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Female breast cancer is the most common tumour diagnosed worldwide and is one of the leading causes of cancer-related death. The management of elderly, male and pregnant patients with breast cancer requires some additional considerations which are reviewed in this chapter. Breast screening is routinely offered to women aged between 50 and 70 years in England. There are substantial regional variations among UK hospitals in the clinical management of elderly breast cancer patients. Primary endocrine therapy is used in the treatment of ER-positive elderly breast cancer patients not fit for surgical intervention. Male breast cancer is rare, accounting for less than 1% of all breast cancers. It is more common in elderly men and tends to behave like post-menopausal breast cancer. Although breast cancer is one of the most frequently diagnosed malignancies among pregnant women, breast cancer during pregnancy is a rare condition and has been associated with more aggressive, high-grade, poorly differentiated tumours and with a predominance of more aggressive molecular subtypes such as triple negative, HER-2-positive and lower rates of ER and PR expression. [ABSTRACT FROM AUTHOR]

Hormone receptor-positive breast cancer may recur or metastasize years or decades after its diagnosis. Furthermore, hormone receptor expression may persist in relapsed or metastatic cancer cells. Endocrine therapy is one of the most efficacious treatments for hormone receptor-positive breast cancers. Nevertheless, a considerable proportion of patients develop resistance to endocrine therapy. Previous studies have identified numerous mechanisms underlying drug resistance, such as epigenetic abnormalities in the estrogen receptor (ER) genome, activation of ER-independent ligands, and alterations in signaling pathways including PI3K/AKT/mTOR, Notch, NF-κB, FGFR, and IRE1-XBP1. This article reviews the mechanisms of endocrine resistance in hormone receptor-positive advanced breast cancer, drawing from previous studies, and discusses the latest research advancements and prospects. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates how frequently breast cancer patients develop mental disorders compared to a control group without breast cancer. We analyzed data from over 11,000 breast cancer patients and nearly 32,000 healthy controls, finding that breast cancer patients were significantly more likely to suffer from mental disorders. Anxiety disorders, hypochondria, adjustment disorders, and depression were particularly common. This study also examined factors such as the type of therapy: endocrine therapy and breast reconstruction were strongly associated with psychological distress, and simple-mastectomy patients showed the lowest rates of mental illness. This work is of particular importance because it highlights how significantly the mental health of breast cancer patients can deteriorate due to their diagnosis and treatment. Thus, psychological counseling should be part of every treatment for breast cancer, especially when endocrine therapy is recommended. The practice of recommending breast reconstruction after mastectomy should be reconsidered, as it could have a negative effect on mental health. Background/Objectives: With breast cancer (BC) survival improving due to optimized therapy, enhancing quality of life has become increasingly important. Both diagnosis and treatment, with their potential side effects, pose risks to mental well-being. Our study aimed to analyze the incidence and potential risk factors for mental disorders in BC patients. Methods: This retrospective analysis used claims data from AOK Baden-Wuerttemberg, including 11,553 BC patients diagnosed via ICD code C50 between 2010 and 2020 and 31,944 age-matched controls. Patients with mental disorders in the 12 months prior to diagnosis were excluded. Mental disorders were categorized into eight groups based on ICD codes: anxiety, obsessive compulsive disorder, adjustment disorder, dissociative disorder, hypochondriac disorder, affective disorder, mania, and other neuroses. Results: Mental disorders were significantly more common in BC patients than in controls (64.2% vs. 38.1%, p < 0.01, OR 2.91, 95%CI [2.79, 3.04]). In particular, hypochondriac, anxiety, affective, and adjustment disorders occurred significantly more often in BC patients. No differences were found for mania, bipolar disease, other neuroses, obsessive compulsive-, or dissociative disorders. Furthermore, endocrine therapy was associated with psychological comorbidities (OR 1.69, p < 0.001, 95%CI [1.53, 1.86]), while primarily metastasized patients (stage C) had a lower risk than adjuvant patients in stage A (OR 0.55, p < 0.0001, 95%CI [0.49, 0.61]). Regarding surgical treatment, mastectomy patients showed lower rates of mental illnesses (61.2%) than those with breast-conserving treatment (71.6%), or especially breast reconstruction (78.4%, p < 0.01). Breast reconstruction was also associated with more hypochondriac (p < 0.01) and adjustment disorders (p < 0.01). Conclusions: So, BC patients experience significantly more mental disorders than controls, particularly when treated with endocrine therapy and breast reconstructive surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: Low-grade serous ovarian cancer is a rare and complex subtype that usually develops slowly and predominantly affects younger women. Conventional treatment, which generally involves a combination of primary surgery and chemotherapy, often fails, leading to frequent recurrences. Due to the rarity of this cancer subtype, there are limited clinical data available to guide optimal treatment decisions. However, recent research is focusing on new, promising therapies, including targeted treatments that address specific molecular pathways and hormonal therapies. These emerging options offer hope for improved outcomes by enabling more personalized and effective management. This review aims to address the current treatment challenges and summarize the innovative therapies and their potential to enhance treatment strategies, aiming to provide better management for patients with this uncommon ovarian cancer subtype. Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer, characterized by a unique molecular background and specific clinical behavior. A growing body of molecular data underscores LGSOC as a distinct disease entity; however, clinical evidence on the optimal treatment regimens for LGSOC remains limited due to the low incidence of the disease. Consequently, treatment recommendations for LGSOC are still often derived from findings on the more common high-grade serous ovarian carcinoma (HGSOC) and typically focus on radical cytoreductive surgery and platinum-based chemotherapy. Since LGSOCs typically exhibit only limited responsiveness to platinum-based chemotherapy, the clinical management of advanced and recurrent LGSOCs remains a significant therapeutic challenge and often results in limited treatment options and suboptimal outcomes. Recent advances in molecular profiling and the identification of new, promising targets, such as the mitogen-activated protein kinase (MAPK) pathway, offer hope for improving both the prognosis and health-related quality of life in affected patients. Given the high unmet clinical need to establish new therapeutic standards beyond cytotoxic chemotherapy, this review aims to summarize the most promising molecular targets and emerging targeted agents. [ABSTRACT FROM AUTHOR]

Abstract Background Indigenous peoples worldwide experience inequitable cancer outcomes, and it is unclear if this is underpinned by differences in or inadequate use of endocrine treatment (ET), often used in conjunction with other cancer treatments. Previous studies examining ET use in Indigenous peoples have predominately focused on the sub-national level, often resulting in small sample sizes with limited statistical power. This systematic review aimed to collate the findings ofarticles on ET utilisation for Indigenous cancer patients and describe relevant factors that may influence ET use. Methods We conducted a systematic review and meta-analysis of studies reporting ET use for cancer among Indigenous populations worldwide. PubMed, Scopus, CINAHL, Web of Science, and Embase were searched for relevant articles. A random-effect meta-analysis was used to pool proportions of ET use. We also performed a subgroup analysis (such as with sample sizes) and a meta-regression to explore the potential sources of heterogeneity. A socio-ecological model was used to present relevant factors that could impact ET use. Results Thirteen articles reported ET utilisation among Indigenous populations, yielding a pooled estimate of 67% (95% CI:54 − 80), which is comparable to that of Indigenous populations 67% (95% CI: 53 − 81). However, among studies with sufficiently sized study sample/cohorts (≥ 500), Indigenous populations had a 14% (62%; 95% CI:43 − 82) lower ET utilisation than non-Indigenous populations (76%; 95% CI: 60 − 92). The ET rate in Indigenous peoples of the USA (e.g., American Indian) and New Zealand (e.g., Māori) was 72% (95% CI:56–88) and 60% (95% CI:49–71), respectively. Compared to non-Indigenous populations, a higher proportion of Indigenous populations were diagnosed with advanced cancer, at younger age, had limited access to health services, lower socio-economic status, and a higher prevalence of comorbidities. Conclusions Indigenous cancer patients have lower ET utilisation than non-Indigenous cancer patients, despite the higher rate of advanced cancer at diagnosis. While reasons for these disparities are unclear, they are likely reflecting, at least to some degree, inequitable access to cancer treatment services. Strengthening the provision of and access to culturally appropriate cancer care and treatment services may enhance ET utilisation in Indigenous population. This study protocol was registered on Prospero (CRD42023403562).

Purpose: Everolimus in combination with endocrine therapy (ET) was formerly approved as 2nd-line therapy in HR(+)/HER2(−) advanced breast cancer (aBC) patients (pts) progressing during or after a non-steroidal aromatase inhibitor (NSAI). Since this approval, the treatment landscape of aBC has changed dramatically, particularly with the arrival of CDK 4–6 inhibitors. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS), below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce. Methods: A retrospective observational study of patients with aBC treated with everolimus and ET beyond CDK4/6-i progression compiled from February 2015 to December 2022 in 4 Spanish hospitals was performed. Clinical and demographic data were collected from medical records. The main objective was to estimate the median progression-free survival (mPFS). Everolimus adverse events (AE) were registered. Quantitative variables were summarized with medians; qualitative variables with proportions and the Kaplan–Meier method were used for survival estimates. Results: One hundred sixty-one patients received everolimus plus ET (exemestane: 96, fulvestrant: 54, tamoxifen: 10, unknown: 1) after progressing on a CDK4/6 inhibitor. The median follow-up time was 15 months (interquartile range: 1–56 months). The median age at diagnosis was 49 years (range: 35–90 years). The estimated mPFS was 6.0 months (95%CI 5.3–7.8 months). PFS was longer in patients with previous CDK4/6 inhibitor therapy lasting for > 18 months (8.7 months, 95%CI 6.6–11.3 months), in patients w/o visceral metastases (8.0 months, 95%CI 5.8–10.5 months), and chemotherapy-naïve in the metastatic setting (7.2 months, 95%CI 5.9–8.4 months). Conclusion: This retrospective analysis cohort of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor suggests a longer estimated mPFS when compared with the mPFS with ET monotherapy obtained from current randomized clinical data. Everolimus plus ET may be considered as a valid control arm in novel clinical trial designs. [ABSTRACT FROM AUTHOR]

Background: Indigenous peoples worldwide experience inequitable cancer outcomes, and it is unclear if this is underpinned by differences in or inadequate use of endocrine treatment (ET), often used in conjunction with other cancer treatments. Previous studies examining ET use in Indigenous peoples have predominately focused on the sub-national level, often resulting in small sample sizes with limited statistical power. This systematic review aimed to collate the findings ofarticles on ET utilisation for Indigenous cancer patients and describe relevant factors that may influence ET use. Methods: We conducted a systematic review and meta-analysis of studies reporting ET use for cancer among Indigenous populations worldwide. PubMed, Scopus, CINAHL, Web of Science, and Embase were searched for relevant articles. A random-effect meta-analysis was used to pool proportions of ET use. We also performed a subgroup analysis (such as with sample sizes) and a meta-regression to explore the potential sources of heterogeneity. A socio-ecological model was used to present relevant factors that could impact ET use. Results: Thirteen articles reported ET utilisation among Indigenous populations, yielding a pooled estimate of 67% (95% CI:54 − 80), which is comparable to that of Indigenous populations 67% (95% CI: 53 − 81). However, among studies with sufficiently sized study sample/cohorts (≥ 500), Indigenous populations had a 14% (62%; 95% CI:43 − 82) lower ET utilisation than non-Indigenous populations (76%; 95% CI: 60 − 92). The ET rate in Indigenous peoples of the USA (e.g., American Indian) and New Zealand (e.g., Māori) was 72% (95% CI:56–88) and 60% (95% CI:49–71), respectively. Compared to non-Indigenous populations, a higher proportion of Indigenous populations were diagnosed with advanced cancer, at younger age, had limited access to health services, lower socio-economic status, and a higher prevalence of comorbidities. Conclusions: Indigenous cancer patients have lower ET utilisation than non-Indigenous cancer patients, despite the higher rate of advanced cancer at diagnosis. While reasons for these disparities are unclear, they are likely reflecting, at least to some degree, inequitable access to cancer treatment services. Strengthening the provision of and access to culturally appropriate cancer care and treatment services may enhance ET utilisation in Indigenous population. This study protocol was registered on Prospero (CRD42023403562). [ABSTRACT FROM AUTHOR]

For many years, it has been believed that a combination of endocrine therapies with chemotherapeutic agents should not be used in clinical practice as the treatment for either early or advanced breast cancer. These conclusions resulted from clinical trials conducted several decades ago, which combined a selective estrogen receptor modulator (tamoxifen) with polychemotherapy regimens in early breast cancer patients. However, recent results of clinical trials and cohort studies that evaluated combinations of novel chemotherapy regimens with aromatase inhibitors or fulvestrant demonstrated that chemoendocrine therapy is feasible, safe, and active in patients with HR+ breast cancer at various stages of the disease. This article reviews the available data on the safety, activity, and clinical utility of systemic treatment approaches based on the simultaneous administration of endocrine agents with mainly metronomic chemotherapy. [ABSTRACT FROM AUTHOR]

Endocrine therapy is one of the key and most frequently utilized strategies for breast cancer treatment, both in the early and advanced stages of the disease. Its activity relies on the presence of functional estrogen receptors in cancer cells, which are responsible for stimulating the survival and growth of breast cancer. Over the past four decades, endocrine therapy significantly has progressed not only due to the emergence of new drugs disrupting the estrogen receptor functions but also thanks to the development of new targeted agents that block intracellular mechanisms of hormone resistance. The large number of endocrine therapies used either as monotherapy or in combination with other agents vary not only in their mechanisms of action but also their safety profiles. This diversity poses a big and continuously growing challenge in planning and conducting an optimal, multi-stage palliative hormonal treatment in clinical practice. This article aims to summarize current knowledge on contemporary endocrine treatment options and highlight the possibilities for making hormone therapies a truly personalized treatment for advanced breast cancer patients. [ABSTRACT FROM AUTHOR]

Hormone receptor-positive breast cancer may recur or metastasize years or decades after its diagnosis. Furthermore, hormone receptor expression may persist in relapsed or metastatic cancer cells. Endocrine therapy is one of the most efficacious treatments for hormone receptor-positive breast cancers. Nevertheless, a considerable proportion of patients develop resistance to endocrine therapy. Previous studies have identified numerous mechanisms underlying drug resistance, such as epigenetic abnormalities in the estrogen receptor (ER) genome, activation of ER-independent ligands, and alterations in signaling pathways including PI3K/AKT/mTOR, Notch, NF-κB, FGFR, and IRE1-XBP1. This article reviews the mechanisms of endocrine resistance in hormone receptor-positive advanced breast cancer, drawing from previous studies, and discusses the latest research advancements and prospects.

Opinion statement: Around 90% of breast tumours are diagnosed in the early stage, with approximately 70% being hormone receptor-positive. The cornerstone of adjuvant therapy for early-stage hormone receptor-positive breast cancer is endocrine therapy, tailored according to disease stage, biological characteristics of the tumour, patient's comorbidities, preferences and age. In premenopausal patients with hormone receptor-positive breast cancer, ovarian function suppression is a key component of the adjuvant endocrine treatment in combination with an aromatase inhibitor or tamoxifen. Moreover, it can be used during chemotherapy as a standard strategy for ovarian function preservation in all breast cancer subtypes. In the metastatic setting, ovarian function suppression should be used in all premenopausal patients with hormone receptor-positive breast cancer to achieve a post-menopausal status. Despite its efficacy, ovarian function suppression may lead to several side effects that can have a major negative impact on patients' quality of life if not properly managed (e.g. hot flashes, depression, cognitive impairment, osteoporosis, sexual dysfunction, weight gain). A deep knowledge of the side effects of ovarian function suppression is necessary for clinicians. A correct counselling in this regard and proactive management should be considered a fundamental part of survivorship care to improve treatment adherence and patients' quality of life. [ABSTRACT FROM AUTHOR]

Introduction: The partial estrogen-agonist action of tamoxifen on bone receptors has beneficial effects on bone mineral density. However, in premenopausal women, the use of tamoxifen causes systemic estrogen depletion, which has detrimental effects on bone health. We aim to investigate the association between tamoxifen and osteoporosis in the real world using data from a longitudinal nationwide cohort of Korean patients. Methods: Data were collected from the National Health Insurance claims database in South Korea. Osteoporosis was defined by diagnostic codes accompanying prescription data for osteoporosis. The cumulative incidence was analyzed by Kaplan-Meier survival curves and the risk factors were analyzed using a multivariable Cox proportional hazard regression model. Results: Between 2009 and 2015, of the 4,654 women with ductal carcinoma in situ (DCIS) without prior osteoporosis, 2,970 were prescribed tamoxifen and 1,684 were not. A total of 356 DCIS survivors were later diagnosed with osteoporosis during a median follow-up period of 84 months. In the overall population, tamoxifen was associated with a low risk of osteoporosis, before and after propensity matching adjusted for age, operation type, and comorbidities (before matching, hazard ratio [HR]=0.69, 95% confidence interval [CI]=0.559-0.851, p<0.001; after matching, HR=0.664, 95% CI=0.513-0.858, p=0.002). In the subgroup analysis, findings were consistent in postmenopausal women but were not evident in the younger age group. Conclusion: In a nationwide cohort study, a low risk of osteoporosis was associated with the use of tamoxifen. The protective effect of tamoxifen was more profound in older women and was not related to the incidence of osteoporosis in younger women. [ABSTRACT FROM AUTHOR]

Background: The appropriate time to discontinue chemotherapy at the end of life has been widely discussed. In contrast, few studies have investigated the patterns of endocrine treatment near death. In this study, we aimed to investigate the end-of-life endocrine treatment patterns of older women with metastatic breast cancer and explore characteristics associated with treatment. Methods: A retrospective cohort study of all older women (age =65 years) with hormone receptor-positive breast cancer who died in Sweden, 2016 - 2020. We used routinely collected administrative and health data with national coverage. Treatment initiation was defined as dispensing during the last three months of life with a nine-month washout period, while continuation and discontinuation were assessed by previous use during the same period. We used log-binomial models to explore factors associated with the continuation and initiation of endocrine treatments. Results: We included 3098 deceased older women with hormone receptorpositive breast cancer (median age 78). Overall, endocrine treatment was continued by 39% and initiated by 5% and of women during their last three months of life, while 31% discontinued and 24% did not use endocrine treatment during their last year of life. Endocrine treatment continuation was more likely among older and less educated women, and among women who had multidose drug dispensing, chemotherapy, and CDK4/6 use. Only treatment-related factors were associated with treatment initiation. Conclusion: More than a third of women with metastatic breast cancer continue endocrine treatments potentially past the point of benefit, whereas late initiation is less frequent. Further research is warranted to determine whether our results reflect overtreatment at the end of life once patients' preferences and survival prognosis are considered. [ABSTRACT FROM AUTHOR]

Purpose: In this study of oestrogen receptor (ER) Low Positive breast cancers (BC) in three large cohorts of BC patients, we assess associations between levels of ER expression and tumour characteristics and prognosis. Methods: Cases were stratified into patients unlikely to have received adjuvant therapy according to treatment guidelines at time of diagnosis (before 1995), and those who could have received adjuvant therapy (diagnosed in 1995 or later). ER status was divided into < 1%; ≥ 1 < 10%; ≥ 10%. Results were correlated with time of diagnosis, histopathological grade, proliferation status, and molecular subtypes, using Pearson's Chi-square test. For prognosis, hazard ratios and cumulative incidence of death from BC were used. Results: Of the 1955 tumours, 65 (3.3%) were ER Low Positive (ER ≥ 1 < 10%). Overall, the highest proportion of ER Low Positive tumours was observed among Luminal B (HER2 +) subtype (9.4%) and grade 3 tumours (4.3%). The risk of death from BC was lower in ER Low Positive and ER ≥ 10% compared to ER-negative cases. Compared to patients diagnosed before 1995, women diagnosed in 1995 or later showed a higher proportion of ER Low Positive BCs, and their tumours were of smaller size, lower grade, and lower proliferative status. There was no significant difference in prognosis compared to those with ER ≥ 10% tumours. Conclusion: Women with ER Low Positive tumours diagnosed in a time period when adjuvant therapy was available had tumours of smaller size, lower grade, and lower proliferative status, and similar prognosis to those with ER ≥ 10% compared to women diagnosed earlier. [ABSTRACT FROM AUTHOR]

BackgroundThe appropriate time to discontinue chemotherapy at the end of life has been widely discussed. In contrast, few studies have investigated the patterns of endocrine treatment near death. In this study, we aimed to investigate the end-of-life endocrine treatment patterns of older women with metastatic breast cancer and explore characteristics associated with treatment.MethodsA retrospective cohort study of all older women (age ≥65 years) with hormone receptor-positive breast cancer who died in Sweden, 2016 − 2020. We used routinely collected administrative and health data with national coverage. Treatment initiation was defined as dispensing during the last three months of life with a nine-month washout period, while continuation and discontinuation were assessed by previous use during the same period. We used log-binomial models to explore factors associated with the continuation and initiation of endocrine treatments.ResultsWe included 3098 deceased older women with hormone receptor-positive breast cancer (median age 78). Overall, endocrine treatment was continued by 39% and initiated by 5% and of women during their last three months of life, while 31% discontinued and 24% did not use endocrine treatment during their last year of life. Endocrine treatment continuation was more likely among older and less educated women, and among women who had multi-dose drug dispensing, chemotherapy, and CDK4/6 use. Only treatment-related factors were associated with treatment initiation.ConclusionMore than a third of women with metastatic breast cancer continue endocrine treatments potentially past the point of benefit, whereas late initiation is less frequent. Further research is warranted to determine whether our results reflect overtreatment at the end of life once patients’ preferences and survival prognosis are considered.

Background: The risk of late distant recurrence (LDR) of estrogen receptor (ER)-positive breast cancer continues even after 5 years of endocrine treatment. Clinical Treatment Score after 5 years (CTS5) was developed and validated as a tool to assess the risk of LDR using data from Tamoxifen, Arimidex Alone or in Combinations (ATAC) and Breast International Group 1-98 (BIG1-98) trials. This study aimed to externally validate CTS5 in a real-world cohort of patients treated at an academic center in Thailand. Methods: The study was a retrospective analytical research study of early-stage, ER-positive breast cancer patients. The primary endpoint was LDR. The risk of LDR was determined using the CTS5 calculator. Cox regression model and Kaplan-Meier survival analysis were applied for prognostic validation of CTS5. Calibration was performed by comparing observed LDR to expected LDR using the Hosmer-Lemeshow (H-L) test. Results: A total of 323 women were included with a median follow-up period of 11.6 years. The rate of LDR was 10.8%. The CTS5 was prognostic for LDR. C-index of the area under the ROC curve was 0.672. There was no significant difference between actual and expected numbers of LDR with an observed (O) LDR events to expected (E) number of LDR events ratio of 0.99 (0.86-1.12) (H-L P =.79) indicating a proper calibration in this cohort. Conclusions: Our study validated that CTS5 is accurate in predicting the risk of LDR in ER-positive breast cancer cases in Thai patients. Its performance seemed to be better in postmenopausal patients. CTS5 could be applied in routine clinical practice to improve decisions regarding prolonged endocrine therapy, particularly in resource-limited countries where molecular profiling are inaccessible. [ABSTRACT FROM AUTHOR]

Endometrial stromal tumors (EST) are uterine mesenchymal tumors, which histologically resemble endometrial stroma of the functioning endometrium. The majority of EST are malignant tumors classified as low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). Overall, ESTs are rare malignancies, with an annual incidence of approximately 0.30 per 100′000 women, mainly affecting peri- or postmenopausal women. The most common genetic alteration identified in LG-ESS is the JAZF1-SUZ12 rearrangement, while t(10;17)(q23,p13) translocation and BCOR gene abnormalities characterize two major subtypes of HG-ESS. The absence of specific genetic abnormalities is the actual hallmark of UUS. Unlike HG-ESSs, LG-ESSs usually express estrogen and progesterone receptors. Total hysterectomy without morcellation and bilateral salpingo-oophorectomy (BSO) is the first-line treatment of early-stage LG-ESS. Ovarian preservation, fertility-sparing treatment, and adjuvant hormonal therapy ± radiotherapy may be an option in selected cases. In advanced or recurrent LG-ESS, surgical cytoreduction followed by hormonal treatment, or vice versa, are acceptable treatments. The standard treatment for apparently early-stage HG-ESS and UUS is total hysterectomy without morcellation with BSO. Ovarian preservation and adjuvant chemotherapy ± radiotherapy may be an option. In advanced or recurrent HG-ESS, surgical cytoreduction and neoadjuvant or adjuvant chemotherapy can be considered. Alternative treatments, including biological agents and immunotherapy, are under investigation. LG-ESSs are indolent tumor with a 5-year overall survival (OS) of 80–100% and present as stage I-II at diagnosis in two third of patients. HG-ESSs carry a poor prognosis, with a median OS ranging from 11 to 24 months, and 70% of patients are in stage III-IV at presentation. UUS median OS ranges from 12 to 23 months and, at diagnosis, 70% of patients are in stage III-IV. The aim of this review is to assess the clinical, pathological, and biological features and the therapeutic options for malignant ESTs. • ESTs are rare malignancies, mainly affecting peri- or postmenopausal women. • Most common genetic alteration identified in LG-ESS is the JAZF1-SUZ12 rearrangement. • YWHAE-NUTM2A/B and BCOR rearrangements characterize two subtypes of HG-ESS. • The absence of specific genetic abnormalities is the actual hallmark of UUS. • LG-ESSs usually express estrogen and progesterone receptors. [ABSTRACT FROM AUTHOR]

Simple Summary: Abemaciclib, dalpiciclib, palbociclib and ribociclib have all demonstrated significant improvements in progression-free survival in advanced disease. However, to date, abemaciclib and ribociclib are the only CDK4/6 inhibitors shown to improve the overall survival in patients with metastatic breast cancer. Moreover, abemaciclib is the first CDK4/6 inhibitor to also reduce the risk of recurrence in those with early-stage disease. Thus, achieving significant improvements in survival rates in the advanced and early breast cancer treatment setting, CDK4/6 inhibitors are the first substances in almost two decades to substantially change the standard of care for advanced breast cancer patients. This review is designed to discuss the recent history, current role, future directions and opportunities of this substance class. Purpose of review: Tamoxifen and aromatase inhibitors can be considered as some of the first targeted therapies. For the past 30 years, they were the endocrine treatment standard in the advanced and early breast cancer setting. CDK4/6 inhibitors, however, are the first substances in almost two decades to broadly improve the therapeutic landscape of hormone receptor-positive breast cancer patients for the upcoming years. This review is designed to discuss the recent history, current role, future directions and opportunities of this substance class. Recent findings: The CDK4/6 inhibitors abemaciclib, dalpiciclib, palbociclib and ribociclib have all demonstrated a statistically significant improvement in progression-free survival in advanced disease. However, to date, abemaciclib and ribociclib are the only CDK4/6 inhibitors to have shown an improvement in overall survival in patients with metastatic breast cancer. Moreover, abemaciclib is the first CDK4/6 inhibitor to also reduce the risk of recurrence in those with early-stage disease. Further CDK inhibitors, treatment combinations with other drugs and different therapy sequences are in development. Summary: Achieving significant improvements in survival rates in the advanced and early breast cancer treatment setting, CDK4/6 inhibitors have set a new standard of care for patients with advanced breast cancer. It remains important to better understand resistance mechanisms to be able to develop novel substances and treatment sequences. [ABSTRACT FROM AUTHOR]

Background: There is no standard treatment recommended at category 1 level in international guidelines for subsequent therapy after cyclin-dependent kinase 4/6 inhibitor (CDK4/6) based therapy. We aimed to evaluate which subsequent treatment oncologists prefer in patients with disease progression under CDKi. In addition, we aimed to show the effectiveness of systemic treatments after CDKi and whether there is a survival difference between hormonal treatments (monotherapy vs. mTOR-based). Methods: A total of 609 patients from 53 centers were included in the study. Progression-free-survivals (PFS) of subsequent treatments (chemotherapy (CT, n:434) or endocrine therapy (ET, n:175)) after CDKi were calculated. Patients were evaluated in three groups as those who received CDKi in first-line (group A, n:202), second-line (group B, n: 153) and ≥ 3rd-line (group C, n: 254). PFS was compared according to the use of ET and CT. In addition, ET was compared as monotherapy versus everolimus-based combination therapy. Results: The median duration of CDKi in the ET arms of Group A, B, and C was 17.0, 11.0, and 8.5 months in respectively; it was 9.0, 7.0, and 5.0 months in the CT arm. Median PFS after CDKi was 9.5 (5.0–14.0) months in the ET arm of group A, and 5.3 (3.9–6.8) months in the CT arm (p = 0.073). It was 6.7 (5.8–7.7) months in the ET arm of group B, and 5.7 (4.6–6.7) months in the CT arm (p = 0.311). It was 5.3 (2.5–8.0) months in the ET arm of group C and 4.0 (3.5–4.6) months in the CT arm (p = 0.434). Patients who received ET after CDKi were compared as those who received everolimus-based combination therapy versus those who received monotherapy ET: the median PFS in group A, B, and C was 11.0 vs. 5.9 (p = 0.047), 6.7 vs. 5.0 (p = 0.164), 6.7 vs. 3.9 (p = 0.763) months. Conclusion: Physicians preferred CT rather than ET in patients with early progression under CDKi. It has been shown that subsequent ET after CDKi can be as effective as CT. It was also observed that better PFS could be achieved with the subsequent everolimus-based treatments after first-line CDKi compared to monotherapy ET. [ABSTRACT FROM AUTHOR]

Purpose: Although prospective randomized clinical trials have reported that the use of prophylactic tamoxifen in patients at a high risk of breast cancer is associated with an increased risk of cataracts development, such findings are inconsistent. This study aimed to clarify the relationship between adjuvant tamoxifen use and cataracts risk using a nationwide longitudinal population-based registry. Methods: This retrospective cohort study was conducted using the Korean National Health Insurance claims database over a 15-year period (January 2007–December 2021). Data from all female patients diagnosed with ductal carcinoma in situ (DCIS) between 2009 and 2015 were extracted. We evaluated the incidence of cataracts diagnosis and surgery after adjuvant tamoxifen administration in patients with DCIS. Results: A total of 43,434 patients who met the inclusion criteria were diagnosed with DCIS between 2009 and 2015. Data from 2849 patients receiving tamoxifen and 1615 patients not receiving tamoxifen were analyzed before matching. After matching for comorbidities, type of breast surgery, and age, both groups consisted of 1597 patients. Both before and after matching, adjuvant tamoxifen was not a significant factor for an increased risk of cataracts diagnosis alone or with surgery. Conclusion: Our study showed that adjuvant tamoxifen was not a risk factor for increased cataracts diagnosis and surgery in patients with DCIS. This finding provides a basis for physicians to reduce their ocular toxicity concerns regarding the risk of patients developing cataracts by tamoxifen treatment. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common cancer in females and BC brain metastasis (BCBM) is considered as the second most frequent brain metastasis. Although the advanced treatment has significantly prolonged the survival in BC patients, the prognosis of BCBM is still poor. The management of BCBM remains challenging. Systemic treatments are important to maintain control of central nervous system disease and improve patients' survival. BCBM medical treatment is a rapidly advancing area of research. With the emergence of new targeted drugs, more options are provided for the treatment of BM. This review features currently available BCBM treatment strategies and outlines novel drugs and ongoing clinical trials that may be available in the future. These treatment strategies are discovered to be more efficacious and potent, and present a paradigm shift in the management of BCBMs. [ABSTRACT FROM AUTHOR]

Simple Summary: The presence of immune cells within the tumor (TILs) indicates good prognosis for some aggressive breast cancer subtypes. However, less is known about TILs role within the hormone-responsive breast cancer (ER+/HER2−). These tumors represent up to 70% of all breast cancers and often exhibit long-term metastasis. TILs were quantified in tumor section samples from 763 postmenopausal women who received tamoxifen vs. no treatment and categorized into low, intermediate, or high. Among the ER+/HER2−, TILs were associated with poor prognostic variables but did not have prognostic value. High TILs indicate less benefit from tamoxifen. Interestingly, high gene expression of some TIL markers did indicate good prognosis even after adjusting for other clinical variables or were associated with less tamoxifen benefit. These results suggest that TIL markers could be used as prognostic, predictive indicators, and potential candidates for immunotherapy interventions after tamoxifen failure. The clinical impact of tumor-infiltrating lymphocytes (TILs) is less known for breast cancer patients with the estrogen receptor-positive (ER+)/human epidermal growth factor receptor-negative (HER−) subtype. Here, we explored the prognostic and predictive value of TILs regarding distant recurrence-free interval (DRFI) and breast cancer-specific survival (BCSS) in 763 postmenopausal patients randomized to receive tamoxifen vs. no systemic treatment. TILs were assessed in whole section tumor samples stained with H&E and divided into low (<10%), intermediate (10–39%), or high (≥40%). High TILs were associated with poor prognostic variables and good prognoses for all patients, but not within the ER+/HER2− group. Within the ER+/HER2− group, high gene expression of CD19 and PD-L1 and high IMMUNE1 score indicated good prognosis in multivariable analysis while high CD8 and CD19 gene expression and high IMMUNE1 score were associated with less tamoxifen benefit. These results indicate that within the ER+/HER2− subtype there could be subsets of patients where expression of specific TIL markers might be used to reveal candidates for immune therapy interventions upon failure of the endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: Although previous studies demonstrated no association between depression and tamoxifen in patients with breast cancer, there is still a limited amount of long-term follow-up data. This study aimed to evaluate the relationship between endocrine treatment and the risk of depression. Methods: This nationwide population-based cohort study used data obtained over a 14-year period (January 2007 to December 2021) from the Korean National Health Insurance claims database. All female patients with breast cancer were included. We examined the incidence of depression in patients who underwent endocrine treatment, and those who did not undergo endocrine treatment constituted the control group. Results: The data from 11,109 patients who underwent endocrine treatment and 6,615 control patients between 2009 and 2010 were analyzed. After performing matching for comorbidities and age, both groups comprised 6,532 patients. The median follow-up were 119.71 months. Before and after matching was performed, the endocrine treatment was not a significant risk factor for developing depression (p=0.7295 and p=0.2668, respectively), nor was it a significant factor for an increased risk for suicide attempt (p=0.6381 and p=0.8366, respectively). Conclusions: Using a real-world population-based cohort, this study demonstrated that there is no evidence that the endocrine treatment increases the risk of depression. [ABSTRACT FROM AUTHOR]

Purpose: Guidelines recommend endocrine treatment for estrogen receptor-positive (ER+) breast cancers for up to 10 years. Earlier data suggest that the 70-gene signature (MammaPrint) has potential to select patients that have an excellent survival without chemotherapy and limited or no tamoxifen treatment. The aim was to validate the 70-gene signature ultralow-risk classification for endocrine therapy decision making. Methods: In the IKA trial, postmenopausal patients with non-metastatic breast cancer had been randomized between no or limited adjuvant tamoxifen treatment without receiving chemotherapy. For this secondary analysis, FFPE tumor material was obtained of ER+HER2− patients with 0–3 positive lymph nodes and tested for the 70-gene signature. Distant recurrence-free interval (DRFI) long-term follow-up data were collected. Kaplan–Meier curves were used to estimate DRFI, stratified by lymph node status, for the three predefined 70-gene signature risk groups. Results: A reliable 70-gene signature could be obtained for 135 patients. Of the node-negative and node-positive patients, respectively, 20% and 13% had an ultralow-risk classification. No DRFI events were observed for node-negative patients with an ultralow-risk score in the first 10 years. The 10-year DRFI was 90% and 66% in the low-risk (but not ultralow) and high-risk classified node-negative patients, respectively. Conclusion: These survival analyses indicate that the postmenopausal node-negative ER+HER2− patients with an ultralow-risk 70-gene signature score have an excellent 10-year DRFI after surgery with a median of 1 year of endocrine treatment. This is in line with published results of the STO-3-randomized clinical trial and supports the concept that it is possible to reduce the duration of endocrine treatment in selected patients. [ABSTRACT FROM AUTHOR]

Aim: To describe real-world treatment patterns/outcomes among patients with HER2+ metastatic breast cancer (MBC). Materials & methods: Real-world treatments and overall survival (OS) were evaluated among adult women diagnosed with HER2+ MBC, with and without brain metastases (BMs), between 1 June 2012 and  31 May 2018 using electronic medical records from the Definitive Oncology Dataset. Results: Among 372 patients, 69% initiated first-line trastuzumab plus pertuzumab-based therapy; many therapy combinations were utilized in the second- to fourth-line. During follow-up (median 24.8 months), 18% of patients died (22% with and 16% without BMs). Mean OS was shortest among patients with BMs at MBC diagnosis in the third- and fourth-line. Conclusion: OS was poor, and no clear standard of care was observed among patients with HER2+ MBC progressing on trastuzumab-based therapies. [ABSTRACT FROM AUTHOR]

Female breast cancer is the most common tumour diagnosed worldwide and is one of the leading causes of cancer-related death. The management of elderly, male and pregnant patients with breast cancer requires some additional considerations which are reviewed in this chapter. Breast screening is routinely offered to women aged between 50 and 70 years in England. There are substantial regional variations among UK hospitals in the clinical management of elderly breast cancer patients. Primary endocrine therapy is used in the treatment of ER-positive elderly breast cancer patients not fit for surgical intervention. Male breast cancer is rare, accounting for less than 1% of all breast cancers. It is more common in elderly men and tends to behave like post-menopausal breast cancer. Although breast cancer is one of the most frequently diagnosed malignancies among pregnant women, breast cancer during pregnancy is a rare condition and has been associated with more aggressive, high-grade, poorly differentiated tumours and with a predominance of more aggressive molecular subtypes such as triple negative, HER-2-positive and lower rates of ER and PR expression. [ABSTRACT FROM AUTHOR]

Abstract Aim The aim was to explore stressful events, experienced problems and used coping strategies during the first three months of undergoing ET. Design This study used a mixed method design. Methods A consecutive sample of 39 women newly diagnosed with breast cancer were included at the start of their adjuvant endocrine therapy. A daily coping assessment was used to create daily reports about stressful events or experienced problems and coping strategies. Results The most frequently reported physical problems were sleeping difficulties. Anxiety was the most reported emotional problem. Patients used both emotion‐and problem‐focused coping, and sleeping difficulties were coped by relaxing, and anxiety was coped by thinking about something else. Conclusions Patients experienced a variety of stressful events or problems during the first three months of endocrine therapy. They also used several coping strategies to endure the treatment.

Abstract Background Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~ 1%) but are relatively common (10–50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagnosed metastatic disease. Methods We collected 130 archival tumor samples from 103 breast cancer patients treated with endocrine therapy prior to their local/metastatic recurrence. The cohort consisted of 41 patients having at least 1 sample from local/loco-regional recurrence and 62 patients with metastatic disease (of whom 41 newly diagnosed and 28 with advanced disease). The 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed either by targeted sequencing or by droplet digital PCR. Progression-free survival (PFS), disease-free survival (DFS), and distant recurrence-free survival (DRFS) were statistically tested by Kaplan-Meier analysis. Results The prevalence of ESR1 mutations was 5/41 (12%) in newly diagnosed metastatic patients and 5/28 (18%) for advanced metastases, detected at allele frequency > 1%. All mutations in advanced metastases were detected in patients previously treated with both tamoxifen (TAM) and aromatase inhibitors (AI). However, in newly diagnosed metastatic patients, 4/5 mutations occurred in patients treated with TAM alone. PFS on AI treatment in metastatic patients was significantly shorter for ESR1 mutation carriers (p = 0.017). In the local recurrence cohort, ESR1 mutations were identified in 15/41 (36%) patients but only 4/41 (10%) were detected at allele frequency > 1%. Again, most mutations (3/4) were detected under TAM monotherapy. Notably, 1 patient developed ESR1 mutation while on neoadjuvant endocrine therapy. DFS and DRFS were significantly shorter (p = 0.04 and p = 0.017, respectively) in patients that had ESR1 mutations (> 1%) in their loco-regional recurrence tumor. Conclusions Clinically relevant ESR1 mutations are prevalent in newly diagnosed metastatic and local recurrence of endocrine-treated breast cancer. Since local recurrences are amenable to curative therapy, these mutations may inform the selection of subsequent endocrine therapies.

Objectives: To investigate the most common concomitant symptoms and the urgent demand of solution in the breast cancer patients undergoing postoperative endocrine treatment, as well as the acceptance and expectation of acupuncture in the patients so as to provide the scientific data for promoting the application of acupuncture in the breast cancer patients., Methods: Breast cancer patients treated in Tianjin Medical University Cancer Institute and Hospital from January 2022 to March 2023 were randomly selected as the subjects. Using "questionnaire star" website, the questionnaire was conducted to investigate the relevant concomitant symptoms of the patients in postoperative endocrine treatment and the questions related to acupuncture treatment., Results: In this study, 229 questionnaires were distributed and 211 valid ones were collected, with the response rate of 92.1%. Among these patients, the first three common symptoms were sleep disorders (157 cases, 74.4%), hot flashes (138 cases, 65.4%) and joint / muscle pain (118 cases, 55.9%)；the top three symptoms to be solved the most urgently were sleep disorders (131 cases, 62.1%), joint / muscle pain (62 cases, 29.4%) and hot flashes (45 cases, 21.3%). 79.1% of the patients (167 cases) were willing to receive acupuncture treatment because of the high expectations on its potential effect (93%). 20.9% of them (44 cases) refused acupuncture because they were worried not to be treated by the experienced physicians of TCM (52%) or afraid of needling feelings (48%). The average expectation value of acupuncture treatment was 4.02 points (5 points for the total score) among patients willing to receive acupuncture treatment. The main purposes of receiring acupuncture for the patients undergoing endocrine treatment were to strengthen the immune function (92%), reduce the adverse reactions (83%), and improve the physical condition (75%), et al., Conclusions: Sleep disorder is one of the most concerned symptoms in endocrine treatment for the patients after breast cancer surgery. The patients highly expect for acupuncture treatment even though some patients dislike the needling sensation. How to provide the acceptable and high-quality acupuncture services for cancer patients will be one of the major directions of acupuncture research in the future.

Long-term endocrine treatment which results in estrogen deprivation causes chronic stress associated with a series of uncomfortable symptoms leading not only to a decrease in quality of life but also to cancer recurrence, which may be mediated primarily through the enhanced expression of angiogenic factors, as well as a series of inflammatory microenvironmental changes that favor tumor progression. In this study, we designed a clinical trial and aimed to explore the effects of Sanhuang Decoction (SHD) treatment on chronic stress, inflammatory factors, and breast cancer recovery. A total of 90 patients with breast cancer who met the inclusion/exclusion criteria were randomly allocated to a treatment or control group. The treatment group received the standard endocrine treatment and the traditional Chinese medicine decoction known as SHD. The control group received the standard endocrine treatment only. The treatment period was 6 months. The modified Kupperman Menopausal Index, the self-rating anxiety scale, and the self-rating depression scale were evaluated once per month. The body microenvironment plasma indices related to chronic stress, such as oxidative and antioxidative stress markers, inflammatory factors, hemorheology, coagulation, lipid and D-dimer, immunologic functions, tumor biomarkers, and angiogenic factors of the vascular endothelial growth factor (VEGF) were measured before and after 6 months of treatment. After treatment for 5 months, the scores in the treatment group decreased to nearly normal levels and the control group showed no significant improvement. After treatment for 6 months, all indices related to the body microenvironment, as well as the tumor biomarkers and carcinoembryonic antigen, carbohydrate antigen 153, and angiogenic factor VEGF levels improved significantly to normal levels in the treatment group. Our primary research showed that treatment with SHD effectively improved the quality of life of breast cancer patients by facilitating a change in the body microenvironment that controlled tumor growth and prevented drug resistance.Clinical Trial RegistrationChinese Clinical Trial Registry, identifier ChiCTR-IIR-2000041413. Date of registration: 2017-06-07 (retrospective registration).

Long-term endocrine treatment which results in estrogen deprivation causes chronic stress associated with a series of uncomfortable symptoms leading not only to a decrease in quality of life but also to cancer recurrence, which may be mediated primarily through the enhanced expression of angiogenic factors, as well as a series of inflammatory microenvironmental changes that favor tumor progression. In this study, we designed a clinical trial and aimed to explore the effects of Sanhuang Decoction (SHD) treatment on chronic stress, inflammatory factors, and breast cancer recovery. A total of 90 patients with breast cancer who met the inclusion/exclusion criteria were randomly allocated to a treatment or control group. The treatment group received the standard endocrine treatment and the traditional Chinese medicine decoction known as SHD. The control group received the standard endocrine treatment only. The treatment period was 6 months. The modified Kupperman Menopausal Index, the self-rating anxiety scale, and the self-rating depression scale were evaluated once per month. The body microenvironment plasma indices related to chronic stress, such as oxidative and antioxidative stress markers, inflammatory factors, hemorheology, coagulation, lipid and D-dimer, immunologic functions, tumor biomarkers, and angiogenic factors of the vascular endothelial growth factor (VEGF) were measured before and after 6 months of treatment. After treatment for 5 months, the scores in the treatment group decreased to nearly normal levels and the control group showed no significant improvement. After treatment for 6 months, all indices related to the body microenvironment, as well as the tumor biomarkers and carcinoembryonic antigen, carbohydrate antigen 153, and angiogenic factor VEGF levels improved significantly to normal levels in the treatment group. Our primary research showed that treatment with SHD effectively improved the quality of life of breast cancer patients by facilitating a change in the body microenvironment that controlled tumor growth and prevented drug resistance. Clinical Trial Registration: Chinese Clinical Trial Registry, identifier ChiCTR-IIR-2000041413. Date of registration: 2017-06-07 (retrospective registration). [ABSTRACT FROM AUTHOR]

Abstract Background The effect of extended adjuvant aromatase inhibition in hormone-positive breast cancer after sequential tamoxifen, aromatase inhibitor treatment of 5 years was recently investigated by the DATA study. This study found no statistically significant effect of prolonged aromatase therapy. However, subgroup analysis showed post hoc statistically significant benefits in certain sub-populations. The trans-DATA study is a translational sub-study aiming to identify DNA methylation markers prognostic of patient outcome. Methods Patients from the DATA study are included in the trans-DATA study. Primary breast tumour tissue will be collected, subtyped and used for DNA isolation. A genome-wide DNA methylation discovery assay will be performed on 60 patients that had a distant recurrence and 60 patients that did not have a distant recurrence using the Infinium Methylation EPIC Bead Chip platform. Differentially methylated regions of interest will be selected based on Akaike’s Information Criterion, Gene Ontology Analysis and correlation between methylation and expression levels. Selected candidate genes will subsequently be validated in the remaining patients using qMSP. Discussion The trans-DATA study uses a cohort derived from a clinical randomised trial. This study was designed to avoid common pitfalls in marker discovery studies such as selection bias, confounding and lack of reproducibility. In addition to the usual clinical risk factors, the results of this study may identify predictors of high recurrence risk in hormone receptor-positive breast cancer patients treated with sequential tamoxifen and aromatase inhibitor therapy.

Purpose: There are conflicting results on the potential role of HER2-status on the efficacy of aromatase inhibitors (AIs) and tamoxifen (TAM) in patients with hormone receptor (HR)-positive breast cancer (BC). The purpose of this population-based cohort study was to investigate the potential benefit of AIs compared to TAM as adjuvant therapy in postmenopausal BC patients by HER2-status in the era of modern therapy with HER2-blockade. Methods: A population-based cohort study was performed including all postmenopausal women diagnosed with HR-positive BC without distant metastasis between 2007 and 2012 in three healthcare regions in Sweden. We analyzed the breast cancer-specific survival (BCSS) and overall survival (OS) in two distinct cohorts (HER2-negative, HER2-positive) based on the type of endocrine therapy (ET) used. A propensity score matching was performed separately in the HER2-negative and HER2-positive cohorts, respectively. Results: After propensity score matching, 4368 patients with HER2-negative and 214 patients with HER2-positive BC were available for analysis. In the HER2-negative cohort, an improved BCSS [Hazard Ratio (HR): 0.51; 95% confidence interval (CI): 0.34–0.77, p value < 0.001] and a trend toward improved OS (HR: 0.66; 95% CI: 0.41–1.08, p value = 0.093) in favor of AI-based therapy was observed. In the HER2-positive cohort, no statistically significant difference between AI-based ET and TAM was found in terms of either BCSS or OS, although the direction of HR was similar as in the HER2-negative cohort (HR for BCSS: 0.84; 95% CI: 0.14–5.04, p = 0.849; HR for OS: 0.62; 95% CI: 0.10–3.38, p = 0.345). Conclusion: Our study results, based on propensity-matched cohorts, did not support any predictive value of HER2-status on endocrine therapy in postmenopausal BC patients. AI-based ET remains the treatment of choice for postmenopausal BC patients with HR-positive disease in the modern era of HER2-directed therapy irrespective of HER2-status. [ABSTRACT FROM AUTHOR]

BackgroundClinical guidelines generally recommend endocrine therapy (ET) as first-line treatment of hormone receptor-positive advanced breast cancer (HR+ ABC) whereas chemotherapy (CT) should be considered in the presence of life-threatening disease or limited clinical benefit after three sequential ET regimens. However, it is unclear if real-world clinical practice is in accordance with the current guidelines. This study was to present the real-world treatment patterns and ET regimens among HR+ ABC patients in China.MethodsUsing data from the Nation-wide Multicenter Retrospective Clinical Epidemiology Study of Female Advanced Breast Cancer in China (ClinicalTrials.gov identifier: NCT03047889), we investigated the clinicopathological characteristics, clinical profiles, and treatment patterns of HR+ ABC patients from January 2012 to December 2014.ResultsA total of 2,342 patients with HR+ ABC were included in this study. Our findings revealed that, in comparisons with those receiving initial CT (n = 1445), patients initiated ET (n =402) were significantly older, later recurrent after adjuvant treatment, with a lower rate of visceral involvement and a decreasing quantity of metastatic sites. A total of 1,308 patients received palliative ET while only 18.9% patients (n = 247) reached three lines of ET. Among patients completing more than one line of ET, the median treatment duration was 8 months for the first line, 6 months for the second line, and 3 months for the third line for patients receiving ET. In the advanced setting, the choices of palliative ET regimens were diverse, yet aromatase inhibitor (AI) monotherapy was still the overall mainstay of ET; in contrast, patients were less accessible to everolimus plus AI regimen in this population.ConclusionsLess than one quarter of patients initiated palliative ET for HR+ ABC in routine clinical practice. Patients who received multi-lines of ET experienced successive shorter durations following each line of therapy. This real-life data provides a solid overview of ET for HR+ ABC from China, indicating unmet need for treatment options that improve the effectiveness of endocrine therapy.

Background: Clinical guidelines generally recommend endocrine therapy (ET) as first-line treatment of hormone receptor-positive advanced breast cancer (HR+ ABC) whereas chemotherapy (CT) should be considered in the presence of life-threatening disease or limited clinical benefit after three sequential ET regimens. However, it is unclear if real-world clinical practice is in accordance with the current guidelines. This study was to present the real-world treatment patterns and ET regimens among HR+ ABC patients in China. Methods: Using data from the Nation-wide Multicenter Retrospective Clinical Epidemiology Study of Female Advanced Breast Cancer in China (ClinicalTrials.gov identifier: NCT03047889), we investigated the clinicopathological characteristics, clinical profiles, and treatment patterns of HR+ ABC patients from January 2012 to December 2014. Results: A total of 2,342 patients with HR+ ABC were included in this study. Our findings revealed that, in comparisons with those receiving initial CT (n = 1445), patients initiated ET (n =402) were significantly older, later recurrent after adjuvant treatment, with a lower rate of visceral involvement and a decreasing quantity of metastatic sites. A total of 1,308 patients received palliative ET while only 18.9% patients (n = 247) reached three lines of ET. Among patients completing more than one line of ET, the median treatment duration was 8 months for the first line, 6 months for the second line, and 3 months for the third line for patients receiving ET. In the advanced setting, the choices of palliative ET regimens were diverse, yet aromatase inhibitor (AI) monotherapy was still the overall mainstay of ET; in contrast, patients were less accessible to everolimus plus AI regimen in this population. Conclusions: Less than one quarter of patients initiated palliative ET for HR+ ABC in routine clinical practice. Patients who received multi-lines of ET experienced successive shorter durations following each line of therapy. This real-life data provides a solid overview of ET for HR+ ABC from China, indicating unmet need for treatment options that improve the effectiveness of endocrine therapy. [ABSTRACT FROM AUTHOR]

Background: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions., Patients and Methods: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed., Results: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94)., Conclusion: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer patients often use antioxidants that may interact with adjuvant treatments. The purpose was to investigate pre- and postoperative antioxidant use in relation to clinicopathological characteristics and prognosis in different breast cancer treatment groups., Methods and Patients: Pre- and postoperative antioxidant (vitamin A, C, E, carotenoids, or Q10) or multivitamin use was self-reported by patients from Lund (n = 1855) and Helsingborg (n=478), Sweden. Patients were followed for up to 15 years. Clinical data were obtained from patient charts. The aryl hydrocarbon receptor (AhR) was evaluated in tumor tissue arrays from 915 patients from Lund and with Western blot in MCF-7 and MDA-MB-231 cells., Results: About 10% of patients used antioxidants. Nuclear AhR (AhR nuc ) positivity was twice as common in preoperative antioxidant users compared to non-users. In mechanistic studies vitamin C increased AhR levels and its downstream target CYP1B1, indicating AhR activation. There were significant interactions between tumor AhR nuc status and preoperative antioxidant use in relation to clinical outcome. In all patients, antioxidant use (other than multivitamins) at both visits was associated with poorer prognosis, while use only at the follow-up visit was associated with better prognosis, compared with no use at either visit., Conclusion: The clinical impact of antioxidants depended on antioxidant type, timing of use, and tumor AhR activation. Antioxidants may influence clinical outcome by activation of the master regulator AhR in addition to interference with free radicals. Further studies are needed to identify breast patients that might improve or worsen their prognosis when using antioxidants postoperatively., Competing Interests: Disclosure KI has received speaker honorarium from Pierre Fabre. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

BackgroundEndocrine therapy (ET) is the mainstay of treatment for hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer; however, adaptive mechanisms emerge in about 25–30% of cases through alterations in the estrogen receptor ligand-binding domain, with a consequent ligand-independent estrogen receptor activity. Epigenetic-mediated events are less known and potentially involved in alternative mechanisms of resistance. The aim of this study was to test the feasibility of estrogen receptor 1 (ESR1) epigenetic characterization through liquid biopsy and to show its potential longitudinal application for an early ET sensitivity assessment.MethodsA cohort of 49 women with hormone receptor-positive HER2-negative MBC was prospectively enrolled and characterized through circulating tumor DNA using methylation-specific droplet digital PCR (MS-ddPCR) before treatment start (BL) and after 3 months concomitantly with computed tomography (CT) scan restaging (EV1). ESR1 epigenetic status was defined by assessing the methylation of its main promoters (promA and promB). The most established cell-free tumor DNA (ctDNA) factors associated with ET resistance [ESR1 and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations] were assessed through next-generation sequencing. Associations were tested through Mann–Whitney U test, matched pairs variations through Wilcoxon signed rank test, and survival was analyzed by log-rank test.ResultsThe ET backbone was mainly based on aromatase inhibitors (AIs) (70.83%) in association with CDK4/6 inhibitors (93.75%). Significantly lower promA levels at baseline were observed in patients with liver metastases (P = 0.0212) and in patients with ESR1 mutations (P = 0.0091). No significant impact on PFS was observed for promA (P = 0.3777) and promB (P = 0.7455) dichotomized at the median while a ≥2-fold increase in promB or in either promA or promB at EV1 resulted in a significantly worse prognosis (respectively P = 0.0189, P = 0.0294). A significant increase at EV1 was observed for promB among patients with PIK3CA mutation (P = 0.0173). A trend was observed for promB in ESR1 wild-type patients and for promA in the ESR1 mutant subgroup.ConclusionThe study proofed the concept of an epigenetic characterization strategy based on ctDNA and is capable of being integrated in the current clinical workflow to give useful insights on treatment sensitivity.

Summary: The emerging immune checkpoint blockade (ICB) therapy has ushered the cancer therapeutics field into an era of immunotherapy. Although ICB treatment provides remarkable clinical responses in a subset of patients with cancer, this regimen fails to extend survival in a large proportion of patients. Here, we found that a combined treatment of estrogen receptor beta (ERβ) agonist and PD-1 antibody treatment improved therapeutic efficacy in mouse tumor models, compared with monotherapies, by reducing infiltration of myeloid-derived suppressor cells (MDSCs) and increasing CD8+ T cells in tumors. Mechanistically, LY500307 treatment reduced tumor-derived CSF1 and decreased infiltration of CSF1R+ MDSCs in the tumor bed. CSF1 released by tumor cells induced CSF1R+ MDSC chemotaxis in vitro and blockade of CSF1R demonstrated similar therapeutic effects as ERβ activation in vivo. Collectively, our study proved combined treatment of ERβ agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy.

Background: Endocrine therapy (ET) is the mainstay of treatment for hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer; however, adaptive mechanisms emerge in about 25–30% of cases through alterations in the estrogen receptor ligand-binding domain, with a consequent ligand-independent estrogen receptor activity. Epigenetic-mediated events are less known and potentially involved in alternative mechanisms of resistance. The aim of this study was to test the feasibility of estrogen receptor 1 (ESR1) epigenetic characterization through liquid biopsy and to show its potential longitudinal application for an early ET sensitivity assessment. Methods: A cohort of 49 women with hormone receptor-positive HER2-negative MBC was prospectively enrolled and characterized through circulating tumor DNA using methylation-specific droplet digital PCR (MS-ddPCR) before treatment start (BL) and after 3 months concomitantly with computed tomography (CT) scan restaging (EV1). ESR1 epigenetic status was defined by assessing the methylation of its main promoters (promA and promB). The most established cell-free tumor DNA (ctDNA) factors associated with ET resistance [ ESR1 and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations] were assessed through next-generation sequencing. Associations were tested through Mann–Whitney U test, matched pairs variations through Wilcoxon signed rank test, and survival was analyzed by log-rank test. Results: The ET backbone was mainly based on aromatase inhibitors (AIs) (70.83%) in association with CDK4/6 inhibitors (93.75%). Significantly lower promA levels at baseline were observed in patients with liver metastases (P = 0.0212) and in patients with ESR1 mutations (P = 0.0091). No significant impact on PFS was observed for promA (P = 0.3777) and promB (P = 0.7455) dichotomized at the median while a ≥2-fold increase in promB or in either promA or promB at EV1 resulted in a significantly worse prognosis (respectively P = 0.0189, P = 0.0294). A significant increase at EV1 was observed for promB among patients with PIK3CA mutation (P = 0.0173). A trend was observed for promB in ESR1 wild-type patients and for promA in the ESR1 mutant subgroup. Conclusion: The study proofed the concept of an epigenetic characterization strategy based on ctDNA and is capable of being integrated in the current clinical workflow to give useful insights on treatment sensitivity. [ABSTRACT FROM AUTHOR]

Purpose: Endocrine therapy (ET) is the mainstream adjuvant treatment for ER-positive breast cancer (BC). We analysed 9293 ER-positive BC patients diagnosed in nine European countries in 2009–2013 to investigate how comorbidities at diagnosis, age, stage and subtype affected ET use over time, and relapse. Methods: Adjusted odds ratios (ORs) and 95% confidence intervals (95%CIs) of receiving ET were estimated according to Charlson comorbidity, age, stage and subtype using logistic regression. The 2-year cumulative incidence and adjusted sub-hazard ratios (SHRs) of relapse were estimated using competing risk analysis, with all-cause death as the competing event. The z-test was used to assess differences in the proportion of patients receiving ET in 1996–1998 and 2009–2013. Results: Ninety percent of the patients started adjuvant ET, range 96% (Belgium, Estonia, Slovenia, Spain)—75% (Switzerland). ORs of starting ET were lower for women aged > 75 years, with severe comorbidities, or luminal B HER2-positive cancer. The factors independently increasing the risk of relapse were: not receiving ET (SHR 2.26, 95%CI 1.02–5.03); severe comorbidity (SHR 1.94, 95%CI 1.06–3.55); luminal B, either HER2 negative (SHR 3.06, 95%CI 1.61–5.79) or positive (SHR 3.10, 95%CI 1.36–7.07); stage II (SHR 3.20, 95%CI 1.56–6.57) or stage III (SHR 7.41, 95%CI 3.48–15.73). ET use increased significantly but differently across countries from 51–85% in 1996–1998 to 86–96% in 2009–2013. Conclusions: ER-positive BC patients in Europe are increasingly prescribed ET but between-country disparities persist. Older women and women with severe comorbidity less frequently receive ET. ET omission and severe comorbidity independently predict early disease relapse. [ABSTRACT FROM AUTHOR]

Background: Endocrine treatment is one of the most effective therapies for estrogen receptor-positive breast cancer. However, most tumors will develop resistance to endocrine therapy as the cancer progresses. This review focuses on the mechanisms and markers of endocrine-resistant breast cancer. In addition, current and future strategies to overcome endocrine resistance are discussed. Summary: Several molecular mechanisms of endocrine resistance have been identified, including alterations in the ESR1 gene or in the PIK3CA/mTOR pathway. Meanwhile, CDK4/6, mTOR, and PI3K inhibition have shown to improve the efficacy of endocrine treatment and new promising approaches are being developed. Key Message: Overcoming primary or acquired resistance to endocrine treatment remains a major challenge. Since the molecular mechanisms of endocrine resistance are manifold, optimal combination and sequencing strategies will have to be developed in the future. [ABSTRACT FROM AUTHOR]

Purpose: Sexual dysfunction is an important concern of premenopausal women with early breast cancer. We investigated predictors of sexual problems in two randomized controlled trials. Methods: A subset of patients enrolled in TEXT and SOFT completed global and symptom-specific quality-of-life indicators, CES-Depression and MOS-Sexual Problems measures at baseline, six, 12 and 24 months. Mixed models tested the association of changes in treatment-induced symptoms (baseline to 6 months), depression at 6 months, and age at randomization with changes in sexual problems over 2 years. Results: Sexual problems increased by 6 months and persisted at this level. Overall, patients with more severe worsening of vaginal dryness, sleep disturbances and bone or joint pain at 6 months reported a greater increase in sexual problems at all time-points. Depression scores were significantly associated with sexual problems in the short-term. All other symptoms had a smaller impact on sexual problems. Age was not associated with sexual problems at any time-point. Conclusion: Among several key symptoms, vaginal dryness, sleep disturbance, and bone and joint pain significantly predicted sexual problems during the first 2 years. Early identification of these symptoms may contribute to timely and tailored interventions. [ABSTRACT FROM AUTHOR]

Background: Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~ 1%) but are relatively common (10-50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagnosed metastatic disease.Methods: We collected 130 archival tumor samples from 103 breast cancer patients treated with endocrine therapy prior to their local/metastatic recurrence. The cohort consisted of 41 patients having at least 1 sample from local/loco-regional recurrence and 62 patients with metastatic disease (of whom 41 newly diagnosed and 28 with advanced disease). The 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed either by targeted sequencing or by droplet digital PCR. Progression-free survival (PFS), disease-free survival (DFS), and distant recurrence-free survival (DRFS) were statistically tested by Kaplan-Meier analysis.Results: The prevalence of ESR1 mutations was 5/41 (12%) in newly diagnosed metastatic patients and 5/28 (18%) for advanced metastases, detected at allele frequency > 1%. All mutations in advanced metastases were detected in patients previously treated with both tamoxifen (TAM) and aromatase inhibitors (AI). However, in newly diagnosed metastatic patients, 4/5 mutations occurred in patients treated with TAM alone. PFS on AI treatment in metastatic patients was significantly shorter for ESR1 mutation carriers (p = 0.017). In the local recurrence cohort, ESR1 mutations were identified in 15/41 (36%) patients but only 4/41 (10%) were detected at allele frequency > 1%. Again, most mutations (3/4) were detected under TAM monotherapy. Notably, 1 patient developed ESR1 mutation while on neoadjuvant endocrine therapy. DFS and DRFS were significantly shorter (p = 0.04 and p = 0.017, respectively) in patients that had ESR1 mutations (> 1%) in their loco-regional recurrence tumor.Conclusions: Clinically relevant ESR1 mutations are prevalent in newly diagnosed metastatic and local recurrence of endocrine-treated breast cancer. Since local recurrences are amenable to curative therapy, these mutations may inform the selection of subsequent endocrine therapies. [ABSTRACT FROM AUTHOR]