – 90%, ovarian cancer to 10 – 60%, and males’ lifetime prostate cancer risk to ~ 10 – 25%. Psychosocial issues such as heightened distress can, therefore, occur in this population. This study aimed to explore the subjective experiences and needs of the BRCA1/2 alteration population in navigating cancer risk reduction measures.BRCA1/2 alteration carriers, recruited through strategic sampling. A public and patient panel (N = 6) collaborated on study development. Data were analysed using reflexive thematic analysis.This study aimed to explore the experiences and identify the needs of 18 Two themes were identified: (i) Healthcare Services as a Burden to Navigate, and (ii) Burden Experienced Through Interactions with Healthcare Professionals. Results indicated uncertainty regarding care pathways, alongside a lack of relevant information. Participants felt unsupported by healthcare professionals, and as though healthcare professionals often perceive them as a burden.BRCA1/2 alteration population, and that uncertainty surrounding access to services and information is prevalent. The establishment of specialist hereditary cancer clinics could reduce such burden.These findings suggest that the quality of interactions in healthcare systems are of relevance to the The online version contains supplementary material available at 10.1186/s12913-022-08372-w. BRCA1/2) act as tumour suppressors, assisting in preventing tumorous growths. These genes can become altered, known as BRCA1/2 alterations or mutations, significantly increasing the cumulative lifetime risk for numerous cancers. In females, BRCA1 and BRCA2 alterations lead to a 72% and 69% cumulative lifetime risk of breast cancer, respectively  were dealing with my screening but they really had no expertise … it was traumatic, to be honest”.The second theme represented the influence that healthcare professionals had on individuals’ feelings of being dismissed and is comprised of two subthemes. The first subtheme depicted the lack of understanding among healthcare professionals about the emotional impact of having to make decisions about risk management, which often led to negative interactions. This was expressed through commentary on the lack of awareness and empathy shown by a variety of healthcare professionals. The second subtheme portrayed a disempowerment around decision making, wherein participants discussed how they were regularly dismissed by their healthcare professionals.BRCA1/2 alteration, as one participant noted “the attitude some of the doctors meet you with, when you’re going in, it’s like, ‘you’re here, there’s nothing wrong with ya’”. One individual had a similar experience with her GP when presenting with potential breast cancer symptoms, and was dismissed due to the fact that she had recently had a child:He literally laughed at me down the phone … "you're only young. I don't think it's anything to worry about. Just put a hot cloth on your boob, you'll be fine" … I paid 30 quid for the pleasure of that … He just kept referring to my age … "You're too young to have anything wrong with you". And I was like, I don't think life works like that, it would be great if it did, but, unfortunately, it doesn't.Adding to the burden that individuals perceive that they present in the healthcare system, participants often felt misunderstood by healthcare professionals, as per one participant: “…like doctors, they work in it and it’s grand and all, but I’ve known, I know from my own experience, they don’t understand”. As another participant stated, “there is such a lack of awareness of something like that, life-changing impact… I definitely had to carry a huge amount of it myself”. This is reiterated by other participants, “there wasn’t any support, or there wasn’t anybody that you were told, okay, this is somebody that you can go and speak to now to give you guidance or you know”. Healthcare professionals were often perceived to be dismissive towards individuals with a BRCA alteration status, “he was like … chill … it's no biggie … don't be too worried about it”, which she considered “about as helpful now as a slap in the head”. There were numerous counts where individuals described insensitive interactions with healthcare professionals, “one consultant … was very clinical … just asked me to open up my top and the whole team was there, and I remember crying, doing it”.One participant recalled an interaction with her GP, wherein after being informed of her I told him that, you know, I think I was gonna keep me body parts… he agreed … then I saw him the next time he took the head off me! There was students standing outside the door when he left I said ‘I feel like I just left the principal’s office’… he was giving out hell to me that I hadn’t done anything… he said “this is a cancer clinic. People in here have cancer. You’re coming here to see if your cancer has arrived yet.Participants also experienced conflicting interactions with healthcare professionals. One participant described how her physician reacted negatively to her because of her decision to proceed with screening, rather than undergo preventative surgery:I wouldn’t like to be back there with the stress that caused… I came up against such a brick wall… I am really glad that I really found it somewhere to stand up to it…And in the end, they agreed to it. But I don’t think unless I created an awful argy bargy, that they would have done it… when I did go in for that meeting with the surgeon… I actually felt like, ‘I’m going in here to fight for my life’.Another participant also described a stressful situation with a healthcare professional dismissing her concerns, wherein she had an active cancer diagnosis and was advised to undergo a unilateral mastectomy. This participant had, however, requested to undergo a bilateral mastectomy to reduce her cancer reoccurrence risk. This was met with resistance:A similar issue was noted by another participant, who felt dismissed when a healthcare professional addressed her husband when he was accompanying her to an appointment to consider undergoing a salpingo-oophorectomy. She recalled how “the doctor spoke to [husband] about it. He said you do realise what this entails now, don’t you?”, and how “that was something that annoyed” her.BRCA1/2 alteration population. This uncertainty was heightened by the lack of clear information available for this population. In past research, information has been noted by BRCA1/2 alteration carriers as a tool that can alter the potential course of cancer development [BRCA1/2 alteration population for management strategies to alleviate the disempowerment and uncertainty noted in the current study. There are avenues through which such support can be offered by the nursing profession to hereditary cancer cohorts. Psycho-educational interventions have been previously noted as efficacious in assisting in reducing anxiety in this cohort [The concerns raised by the study participants indicate that the services they are engaging with are difficult to navigate. Such services are vital in mitigating a cancer risk in the elopment . As infoelopment , the tras cohort , and theBRCA1/2 alteration. There is a strong need for healthcare professionals across all specialities to be provided with assistance and training in genetics [n = 359), only 6% reported always taking a family history [BRCA1/2 alteration carriers face, in this instance focusing on those that are young and female [BRCA1/2 alteration carrier, and how this can impact childbearing and relationships with spouses has been highlighted as a means to support individuals in this population [BRCA1/2 healthcare service users, and further bolsters the need for better education on genetics among those involved in providing care to this population.A clear issue reported by participants in the current study was the lack of knowledge held by healthcare professionals regarding the implications of a genetics , 46. Pasgenetics . This isgenetics . While m history . This ind female . An acknpulation . The curBRCA1/2 alteration, findings may also encapsulate the experiences of other populations with chronic conditions that are similarly living with a continued need to engage with health services. This article highlights the BRCA1/2 alteration populations’ need for coordinated and well-informed interactions with health care professionals. The lack of a centralised, clear cancer genetics service heightened distress in the study sample as individuals could not access relevant information. A common issue noted was poor access to services, which was often heightened due to waiting times. Additional problems emerged in trying to navigate services that were not designed with a hereditary cancer population in mind, leaving individuals often feeling as though they were a burden when presenting for appointments in symptomatic cancer units.While the results from this study demonstrated the experiences of those with a BRCA1/2 alteration [Contextual factors are important when addressing experiences of individuals with a teration , and so teration . FurtherPALB2 gene, may experience similar difficulties in accessing the appropriate healthcare in tiered systems. Similar findings pertaining to the stress created by barriers in gaining access to healthcare have already been identified in other hereditary cancer conditions. This further highlights the need for specialist cancer genetic care within the broader healthcare system [As more pathogenic variants are identified that denote a high to medium risk of lifetime breast cancer risk , researce system , 53.BRCA1 alteration and is heavily involved in the charitable and advocacy field for this population. The personal relationship of the researcher to the research topic and the influence of PPI in the focus of the study seemed to promote a level of openness in response to the questions, by allowing a shared ‘commonality’ between the participants and the researcher [The use of a PPI panel further strengthened this research as the focus of the study was chosen based on discussion with the panel members. Furthermore, the lead author in the study carries a searcher , 55. ThiBRCA1/2 alteration across the country . This, combined with recruitment of participants through private Facebook groups, led the researchers to conclude that the risk of identifying participants by PPI panel members was too high, should they be involved in analysis. Themes were therefore reviewed by the study supervisor (AMG), with continued reflexive practice employed. Informal discussions with members of the BRCA1/2 alteration population also took place, to report results and gain insight into the comprehensibility of themes. This was not included as official PPI activity since it was neither formally structured nor planned. It did, however, influence the interpretation of study findings. Through these discussions of developed themes, NW was afforded the opportunity to further reflect on how the community at large interpreted results. The inaccessibility of healthcare was especially prominent in discussions, which bolstered the meaning derived from quotes for the subtheme “Healthcare Services as Largely Inaccessible”. While the lack of formal input into analysis was a potential limitation, the significant contribution from the Irish BRCA1/2 alteration community at the outset of this research ensured that the study aims, and design, were deemed of relevance to the population under study.A limitation of this study design was that it was not feasible to involve the PPI panel in the analysis of this study. This was due, in part, to not having the opportunity to provide remuneration. In addition to this, there was a concern among the authors that the PPI panel may be able to identify participants from details in study transcripts. This is attributable to the small population of Ireland, and therefore relatively small population of people identified as carrying a BRCA1/2 alteration community (NW), a considerable amount of time was spent reflecting on how NW interpreted and situated their understanding of the data produced. In research of this nature, there is potential for an inside researcher to highlight shared experiences with participants, over experiences not shared [BRCA1/2 alterations may be mutual, the emphasis of the interview is not to find shared commonalities between researcher and participant, but to hear about theirs. In future, including the PPI panel in the analysis of the study findings may further enhance this process.Alongside this, the familiarity of the topic at hand to the researcher was an aspect that required continued addressing throughout the data analysis. In reflexive thematic analysis, the subjectivity of the researcher is not considered a threat to the study findings, nor a negative source of bias . Rather,t shared . From thBRCA1/2 alteration, nor were participants recruited on the basis of preventative measures undertaken. This was mainly due to practical considerations – as minimal research has been conducted in this population to date, the researchers left recruitment as open as possible. Furthermore, all the PPI panel sampled in this research identified as female, and all PPI panel members and the majority of participants were White-Irish. This is not representative of Ireland’s population, a country with a growing rate of non-native residents, whereby in 2018 over 12% of the population were non-Irish nationals [BRCA2 alterations [A potential limitation of this study was participants were not selected based on time since the identification of their ationals . Populatationals . A recenationals . It is, erations . This poerations . Future BRCA1/2 alteration face when trying to navigate a medical system which was not designed with a hereditary cancer population in mind. It notes the importance placed by the BRCA1/2 population on the quality of both available services and interactions with healthcare professionals. Due to underdeveloped services and a lack of access to appropriate services, hereditary cancer populations continue to experience uncertainty. While the provision of preventative care for the management of hereditary cancer risks is still relatively novel, the findings from this study suggest that the perceived quality and availability of care may play a role in the adjustment experiences of the BRCA1/2 population. Such populations should be enrolled in a healthcare system that is well-equipped and designed to facilitate individuals with hereditary cancer conditions.This study highlights the undue burden that individuals with a Additional file 1.


Male breast cancer is rare but its incidence and mortality are increasing in the United States, with racial/ethnic disparities in survival reported. There is limited evidence for cardiotoxicity of cancer treatment among men with breast cancer. We evaluated the relation between breast cancer treatment and cardiovascular disease (CVD) mortality among men and investigated the salient roles that race/ethnicity play on this relation. Data were from 5216 men with breast cancer aged ≥ 40 years from the Surveillance, Epidemiology, and End Results program who were diagnosed from 2000 to 2019 and underwent surgery. Competing risk models were used to estimate hazards ratios (HR) and 95% confidence intervals (CI). During a median follow-up of 5.6 years, 1914 deaths occurred with 25% attributable to CVD. In multivariable-adjusted models, men who received chemotherapy had elevated risk for CVD . This risk was higher among Hispanic men  than non-Hispanic Black and non-Hispanic White men. There was no significant association between radiotherapy and CVD deaths. In this population-based study, treatment with chemotherapy was associated with elevated risk of CVD mortality in men with breast cancer. Racial/ethnic disparities in the association of chemotherapy and CVD mortality were observed. Male breast cancer (MBC) is a rare and understudied cancer that accounts for about 1% of all breast cancer cases in the United States ,3. WhileDue to its rarity, most MBC patients in the past have not been included in therapeutic studies, therefore, treatment strategies for MBC have largely been extrapolated from evidence from FBC patients ,5,6,7. WAlthough inconclusive, several studies have reported worse prognosis for MBC patients compared to FBC patients . Recent Noncancer death, especially cardiovascular disease (CVD)-related deaths, accounts for a large proportion of deaths in MBC survivors as these two conditions share in common several risk factors ,12. OnlyTremendous changes in treatment modalities for breast cancer have occurred over the past five decades that has been suggested to influence cardiovascular outcomes among breast cancer survivors ,14,15. TData for this registry-based prospective cohort study were obtained from National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program which covers about 34% of the US population and obtains information from 17 population-based cancer registries located in the following states: Alaska, California, Connecticut, Georgia, Hawaii, Iowa, Kentucky, Louisiana, New Mexico, New Jersey, Utah. and Washington . Men ageInformation obtained from the SEER database included age at diagnosis, year of diagnosis, race and ethnicity, geographic region, location , marital status, annual median household income of the county of patient’s residence, disease stage, tumor grade, tumor size, laterality, number of regional lymph nodes examined, hormone (estrogen and progesterone) receptor status, cancer therapy, cause of death, and survival time. The main exposure of interest in the current study was first course of cancer therapy. For the current analysis, both radiotherapy and chemotherapy were classified as received or not received. The reported sensitivity, specificity, and positive predictive value of the SEER database correctly identifying individuals with breast cancer who received therapy are 69%, 98%, and 91% for chemotherapy and 80%, 98%, and 98% for radiotherapy . Breast Cause of death information was classified using the World Health Organization’s International Classification of Diseases, Tenth Revision codes. CVD mortality was defined as deaths due to diseases of heart , hypertensive heart disease (I10–115), cerebrovascular diseases (I60–I69), atherosclerosis (I70), aortic aneurysm and dissection (I71), or other diseases of arteries, arterioles, or capillaries (I72–I78). Characteristics of men at the time of cancer diagnosis were described and compared among cancer treatment groups using chi-square test. Competing risk analyses were conducted using cause-specific hazard models, with deaths from all other causes besides CVD considered as competing risk events. Because the incidence of MBC and CVD mortality rates increase with advancing age, attained age in years was used as the time scale for all time-to-event analyses. Thus, estimates from such model are age-adjusted . The valCovariate selection for multivariable models was based on variables that were significant in bivariable analyses at an alpha of 0.2. Variables evaluated in bivariate models were year of diagnosis, race and ethnicity, geographic region, location, marital status, income, disease stage, estrogen and progesterone receptor status, tumor grade, tumor size, laterality, and number of regional lymph nodes examined. Because the impact of radiation on overall survival among MBC patients is not the same between breast conservation surgery and mastectomy , and radp value of less than 0.05.Finally, interaction between race and ethnicity with cancer therapy was tested. The SEER*Stat version 8.4.0.1 software  and the SAS software version 9.4  were used to conduct the statistical analyses with statistical significance determined with a two-tailed test Over the study period, there was an increase in the number men diagnosed with cancer. Approximately 20% of men with breast cancer were diagnosed in 2000–2004 compared to 28% in 2015–2019. The mean age at diagnosis was 66.1  years, with more than half of them (52%) living in the west region of the United States at the time of cancer diagnosis. The racial and ethnic distribution of the sample are as follows: non-Hispanic White, 75%; non-Hispanic Black, 12%; and Hispanic, 7%. Only 12% of men diagnosed with breast cancer lived in counties with median household incomes of less than $50,000. With regards to receipt of cancer treatment, 38.8% and 28.4% of men reported receiving chemotherapy and radiotherapy, respectively, with the median time from diagnosis to treatment being 1 month. Characteristics of participants according to the first course of cancer therapy received are reported in Over the period of the study, the proportion of patients who received radiotherapy (with or without chemotherapy) increased while the proportion of patients who received chemotherapy reduced with age. Additionally, a greater proportion of patients who received both chemotherapy and radiotherapy had stage III cancer while the proportion of patients with mastectomy was lowest among those who received radiotherapy alone. During a median follow-up of 5.6 years (interquartile range: 2.6 to 9.8), 1914 deaths occurred with 25% and 35% attributable to CVD and breast cancer, respectively. Characteristics of patients at the time of diagnosis according to cardiovascular disease mortality status are presented in Multivariable models were adjusted for age, year of cancer diagnosis, race and ethnicity, disease stage, tumor size, and number of lymph nodes examined as these variables were found to be statistically significant in bivariable analyses. In these models, men with breast cancer who received chemotherapy as part of their first course of treatment had elevated risk for CVD (Hazard ratio (HR): 1.32, 95% CI: 1.05–1.66)), with the risk being higher among those who received chemotherapy alone  . p = 0.005). The risk of CVD mortality was observed to be highest among Hispanic men  (There was no significant association between radiotherapy (with or without chemotherapy) and CVD deaths. There was a significant interaction between race and ethnicity and cancer treatment on the risk of CVD mortality (1–12.02) . p = 0.672). Similarly, the relation of radiotherapy and CVD mortality was not significantly influenced by the type of surgery, thus breast conservation surgery or mastectomy (p = 0.206).Among persons who received radiotherapy, there was no significant influence of laterality or the association of radiotherapy and CVD mortality (In this population-based study of men diagnosed with breast cancer in the United States over a 20-year period, treatment with chemotherapy was associated with elevated risk of CVD mortality, while no significant association was observed between radiation therapy and deaths due to CVD. Racial and ethnic disparities in the association of chemotherapy and CVD mortality were observed, with Hispanic men having higher risk of CVD deaths compared to non-Hispanic Black and non-Hispanic White men. To our knowledge, this is the first study to comprehensively characterize CVD mortality due to cancer treatment among men diagnosed with breast cancer.Some breast cancer therapeutics have been reported to result in early or delayed cardiotoxicity comprising of hypertension, arrhythmias, pericarditis, thromboembolism, valvular disease, left ventricular dysfunction, heart failure, and myocardial infarction ,15. AccoThere are several mechanisms by which chemotherapy may influence cardiovascular health in breast cancer patients. Anthracyclines, such as doxorubicin interacts with deoxyribonucleic acids, intercalating and inhibiting macromolecular biosynthesis of cardiac myocytes that eventually leads to apoptosis of myocytes and permanent damage to the myocardium ,31. AddiEmerging evidence suggests that there are declining CVD mortality trends by radiation therapy among breast cancer patients ,39. Vo eThe lack of a positive association of radiotherapy with CVD mortality observed in the current study as well as other studies of cancer therapy administered in the 21st century reflects the impact of changes in radiotherapy procedures ,14. HoweAnother interesting observation from the current study is the racial and ethnic disparities in the relation of chemotherapy with CVD mortality in MBC patients. The risk of CVD mortality in Hispanic men was more than twice the risk in non-Hispanic White men with no association observed between chemotherapy and CVD mortality among non-Hispanic Black men with breast cancer. While reasons for these findings are largely unknown, it is possible that differences in sociodemographic, socioeconomic, behavioral, and biological factors as well as differences in access to cancer treatment may partly explain these findings. For instance, compared to non-Hispanic White individuals, Hispanic populations are less likely to partake in mammography screening and adhere to cancer screening recommendations ,47,48. TWith non-Hispanic Black individuals also experiencing delays in chemotherapy treatment ,55 despiCurrently, most treatment options for breast cancer in men are based on evidence from trials among women with breast cancer . AlthougThe strength of the current study includes the use of a large population-based sample of MBC patients selected within a modern timeframe of cancer treatment. Limitations of the study include the lack of detailed information on specific drugs or hormone therapy not being available in the SEER registry for most of the period of observation for this study. HER2 positivity status was not evaluated in the current study as such information was only available after 2010. Furthermore, information on CVD risk factors at the time of cancer diagnosis as well as information on other comorbid noncancer diseases were not collected by SEER program. Finally, the chance of misclassification bias influencing the results of the study due to the use of death certificates to identify deaths attributable to CVD cannot be entirely ruled out. However, cause-of-death information in the SEER registry have been reported to have good validity .In this population-based study of men with breast cancer, treatment with chemotherapy was significantly associated with elevated risk of CVD mortality, with the highest risk observed among Hispanic men. These findings have important implications for cardio-oncology care as well as extending research in the context of noncancerous outcomes in men with breast cancer. With the proportion of cancer patients receiving radiation therapy and chemotherapy increasing over the past few decades , future


Obesity is a complex metabolic condition considered a worldwide public health crisis, and a deeper mechanistic understanding of obesity-associated diseases is urgently needed. Obesity comorbidities include many associated cancers and are estimated to account for 20% of female cancer deaths in the USA. Breast cancer, in particular, is associated with obesity and is the focus of this review. The exact causal links between obesity and breast cancer remain unclear. Still, interactions have emerged between body mass index, tumor molecular subtype, genetic background, and environmental factors that strongly suggest obesity influences the risk and progression of certain breast cancers. Supportive preclinical research uses various diet-induced obesity models to demonstrate that weight loss, via dietary interventions or changes in energy expenditure, reduces the onset or progression of breast cancers. Ongoing and future studies are now aimed at elucidating the underpinning mechanisms behind weight-loss-driven observations to improve therapy and outcomes in patients with breast cancer and reduce risk. This review aims to summarize the rapidly emerging literature on obesity and weight loss strategies with a focused discussion of bariatric surgery in both clinical and preclinical studies detailing the complex interactions between metabolism, immune response, and immunotherapy in the setting of obesity and breast cancer. Basese BMI > 0 or overght BMI 2–30, with obesity . Since a obesity –12. Curr obesity , includi obesity , 14. Obe obesity , 16. Of  obesity –26, undeObesity and breast cancer remain a complex conundrum that truly highlights the importance of including clinically relevant data in analyses such as tumor subtypes and menopausal status, ensuring adequate representation of diverse populations, predominantly minority and younger patients, and measuring several metrics to quantify obesity in complementary ways. For example, it is well established that obesity is a metabolically dysregulated state that increases the risk for postmenopausal breast cancer, primarily represented by the more prevalent luminal A subtype . In conLikewise, while BMI is convenient for extensive studies and retrospective analyses drawing from patient medical records with relatively little measurement error, BMI is fraught with limitations. Most notably, BMI lacks the ability to account for muscle mass compared to adiposity and fails to capture the compartmentalization of visceral versus central adiposity . Other mOnce investigative teams began to oversample or enroll a disproportionately high percentage of minorities and younger women , includeWhile the impact of obesity on cancer risk is complex, it is abundantly clear that obesity negatively impacts cancer outcomes and survival. In breast cancer patients, women with increased BMI have a higher risk of invasion , 47, disObesity is one of the few modifiable breast cancer risk factors , and weiLifestyle-induced weight loss relies on dietary changes, increased exercise, and similar adaptations to daily routines focused on lowering body adiposity and increasing physical activity. The Look AHEAD studies, for example, found that significant weight loss could be achieved and maintained over eight years. However, these results were most feasible when patients received a personalized lifestyle intervention plan and attended frequent check-ins with healthy lifestyle professionals . HoweverLike obesity, exercise and dietary changes induce varied and complex benefits that can be linked to reduced cancer risk or progression from immunity to growth factors to adipokines to metabolism. For example, exercise upregulates anti-tumor immunity and downregulates immunosuppressive cells . Others In sum, published work supports the idea that healthy exercise habits and dietary choices are vital to reducing breast cancer risk or recurrence. This research area is expanding, with multiple randomized controlled clinical trials underway . One sucThe most effective method for long-term, sustained weight loss in adolescents and adults is bariatric surgery when combined with healthy lifestyle changes –102. Surbile flow alteration, reduction of gastric size, anatomical gut rearrangement with the altered flow of nutrients, vagal manipulation, and enteric gut hormone modulation [Benefits of bariatric surgery include weight loss as well as many molecular changes that improve health. For instance, RYGB has five principle results, known as the BRAVE effects: dulation . Many ofdulation . These pdulation , 117. Indulation . Additiodulation –121.2 or 35–39.9 kg/m2 in combination with one or more obesity-associated comorbidities [Reduction in all-cause mortality after bariatric surgery ranges widely by study from 30 to 60% . Patientbidities . Bariatrbidities , 124–128bidities , especiabidities . Despitebidities . There abidities . Other sbidities , 132. Inbidities . Interesbidities . The sexbidities . Furtherbidities .In sum, while bariatric surgeries are greatly increasing in prevalence, research is lagging to fully estimate the benefits of these approaches. As of 2022, 58.8% of studies had a follow-up time of just 1–2 years, which is a limitation to understanding the full impacts of these surgeries . Thus, lRecent bariatric surgery studies have sparked great interest in the cancer field. Several retrospective studies reported reduced risk for some types of cancer as long-term benefits of bariatric surgery , 138. ThRegarding breast cancer specifically, bariatric surgery reduced breast cancer risk among postmenopausal women compared to non-surgical controls, with the most significant impact on risk reduction in ER-negative tumors, with a 64% decrease in risk , 140. MoHuman cohorts offer insight into the effects of bariatric surgery and weight loss on cancer and other conditions. Still, current studies have been primarily retrospective, and this type of analysis is limited in the questions that can be answered. To be able to examine the mechanisms responsible for the benefits of weight loss, in vivo models are beneficial. Since the mid-1950s, researchers have been developing rodent models to mimic diet-induced obesity (DIO). Naturally occurring mutations in rodents and the development of transgenic mice complement DIO models, but single gene mutant mice are often not the most accurate representation of DIO observed in humans. Therefore, DIO and obesity-related conditions have been induced in murine models for decades by feeding the animals high fat diets; the effects are well-characterized , 148. HoTo best conduct diet studies in pre-clinical models, it is vital to use defined, controlled diets that are matched on important dietary factors such as protein and micronutrient content. A major concern from a nutritional standpoint is that many researchers use chow to keep mice lean as the standard diet control as compared to DIO mice fed a defined high fat diet. This is adequate and understandably cheaper to maintain lean mice, but this approach is not ideal as a proper control. Micronutrients, fiber, and dietary components like phytoestrogens vary from lot to lot in chow, creating extreme variability in studies and introducing mediators that impact cancer outcomes . Murine A critical factor in DIO studies is that mouse strains exhibit different extents of weight gain when exposed to high fat diets, just like individuals respond to various diets differently Fig. . C57BL/6FVB/N mice are a strain commonly used for cancer studies but rarely used in DIO studies. In contrast to the C57BL/6 strain, the FVB/N strain shows significantly greater variability in responsiveness to DIO . For exaInterestingly, a third strain commonly used in cancer studies is BALB/c. It is well-established that BALB/c mice display minimal to no weight gain on a high fat diet compared to C57BL/6 and FVB/N strains. Indeed, the strain is often termed “obesity-resistant” . In maleLast, examining patient-derived cell lines or xenografts (PDXs) in the obese setting introduces another layer of complexity. Immunocompromised murine models are necessary to avoid rejection of human cell lines or patient-derived samples. However, there are immunocompromised mouse strains, such as severe combined immunodeficiency (SCID) mice , that maOverall, numerous studies use the three primary mouse strains discussed here, C57BL/6, FVB/N, and BALB/c, as models of DIO and diet-induced weight gain or resistance. There are multiple preclinical models of DIO to examine cancer risk and progression using carcinogen initiation, transgenic oncogene expression, syngeneic cell implantation, and more, which will be highly informative to the field. Primary study endpoints include obesity per se, specific dietary impacts, and the extent of weight gain or adiposity impacting cancer outcomes. The intention of the study design should inform model selection.DIO and dietary interventions to induce weight loss, such as changing diet, timed feeding, fasting, and caloric restriction, are increasingly common in cancer outcomes studies. However, examining bariatric surgery after DIO is a little studied area that holds great interest based on the epidemiological findings about bariatric surgery and cancer risk discussed above. One major limiting factor is the skill set necessary to perform these complex, expensive, and time-consuming surgeries. Despite the technical challenges of mouse survival surgery, multiple groups have employed surgical models throughout the last decade to examine a wide range of obesity-associated conditions ranging from diabetes to cardiovascular disease and even gut-brain crosstalk. This field is growing immensely with over 170 publications on PubMed in the last year alone using rodent models of bariatric surgery. A selected subset of manuscripts published since 2010 are summarized in Table Both rat and mouse models have been used to examine the effects of surgical weight loss following DIO. In 2010, Stefater et al. described an early method for reviewing the weight loss induced by bariatric surgery in both male and female rats. They showed that in the long term, weight rebounded due to changes in eating habits resulting in a lack of changes in overall calorie intake . The sam2 [In 2011, Yin et al. developed five types of bariatric surgery in C57BL/6 and FVB/N mice to treat DIO resulting from a 60% high fat diet . This st2 . Recent 2 . Like RY2 –192. Mor2 –195, wit2 , and man2 –200.N) to have sufficient statistical power due to lower weight gain compared to low fat diet control. Last, there are fewer established experimental paradigms in the literature to aid in study design or compare ongoing studies to existing literature. Yet including female DIO studies is imperative for reasons detailed below, where we focus on further studies regarding the VSG.A significant factor to consider in interpreting studies, especially about cancers primarily or solely impacting women, such as breast, ovarian, or endometrial cancer, is that most published DIO bariatric surgery studies are completed in male rodents. There are several pros to using male rodents. First, male rodents gain much more weight on a high fat diet and gain that weight faster than females, as noted above. Second, large commercial labs like Jackson Labs, Inc. sell obese males on a high fat diet which makes completing DIO studies much more rapid and feasible. Unfortunately, Jackson Labs does not provide the same DIO service for female mice. This means that each study on female mice must be completed in house over many months to induce DIO. Third, since most publications use male mice, it is possible to compare ongoing studies to previously published work. A significant con when studying diseases specific to females is that females do not gain as much weight as males. To induce sufficient DIO, researchers must maintain mice on a high fat diet for extended periods, often 4–5 months. Some researchers remove the ovary to cause weight gain, but ovariectomy is used to generate a postmenopausal state, which may not be ideal for what the study design intends. Likewise, since Jackson Labs does not stock DIO females, responding to reviewers or implementing new therapies in DIO mice takes a long time. These long-term studies to induce DIO in female mice are costly. Furthermore, female DIO studies typically need larger sample sizes  are accompanied by increased aromatase activity . EnhanceExcess amounts of WAT have a remarkable impact on the immune system systemically and in tissues such as adipose depots –234. ObeHowever, a sometimes-complicated notion is that obesity also leads to compensatory immunosuppressive mechanisms to avoid a constant, full-blown pro-inflammatory response, similar to controlling any immune reaction, to maintain homeostasis. These mechanisms include reduced absolute numbers of activated CD8 + T cells, T cell suppression by PD-1 , 242, T Since obesity induces a pro-oncogenic state, it follows that weight loss may improve or reverse effects. Weight loss, specifically bariatric surgery, has been shown to reverse many of the impacts of obesity on the immune system, particularly low-grade inflammation and oxidative stress in both mouse models  and humaAnother factor that impacts the immune system is the gut or extra-intestinal microbiome . BariatrOverall, bariatric surgery may decrease the expression of pro-inflammatory cytokines and shift the phenotype of adaptive and innate immune cells towards the anti-inflammatory Th2 cells or M2-like phenotypes. This shift from a pro-inflammatory state to a regulatory state benefits tissue homeostasis. It reduces levels of cytokines and growth factors, improving comorbidities associated with obesity, such as insulin resistance. However, this loss of pro-inflammatory cells and increased regulatory cells is an apparent recipe for failed protective immune surveillance and increased cancer risk or progression through weak anti-tumor immunity. Yet, in long-term retrospective studies detailed above, epidemiologic evidence suggests the opposite: bariatric surgery reduces subsequent cancer risk. This implies that multiple factors associated with weight loss impact cancer risk. It is currently unclear as to whether the reversal of immune-mediated changes is entirely due to weight loss or instead due to the impacts of bariatric surgery, which are currently under active study. The investigation of alterations to metabolic pathways  and varied immune cells, phenotypes, microbiome, and changes with time after bariatric surgery with weight loss are critical to examine.Obesity serves as a unique challenge for immunotherapy. Current strategies in immunotherapy target immunosuppressive proteins such as PD-1, PD-L1, and CTLA-4, among others. Immune checkpoint proteins are immune-inhibitory and depend on the crosstalk between the cancer cells, T cells, MDSCs, tumor-associated macrophages (TAMs), NK cells, and more , 290–294A limiting factor with ICB therapy is toxicity, including immune-related adverse events (irAEs) , 304. AcIn fact, in obese patients, obesity has proven favorable in ICB treatment, as reviewed previously , 308. PDWith this review, we have highlighted the complexity of obesity’s impacts on risk and prognoses in epidemiological studies, preclinical models, and clinical trials. Obesity is associated with chronic low-level inflammation and hypoxia that can lead to genomic instability, elevated production of growth factors and adipokines such as estrogen and leptin, altered microbiota, and pro-inflammatory signaling combined with elevated immunosuppression. In general, obesity elevates cancer risk, which is highly consistent in postmenopausal breast cancer studies. Impacts on premenopausal breast cancer risk in different studies are varied from elevated risk of obesity to null to protective, likely depending on breast cancer subtype or methods to measure obesity. As specific subtypes and a more detailed evaluation of obesity metrics with the inclusion of menopausal status, race, and ethnicity are undertaken, we believe that the picture will become more evident. It is certain that obesity negatively impacts patient outcomes, recurrence, and survival in most settings. Weight loss before cancer onset or after treatment is beneficial. These benefits of weight loss are summarized in Fig.


Antidepressants are widely prescribed to treat depression and anxiety disorders that may become chronic conditions among women. Epidemiological studies have yielded inconsistent results on the correlation between antidepressant use and the incidence risk of female breast and gynecological cancer, along with uncertain dose–response relationship. Therefore, we performed a systematic review and dose–response meta-analysis to investigate the association.Web of Science, Embase, PubMed, The Cochrane Library, and PsycINFO were systematically searched in January 2022, with no language limits. Random-effect models were used to calculate pooled effect sizes and 95% confidence intervals between studies. Linear and non-linear dose–response analyses were performed to evaluate the dose or duration of antidepressant use affecting the incidence risk of female breast and gynecological cancer. Further subgroup analyses were systematically performed by stratifying almost all study characteristics and important potential confounders, in order to further clarify and validate the important potential hypotheses regarding the biological mechanism underlying this association.I² = 71.5%, p < 0.001), and even decreased the incidence risk of ovarian cancer . There were a non-linear dose–response relationship (p non-linearity < 0.05) between the duration of antidepressant use and incidence risk of female breast cancer, and an inverse linear dose–response relationship between antidepressant use and the incidence risk of gynecological cancer, specifically with an increase of cumulative defined daily dose or duration to a high level, like 25,550 doses  or 4,380 days , compared to never antidepressant users.Based on a systematic literature search, 34 eligible studies (27 case–control studies and 7 cohort studies) involving 160,727 female breast and gynecological cancer patients found that antidepressant use did not increase the incidence risk of female breast and gynecological cancer (pooled OR: 1.01; 95% CI: 0.97, 1.04, This systematic review and dose–response meta-analysis found that antidepressant use did not increase the incidence risk of female breast and gynecological cancer and even decreased the incidence risk of ovarian cancer, along with a non-linear or linear dose–response relationship.https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=313364, identifier CRD42022313364.PROSPERO  Female breast and gynecological cancers account for 18.7% of all reported new cancer cases in all cancer cases worldwide in 2020, representing 38.9% new incidence and approximately 27.9% mortality  use has been rising for decades , 4, in pin vivo studies from the US Food and Drug Administration (FDA) have found that 63.6% (7/11) of examined ADs were associated with carcinogenicity  and adhered to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist (PRISMA) reporting guideline for all processes , The Cochrane Library (CENTRAL), and PsycINFO. The search strategy was implemented using combined index terms  and free-text keywords, including  AND  AND  AND . A full description of the initial and supplementary search strategies is available in The included studies were limited to (1) observational studies that (2) explored the relationship between AD use and the incidence risk of female breast and gynecological cancer, and (3) provided maximum adjusted risk estimates  or data allowing the calculation of the risk estimates and 95% CIs, and (4) studies were conducted in humans. Exclusion criteria were as follows: studies assessing the relationship between AD use and recurrence and mortality of treated breast and gynecological cancer; studies lacking a control group; specified population ; non-peer-reviewed reports  and ongoing studies; and studies with insufficient information. Additionally, only the latest and/or complete one was used in the meta-analysis for duplicate articles.Two reviewers independently extracted and cross-checked the data from the included studies. The following details were presented in this review: first author’s name, year of publication, country, study design, participant number, age, type of ADs, exposure definition, exposure assessment, statistical indicators, outcome with the maximum covariate-adjusted ORs, RRs, HRs and 95% CIs, and adjusted/matched factors. All of the selected articles were examined by two researchers independently in terms of quality according to a Newcastle–Ottawa Scale  . Any conQ test and I² statistic were employed to evaluate heterogeneity between studies, and I² > 50% was considered statistically significant. In order to examine its source, we performed subgroup analyses according to almost all relevant factors that may lead to significant heterogeneity.Given the lower than 10% incidence of cancer, we approximated RR and HR as OR when pooling the estimates across the studies . Summaryp-value calculated in step 1, we determined whether a linear (p > 0.05) or non-linear (p < 0.05) dose–response meta-analysis should be adopted.Moreover, we used the G-L method  to carryp < 0.05. Analyses were performed with Stata 13.1 .The funnel plots and Egger’s test were used to detect potential publication bias . To asseAfter identifying 7,875 references, 1,703 duplicate publications, 6,019 irrelevant studies, 13 reviews/case reports, 10 dissertations/commentaries/conference abstracts, and 77 other cancers were excluded after screening the titles and abstracts. The remaining 53 potentially studies were carefully read in full, and 18 of them were excluded for shorting the data of risk estimates and one was excluded for duplicate study data. Finally, 34 observational studies (27 case–control studies and 7 cohort studies) , 83–87 wn = 22), Europe (n = 8), and Asia (n = 4). Drug exposure was assessed and collected by questionnaires in 16 studies and databases in 18 studies, respectively. The quality of the included studies is assessed in A total of 160,727 patients with female breast and gynecological cancer were involved, and the cases ranged in size from 20 to 45,147 participants. Overall, the studies were published between 1995 and 2021, involving participants from North America . Furthermore, subgroup analyses for specific cancer sites showed a slightly decreased incidence risk of ovarian cancer ; no significant relation with endometrial, corpus uteri, and cervical cancers ; and a weakly increased incidence risk of female breast cancer , with a high heterogeneity , compared to never AD users , with a high heterogeneity .Applying the leave-one-out sensitivity analysis showed that none of the eligible studies had considerable effect on the overall estimate Figure 5The pooled results of this systematic review and meta-analysis found that AD use did not increase the incidence risk of female breast and gynecological cancer, either by tricyclic ADs  or by selective serotonin reuptake inhibitors , and even decreased the incidence risk of ovarian cancer. Further subgroup analyses of confounders found that AD use was associated with higher risk in almost all of subgroups of unadjusted confounders; thus, the incomplete adjustment for these potential confounders was likely to bias our results toward a positive relationship. Additionally, further subgroup analyses of study characteristics found that the incidence risk of female breast and gynecological cancer was not statistically different across great majority strata, but it appeared to be stronger in exposures that occurred less than 1 year prior to the index date (1.25 for less than 1 year vs. 0.89 for more than 1 year) for ovarian cancer, as protopathic bias and reverse causation might drive the estimates towards an increased risk . It was Kd) in order to accurately assess for levels of prolactin secreted by the secondary pituitary gland, and found that neither higher nor lower inhibitor of serotonin reuptake increased the risk for breast cancer, which was consistent with our result.However, several potential hypotheses have been proposed regarding the biological mechanism underlying this positive association and have been supported by subsequent epidemiologic studies. However, most of them are limited for some reason, such as exposure misclassifications , 43, revIf AD medications work through changes in the secretion of gonadotropins and female sex hormones, the observed association may be more pronounced in premenopausal women who have functioning ovaries than that in postmenopausal women. Our results in this study support this hypothesis, but they are only based on limited two studies , 44 within vivo evidence and found that 63.6% (7/11) of examined ADs were associated with carcinogenicity, including duloxetine (SNRIs), mirtazapine (NaSSas), and NDRI (bupropion), but the agents unassociated with carcinogenicity were trazodone (SARIs) and venlafaxine (SNRIs)  for female breast, ovarian, endometrial, and cervical cancer, and stronger in noradrenergic and specific serotonergic antidepressants (NaSSas) for ovarian cancer. We also found a reduced risk of female breast cancer with the use of monoamine oxidase inhibitors (MAOIs) and serotonin antagonist and reuptake inhibitors (SARIs), and a reduced risk of endometrial, corpus uteri, and cervical cancer with the use of norepinephrine and dopamine reuptake inhibitors (NDRIs) and NaSSas. Amerio et al. reviewed the US Food and Drug Administration (FDA) preclinical  63.6% 7/ of exami (SNRIs) , 92 had  (SNRIs) . However (SNRIs) . Further (SNRIs) , and theFurthermore, there is a non-linear dose–response relationship between the duration of AD use and incidence risk of female breast cancer, in which the bi-phasic phenomenon is characterized by “low-dose stimulation and high-dose inhibition” , 93 of mNotably, our meta-analysis has the following advantages. First, to the best of our knowledge, this is the first study to systematically perform a qualitative dose–response meta-analysis of the relationship between AD use and the incidence of female breast and gynecological cancer as a whole of hormone-related cancer in female patients, along with comprehensive subgroup analyses stratified by almost all study characteristics and important potential confounders. Furthermore, this is the first study to demonstrate shapes of non-linear or linear association between the CDDD or duration of AD use and female breast or gynecological cancer, and further clarify and validate the several important potential hypotheses regarding the biological mechanism underlying this association.Inevitably, this study also has some limitations. First, moderate or high heterogeneity among studies was observed when pooling estimates for female breast cancer. Furthermore, a small portion of subgroup analyses of study characteristics and important potential confounders was based on a limited number of existing studies. Second, a linearity association was not observed in the relation between the CDDD or duration of AD use and the incidence risk of ovarian, endometrial, corpus uteri, and cervical cancer, respectively, partly due to the limited number of existing studies for each cancer site. Finally, the interpretation criteria for exposure were inconsistent, and misclassification bias might affect the results.Overall, the results of the present updated meta-analysis involving the largest sample size to date and mostly included comprehensive observational studies show that AD use does not increase the incidence risk of female breast and gynecological cancer, either by TCA or by SSRI, and even decreases the incidence risk of ovarian cancer, compared to never AD users. There is a non-linear dose–response relationship between the duration of AD use and incidence risk of female breast cancers, with a very slight increase in incidence risk of female breast cancer on short-term usage. An inverse linearity association exists between the CDDD or duration of AD use and incidence risk of gynecological cancer, and also between the CDDD of AD use and incidence risk of endometrial, corpus uteri, and cervical cancer. More future studies specifying dose or duration are needed in order to accurately assess and clarify this protective or bi-phasic effect and biological mechanism.The original contributions presented in the study are included in the article/HS, YYL, and YZ conceived and designed the study. HS, YYL, and YZ selected the studies and collected the data. YYL and YZ analyzed data. All authors interpreted the results. YYL and YZ drafted the paper. All authors revised the draft paper. All authors contributed to the article and approved the submitted version.This study was supported by the Joint Funds for the National Key Research and Development Program of China (Grant No. 2021ZD0202900), the National Natural Science Foundation of China , and the Natural Science Foundation of Shandong Province (Grant No. ZR2020ZD17). The funders of this study had no role in study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.