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Breast cancer is a common and deadly disease, so there is a constant need for research to find efficient targets and therapeutic approaches. Breast cancer can be classified on a molecular and histological base. Breast cancer can be divided into ER (estrogen receptor)-positive and ER-negative, HER2 (human epidermal growth factor receptor2)-positive and HER2-negative subtypes based on the presence of specific biomarkers. Targeting hormone receptors, such as the HER2, progesterone receptor (PR), and ER, is very significant and plays a vital role in the onset and progression of breast cancer. Endocrine treatments and HER2-targeted drugs are examples of targeted therapies now being used against these receptors. Emerging immune-based medicines with promising outcomes in the treatment of breast cancer include immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapy. It is also explored how immune cells and the tumor microenvironment affect breast cancer development and treatment response. The major biochemical pathways, signaling cascades, and DNA repair mechanisms that are involved in the development and progression of breast cancer, include the PI3K/AKT/mTOR system, the MAPK pathway, and others. These pathways are intended to be inhibited by a variety of targeted drugs, which are then delivered with the goal of restoring normal cellular function. This review aims to shed light on types of breast cancer with the summarization of different therapeutic approaches which can target different pathways for tailored medicines and better patient outcomes., (© 2023 John Wiley & Sons Ltd.)

This study was conducted to demonstrate the possible protective and therapeutic effects of naringenin, an estrogenically effective flavonoid, in experimental autoimmune encephalomyelitis (EAE), which is the rodent model of multiple sclerosis. For this purpose, 50 12-week-old C57BL6 male mice were divided into five groups; control, naringenin, EAE, prophylactic naringenin + EAE, and EAE + therapeutic naringenin. The EAE model was induced with myelin oligodendrocyte glycoprotein (35-55) , and naringenin (50 mg/kg) was administered by oral gavage. The prophylactic and therapeutic effects of naringenin were examined according to clinical, histopathological, immunohistochemical, electron microscopic, and RT-PCR (aromatase, 3βHSD, estrogen receptors, and progesterone receptor expression) parameters. The acute EAE model was successfully induced, along with its clinical and histopathological findings. RT-PCR showed that expression of aromatase, 3βHSD, estrogen receptor-β, and progesterone receptor gene decreased, while estrogen receptor-α increased after EAE induction. Electron microscopic analysis showed mitochondrial damage and degenerative changes in myelinated axons and neurons in EAE, which could be behind the downregulation in the expressions of neurosteroid enzymes. Aromatase immunopositivity rates also decreased in EAE, while estrogen receptor α and β, and progesterone receptor immunopositivity rates increased. Naringenin improved aromatase immunopositivity rates and gene expression in both prophylactic and therapeutic use. Clinical and histopathological findings revealed that EAE findings were alleviated in both prophylactic and therapeutic groups, along with significantly decreased inflammatory cell infiltrations in the white matter of the spinal cords. In conclusion, naringenin could provide long-term beneficial effects even in prophylactic use due to stimulating aromatase expression, but it could not prevent or eliminate the EAE model's lesions completely., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hormone receptor-positive (HR + )/human epidermal growth factor receptor 2-negative (HER2 - ) breast cancer is the most prevalent type of breast cancer, in which endocrine therapy resistance and distant relapse remain unmet challenges. Accurate molecular classification is urgently required for guiding precision treatment. We established a large-scale multi-omics cohort of 579 patients with HR + /HER2 - breast cancer and identified the following four molecular subtypes: canonical luminal, immunogenic, proliferative and receptor tyrosine kinase (RTK)-driven. Tumors of these four subtypes showed distinct biological and clinical features, suggesting subtype-specific therapeutic strategies. The RTK-driven subtype was characterized by the activation of the RTK pathways and associated with poor outcomes. The immunogenic subtype had enriched immune cells and could benefit from immune checkpoint therapy. In addition, we developed convolutional neural network models to discriminate these subtypes based on digital pathology for potential clinical translation. The molecular classification provides insights into molecular heterogeneity and highlights the potential for precision treatment of HR + /HER2 - breast cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Breast cancer is the most common type of cancer and the leading cause of death by cancer in women in Colombia. Approximately 15 to 20% of breast cancers overexpress HER2., Objective: To analyze the relationship between multiple clinical and histological variables and pathological complete response in patients with HER2-positive breast cancer undergoing neoadjuvant therapy in a specialized cancer center in Colombia., Materials and Methods: We performed a retrospective analysis of non-metastatic HER2-positive breast cancer patients who received neoadjuvant therapy between 2007 and 2020 at the Instituto de Cancerología Las Americas Auna (Medellín, Colombia). Assessed parameters were tumor grade, proliferation index, estrogen receptor, progesterone receptor, HER2 status, type of neoadjuvant therapy, pathologic complete response rates, and overall survival., Results: Variables associated with low pathologic complete response rates were tumor grades 1-2 (OR = 0.55; 95% CI = 0.37-0.81; p = 0.03), estrogen receptor positivity (OR =0.65; 95%; CI = 0.43-0.97; p=0.04), and progesterone receptor positivity (OR = 0.44; 95% CI = 0.29-0.65; p = 0.0001). HER2 strong positivity (score 3+) was associated with high pathological complete response rates (OR = 3.3; 95% CI = 1.3-8.35; p=0.013). Five-year overall survival was 91.5% (95% CI = 82.6-95.9) in patients with pathological complete response and 73.6% (95% CI = 66.4-79.6) in patients who did not achieve pathological complete response (p = 0.001). Additionally, the pathological complete response rate was three times higher in patients receiving combined neoadjuvant chemotherapy with anti-HER2 therapy than in those with chemotherapy alone (48% versus 16%)., Conclusions: In patients with HER2-positive breast cancer, tumor grade 3, estrogen receptor negativity, progesterone receptor negativity, strong HER2 positivity (score 3+), and the use of the neoadjuvant trastuzumab are associated with higher pathological complete response rates.

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%-70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data., (© 2023 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Young breast cancer (YBC) patients are a unique subpopulation that are often underrepresented in randomized clinical trials. Furthermore, large national cancer databases lack detailed information on recurrence, a meaningful oncologic outcome for young patients., Study Design: A retrospective review of YBC patients (age 40 years or younger) with stage I to III breast cancer diagnosed from 2008 to 2018 was performed. Information on clinicopathologic characteristics, demographics, and outcomes was obtained from the electronic health record and chart review. Chi-square and Fisher's exact tests were used for comparisons of categorical variables and parametric and nonparametric tests for continuous variables., Results: The cohort included 1,431 women with a median follow-up of 4.8 years (range 0.3 to 12.9 years). The median age was 37 years (interquartile range 34 to 39). The study population included 598 (41.8%) White, 112 (7.8%) Black, 420 (29.4%) Asian/Pacific Islander, 281 (19.6%) Hispanic, and 20 (1.4%) "other" race/ethnicity patients. Tumor subtype was as follows: [1] hormone receptor (HR) + /human epidermal growth factor 2 (HER2 - ), grade (G) 1 to 2 = 541 (37.8%); [2] HR + /HER2 - , G3 = 268 (18.7%); [3] HR + /HER2 + = 262 (18.3%); [4] HR - /HER2 + = 101 (7.1%); [5] HR - /HER2 - = 259 (18.1%). The majority (64.2%) presented with stage II/III disease. There were 230 (16.1%) recurrences during follow-up; 74.8% were distant. Locoregional-only recurrence was seen in 17 of 463 (3.7%) patients who underwent breast conservation vs 41 of 968 (4.2%) patients undergoing mastectomy (p < 0.001). Recurrence varied by tumor subtype: [1] HR + /HER2 - , G1 to 2 (14.0%); [2] HR + /HER2 - , G3 (20.9%); [3] HR + /HER2 + (11.1%); [4] HR - /HER2 + (22.8%); [5] HR - /HER2 - (17.8%) (p = 0.005)., Conclusions: In this large, diverse YBC cohort, recurrences were most frequent among HR + /HER2 - , G3, or HR - /HER2 + invasive tumors; most were distant. There were numerically similar locoregional-only recurrences after breast conservation vs mastectomy. Additional research is needed to identify predictors of recurrence., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Context: The high resistance rate and high recurrence rate of progesterone only as a treatment for endometrial cancer (EC) limit its clinical application. Metformin (MET) may have antitumor ability. Combining MET and medroxyprogesterone acetate (MPA) may strengthen their inhibitory effects on proliferation of EC cells, but MET's mechanisms remain unclear., Objective: The study intended to identify the specific molecular mechanism that MET combined with MPA uses against EC progression., Design: The research team performed a controlled animal study., Setting: The study took place at Xuzhou Medical University in Xuzhou, China., Animals: The animals were16 female non-obese diabetic-severe combined immunodeficient (NOD-SCID) nude mice, about 12 to 16 g in weight., Interventions: The research team divided randomly, the mice into four groups and induced EC in all groups, four in each group: (1) The control group which received received normal saline, (2) the MPA group, which received 100 mg/kg of MPA; (3) the MET group, which received metformin at the rate of 200 mg/kg, each gavage volume was 0.1ml; (4) the MET+MPA group, which received 100 mg/kg of MPA and 200 mg/kg of MET., Outcome Measures: The research team: (1) used a CCK-8 kit, an EdU assay, and a flow-cytometry assay to measure cancer-cell proliferation, count, and viability; determine the cell cycle; and measure apoptosis; (2) performed a Western blot analysis to determine the expression of the PR, CD133, pAkt, totalAkt, p-mTOR, and totalTOR antibodies; and (3) determined the size and volume of tumors in vivo and used immunohistochemical staining to determine expression of the Ki67 protein., Results: The MET+MPA group had a significantly lower number of cancer cells than the MET or MDA groups (both P < .001). That group also had significantly more stagnated cancer cells in the G0/G1 phase and significantly fewer cancer cells in the S phase or G2/M phase control, MET, or MPA groups (all P < .01). The MET+MPA group's PCNA and Ki-67 protein expression was significantly lower than that of the MET and MPA group. The EDU assay yielded similar results. Additionally, the MET+MPA group had significantly higher PR expression than that of to MET or MPA group (both P < .001). The MET and MPA groups' expression of CD133, p-Akt, and p-mTOR were significantly lower than those of the control group, while the MET+MPA group's levels were significantly lower than those of the MET and MPA groups. In-vivo experiments revealed that the MET and MPA groups did show decreased tumor size and volume. The MET+MPA group had tumor weights that were significantly lower and tumor volumes were significantly smaller than those of the MET and MPA groups (all P < .001). Immunohistochemical analysis revealed that the MET+MPA group's levels of the Ki-67 antigen were significantly lower than those of the MET and MPA groups., Conclusions: MET inhibited the proliferation of EC cells by increasing MPA-sensitivity, which was dependent on the inhibition of the CD133 expression and the Akt/mTOR pathway. In addition, if MET acts as an effective progestin sensitizer, it certainly offers promising therapeutic prospects for patients with early-stage EC or overgrown endometrium who have fertility requirements.

Objective: Glucose transporter-1 is a marker involved in energy transport in cancer cells. It has been shown to be a poor prognostic factor in many cancer types, including breast cancer. However, there is no satisfactory parameter predicting treatment in breast cancer patients receiving neoadjuvant therapy. This study investigated the effect of glucose transporter-1 in predicting the treatment response of patients receiving neoadjuvant therapy., Methods: In this study, glucose transporter-1 immunohistochemistry was applied to tru-cut biopsy of patients who were diagnosed with breast cancer and received neoadjuvant therapy between 2010 and 2021. A built-in scoring system was used to evaluate both the pattern and intensity of glucose transporter-1 immunohistochemistry staining. The relationship between glucose transporter-1 immunohistochemistry staining and other clinicopathological parameters was examined. In addition, the relationship of glucose transporter-1 with response to treatment was investigated., Results: A relationship was found between high glucose transporter-1 expression and other clinicopathological parameters (such as estrogen and progesterone receptor negativity, high Ki-67, triple-negative, and Her2 status). Cases with high glucose transporter-1 expression had either a complete or a partial pathologic response. The result was statistically significant., Conclusion: Glucose transporter-1 has the potential to be a biomarker that can be evaluated more objectively as an alternative to Ki-67 labeling index in evaluating the response to treatment in patients receiving neoadjuvant therapy.

Objective: The aim of this study was to investigate the predictive importance of the previously validated log(ER)*log(PgR)/Ki-67 predictive model in a larger patient population., Methods: Patients with hormone receptor positive/HER-2 negative and clinical node positive before chemotherapy were included. Log(ER)*log(PgR)/Ki-67 values of the patients were determined, and the ideal cutoff value was calculated using a receiver operating characteristic curve analysis. It was analyzed with a logistic regression model along with other clinical and pathological characteristics., Results: A total of 181 patients were included in the study. The ideal cutoff value for pathological response was 0.12 (area under the curve=0.585, p=0.032). In the univariate analysis, no statistical correlation was observed between luminal subtype (p=0.294), histological type (p=0.238), clinical t-stage (p=0.927), progesterone receptor level (p=0.261), Ki-67 cutoff value (p=0.425), and pathological complete response. There was a positive relationship between numerical increase in age and residual disease. As the grade of the patients increased, the probability of residual disease decreased. Patients with log(ER)*log(PgR)/Ki-67 above 0.12 had an approximately threefold increased risk of residual disease when compared to patients with 0.12 and below (odds ratio: 3.17, 95% confidence interval: 1.48-6.75, p=0.003). When age, grade, and logarithmic formula were assessed together, the logarithmic formula maintained its statistical significance (odds ratio: 2.47, 95% confidence interval: 1.07-5.69, p=0.034)., Conclusion: In hormone receptor-positive breast cancer patients receiving neoadjuvant chemotherapy, the logarithmic model has been shown in a larger patient population to be an inexpensive, easy, and rapidly applicable predictive marker that can be used to predict response.

Introduction: Patients with various advanced cancers devoid of nuclear progesterone receptors (nPR) have demonstrated increased quality and length of life when treated with the PR modulator mifepristone, which likely works by interacting with membrane PRs (mPR)., Areas Covered: Two immunomodulatory proteins are discussed that seem to play a role in cancers that proliferate whether the malignant tumor is positive or negative for the nPR. These two proteins are the progesterone receptor membrane component-1 (PGRMC-1) and the progesterone-induced blocking factor (PIBF). Both PGRMC-1 and the parent form of PIBF foster increased tumor aggressiveness, whereas splice variants of the 90 kDa form of PIBF inhibit immune response against cancer cells., Expert Opinion: The marked clinical improvement following 200-300 mg of mifepristone is likely related to blocking PIBF. In the low dosage used, mifepristone likely acts as an agonist for PGRMC-1 protein. Mifepristone may be less effective for cancers positive for the nPR because the nPR may be protective and blocking it may have detrimental effects. Based on this hypothetical model, the development of other potential treatment options to provide even greater efficacy for treating cancer are discussed.

Background: Adjuvant systemic therapy decreases recurrence and death from breast cancer, but late relapse still occurs. Therapeutic decisions are based heavily on receptor tissue characterization. Even though the vast majority of metastatic sites do not have receptor conversions, they can occur at the time of metastasis and/or during the course of treatment. However, multiple receptor conversions are uncommon., Case Presentation: We present an unusual case of a Caucasian patient originally diagnosed with an estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative primary breast cancer who had a recurrence after 15 years of therapy. Her metastatic tumor had a different receptor status than the original tumor. During the course of therapy, at the time of progression, a new biopsy showed that her tumor had changed once more., Conclusion/discussion: Tracking receptor conversions is important in metastatic breast cancer treatment. Single receptor conversions have been documented to occur, but not much is known of multiple receptor conversions. This case sheds light on the possibility of patients having multiple receptor conversions and the importance of performing multiple biopsies during the course of metastatic treatment., (© 2022. The Author(s).)

Premenstrual dysphoric disorder (PMDD) is characterized by severe cyclic mood symptoms emerging in the luteal phase of the menstrual cycle. The variation in progesterone levels and its metabolites during the luteal phase seems critical to the occurrence of PMDD symptoms. Notably, the efficacy of selective progesterone receptor modulator (SPRM) treatment on the mental symptoms of PMDD has been recently demonstrated. In the present study, structural magnetic resonance imaging was used to assess the effects of SPRM treatment, compared with placebo, on grey matter morphology in women with PMDD. In total, 35 women were scanned during the luteal phase, before and after three months of treatment with SPRM or placebo. Symptom severity was assessed using the Daily Record of Severity of Problems (DRSP), while gonadal hormone levels were measured by liquid chromatography-tandem mass spectrometry. Region-of-interest and whole-brain approaches were employed to perform voxel-based morphometry analyses, subcortical volumetric analyses, and surface-based morphometry analyses. No interaction or main effects of treatment and time were observed on grey matter volume and cortical surface measures (cortical thickness, gyrification index, sulcal depth, and fractal dimension). The relationship between change in brain morphology and symptom severity was also explored but no treatment-dependant grey matter structure change was related to symptom severity change. These findings suggest that SPRM treatment does not impart macrostructural changes onto grey matter structure, at least in the short term., Competing Interests: Conflict of Interest RL received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. ISP has served occasionally on advisory boards or acted as invited speaker at scientific meetings for Asarina Pharma, Bayer Health Care, Gedeon Richter, Peptonics, Shire/Takeda, Sandoz, and Lundbeck A/S. All other authors declare that they have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

BACKGROUND Male breast cancer represents a rare malignancy with identifiable risk factors, including genetics, radiation exposure, liver dysfunction, and concomitant diagnosis of Klinefelter syndrome. Gynecomastia can commonly present in these patients, and despite increased estrogen levels in adipose breast tissue, gynecomastia has not been proven to be a significant risk factor for carcinoma development. Male patients with new-onset breast masses are recommended to undergo diagnostic mammograms and breast ultrasound for further evaluation. Those diagnosed with breast cancer most commonly have invasive ductal carcinoma of the breast, and over half of these patients are found to have estrogen and progesterone receptor (ER/PR) positivity. CASE REPORT In this case report, we present a Black man with gynecomastia and an areolar lesion for a 6-month duration following a traumatic event. He was initially referred to the surgical team for further evaluation, and subsequent imaging and biopsy data revealed ER/PR-positive invasive ductal carcinoma. Multidisciplinary discussions were held, and the patient was arranged to begin neoadjuvant treatment with doxorubicin hydrochloride and cyclophosphamide, followed by treatment with paclitaxel (AC-T) chemotherapy, followed by bilateral mastectomy and adjuvant hormonal therapy. CONCLUSIONS The treatment of male breast cancer has remained relatively like that of female breast cancer, which may be due to the limited data in the treatment of male breast cancer. Thus far, studies involving neoadjuvant chemotherapy of female patients have demonstrated promising responses to expand surgical options for patients and possibly decrease the rates of recurrence. Additional studies are warranted to discern optimal therapy for the male patient population.

Background: Triple-negative breast cancer (TNBC), the subtype of breast cancer with the highest mortality rate, shows clinical characteristics of high heterogeneity, aggressiveness, easy recurrence, and poor prognosis, which is due to lack of expression of estrogen, progesterone receptor and human epidermal growth factor receptor 2. Currently, neoadjuvant chemotherapy (NAT) is still the major clinical treatment for triple-negative breast cancer. Chemotherapy drugs can be divided into platinum and non-platinum according to the presence of metal platinum ions in the structure. However, which kind is more suitable for treating TNBC remains to be determined., Methods: The relevant randomized clinical trials (RCTs) that explore the effectiveness of chemotherapy regimens containing platinum-based drugs (PB) or platinum-free drugs (PF) in treating TNBC patients were retrieved through PubMed, EMBASE, Cochrane Library, CNKI, and other literature platforms, above research findings, were included in the meta-analysis. The incidence of overall remission rate (ORR), pathological complete remission rate (pCR), overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and adverse events (AE) were compared between the two groups., Results: In this study, 12 clinical trials with a total of 4580 patients were included in the analysis. First, the ORR in 4 RCTs was, PB vs PF = 52% vs 48% (RR = 1.05, 95% CI: 0.91-1.21, P = 0.48); the pCR in 5 RCTs was, PB vs PF = 48% vs 41% (RR = 1.38, 95% CI: 0.88-2.16, P = 0.17). CI: 0.88-2.16, P = 0.17; the other 2 RCTs reported significantly higher DFS and OS rates in the PB group compared with the PF group, with the combined risk ratio for DFS in the PB group RR = 0.22 (95% CI:0.06-0.82, P = 0.015); the combined risk ratio for DFS in the PF group RR = 0.15 (95% CI. 0.04-0.61, P = 0.008); OS rate: PB vs PF = 0.046 vs 0.003; secondly, 2 RCTs showed that for patients with BRCA-mutated TNBC, the pCR rate in the PB and PF groups was 18% vs 26%, 95% CI: 2.4-4.2 vs 4.1-5.1; meanwhile, the median subject in the PB group The median PFS was 3.1 months (95% CI: 2.4-4.2) in the PB group and 4.4 months (95% CI: 4.1-5.1) in the PC group; finally, the results of the clinical adverse effects analysis showed that platinum-containing chemotherapy regimens significantly increased the incidence of adverse effects such as thrombocytopenia and diarrhea compared with non-platinum regimens, while the incidence of adverse effects such as vomiting, nausea, and neutropenia was reduced. The incidence of adverse reactions was reduced., Conclusion: Compared with non-platinum drugs, platinum drugs significantly improved clinical treatment effective indexes, such as PCR, ORR, PFS, DFS, and OS rate in the treatment of TNBC patients without BRCA mutant may cause more serious hematological adverse reactions. Accordingly, platinum-based chemotherapy should be provided for TNBC patients according to the patient's special details., (© 2022. The Author(s).)

Mifepristone is the only glucocorticoid receptor antagonist currently approved for the treatment of Cushing's syndrome. Although originally developed as an abortifacient due to its blockade of the progesterone receptor, a number of case reports documented its efficacy as a glucocorticoid receptor blocker going back to 1985. The SEISMIC trial, published in 2012, provided sufficient data on efficacy and adverse effects for regulatory approval. Mifepristone provides clear benefits on glycemia, blood pressure, muscle weakness, body weight and the other myriad clinical manifestations of Cushing's syndrome. However, because it blocks the glucocorticoid receptor, blood cortisol and ACTH levels actually rise, rather than fall; this complicates patient management. Doses are adjusted based on clinical manifestations rather than hormone levels. Adverse effects include adrenal insufficiency due to overdosage, hypokalemia, and menorrhagia. Treatment of severe adrenal insufficiency requires high doses of dexamethasone. Other glucocorticoid receptor blockers without effects on the progesterone receptor are being developed. Because mifepristone inhibits CYP3A and CYP2C8/2C9, drug-drug interactions can occur. These potential adverse effects can largely be avoided with careful attention to detail. My opinion is that its current place in therapy is in patients with severe disease and in those not responding to other treatments., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

ESR1 (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor-positive (ER + ) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, ESR1 mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated Esr1 mutant-expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant.

Introduction: Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering. Therefore, tailored patient management appears of primary importance to address specific issues and identify the appropriate treatment for each woman. Over the years, abundant research has been carried out with the objective to find new therapeutic approaches for this multifaceted disease., Areas Covered: This narrative review aims to present the latest advances in the pharmacological management of endometriosis. In particular, the potential role of GnRH antagonists, selective progesterone receptor modulators (SPRMs), and selective estrogen receptors modulators (SERMs) will be discussed. We performed a literature search in PubMed and Embase, and selected the best quality evidence, giving preference to the most recent and definitive original articles and reviews., Expert Opinion: Medical therapy represents the cornerstone of endometriosis management, although few advances have been made in the last decade. Most studies have focused on the evaluation of the efficacy and safety of GnRH antagonists (plus add-back therapy in cases of prolonged treatment), which should be used as second-line treatment options in selected cases (i.e. non-responders to first-line treatments). Further studies are needed to identify the ideal treatment for women with endometriosis.

First-line CDK4/6 inhibitor ribociclib plus letrozole improves survival in the metastatic setting, but lack of accrual of African American women is a shortcoming. Predicting benefit in the early-stage setting and diverse enrollment in trials need to be priorities. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests. I-SPY2 Trial and EOP is sponsored by the not for profit Quantum Leap Healthcare Collaborative (QLHC). Dr. Esserman is an unpaid board member of QLHC., (Copyright © 2022. Published by Elsevier Inc.)

Background: The CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2- advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2- ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1., Patients and Methods: Men and women of any menopausal status with HR+/HER2- ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured., Results: Safety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events., Conclusions: These findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2- ABC more representative of patients in real-world clinical practice., (© 2022 Simona Borstnar, Marketa Palacova, Aleksandra Łacko, Constanta Timcheva, Einav Nili Gal-Yam, Konstantinos Papazisis, Juraj Beniak, Pavol Kudela, Gábor Rubovszky, published by Sciendo.)

Everolimus combined with exemestane can modulate endocrine resistance. The combination showed significant improvement in progression-free survival (PFS) in phase III clinical trials for hormone receptor positive metastatic breast cancer patients. It also showed serious adverse events. We evaluate the efficacy and prevalence of serious adverse events in a real-world setting. We retrospectively examined 91 breast cancer patients; all were previously treated with chemotherapy and fulvestrant (84% and 59%, respectively). After a 13-month median follow-up, 29% had a partial response, and 32% had stable disease. The PFS was 7.8 months. Due to adverse events, 19% of patients stopped the treatment, while 31% required a dose reduction. Despite enrolling heavier-pretreated patients, our real-world outcome for the efficacy and safety of the exemestane and everolimus match those of the clinical trials. Such results should assure clinicians and lead to wider adoption of this oral, chemotherapy-sparing regimen.

Background: In metastatic breast cancer (MBC), positive estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status allow for more long-term, sequential treatment options compared to ER-negative and HER2-negative diseases. It is unclear if end-of-life care (timely integration of palliative care, discontinuation of chemotherapy, and enrollment into hospice) in MBC is now tailored to the ER and HER2 status., Objectives: This article explores the association between ER and HER2 status and the quality of end-of-life care received among patients with MBC., Methods: A 20-year MBC clinical database captured demographics, tumor characteristics, and treatment histories of deceased patients with MBC (N = 1,258) at a tertiary hospital located in Pittsburgh, Pennsylvania. Descriptive and inferential statistics were used., Findings: Patients with ER-positive MBC had greater odds of receiving quality end-of-life care than those with ER-negative MBC. HER2 status was not associated with differences in the quality of end-of-life care.

Aims: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres., Materials and Methods: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored., Results: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88)., Conclusions: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients., (Copyright © 2021 The Royal College of Radiologists. All rights reserved.)

Aims: We report population pharmacokinetic (popPK) and exposure-response (E-R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids., Methods: A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steady-state AUC) and IA after oral administration of 0.5, 1, 2 or 4 mg/day over 3 months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2 mg/day. The exposure-E2 relationship was analysed visually., Results: Vilaprisan clearance was 22.7% lower in obese vs non-obese patients. The E-R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (P max ) of 59% (95% CI: 49-68%). The exposure at which 50% of P max is obtained was 36.9 μg*h/L (95% CI: 27.7-48.7 μg*h/L). Simulations showed that 36% of the patients will be below 90% of P max for IA after 1 mg/day compared to 2% after 2 mg/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long-term studies., Conclusions: A 2 mg/day dose was selected for Phase 3 as E-R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted., (© 2021 Bayer AG. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: We aimed to evaluate (immunohistochemically) the YAP expression in breast cancer patients undergoing neoadjuvant chemotherapy and to clarify the relationship between the molecular characteristics, treatment response and survival data and the YAP expression, and hence, to clarify the prognostic significance., Material and Methods: One hundred and four patients who were diagnosed with Breast Cancer between 2015-2020 and underwent Neo Adjuvant Chemotherapy were included in the study. Estrogen Receptor(ER), Progesterone Receptor(PR), Human Epidermal Growth Receptor-2(HER2) and Ki-67. Expression are routinely stained immunohistochemically. In this study, existing immunohistochemical markers were reviewed and also, the relationship of YAP with these biological markers was evaluated by using immunohistochemistry and its effect on prognosis has been investigated., Results: The average age of the patients was 52.37. While YAP was positive in 78 patients (75%), it was negative in 26 patients (25%). In the evaluation after neoadjuvant therapy, pathological complete response (MillerPayne Grade5 response) in 28 patients (26.9%), relapse in 6 patients (5.8%), and exitus in 6 patients (5.8%) were detected. In the pathological evaluation, invasive Ductal Carcinoma was the most common one observed in 88 patients (84.6%). As a result of the statistical evaluation, no significant result was obtained between the parameters and YAP negative/positive., Conclusion: As a result of staining with additional YAP in patients who were diagnosed with breast cancer and routinely stained with ER, PR, Cerb B2 and Ki-67 in pathology samples, we could not reach a result that would contribute positively to survival. Longer studies to be conducted prospectively will be meaningful., Key Words: Breast Cancer, Chemotherapy, Neoadjuvant, Yes Associated Protein.

Breast cancer is a common malignancy in women and is a diverse disease. In women, 287,850 and in males 2710 cases are reported in 2022 by WHO. Triple-negative breast cancer (TNBC), a subtype of breast cancer that lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounted for 10-20% of all new cases discovered in the United States in 2017. Because calcium integrin-binding protein1 lacks a suitable pocket that could be used to create a chemical inhibitor, and because the breast cancer-causing protein is nearly identical to its necessary wild-type counterpart, it was thought to be druggable. The structure and function of the newly discovered calcium integrinbinding protein1 have been improved, paving the way for the designing of several therapeutic candidates. Currently, no FDA-approved drugs are available for CIB1-driven cancer. CIB1 has proven to challenge drug target due to several factors, including the fact that the CIB1 protein is highly resistant to small inhibitors. This study aimed to present various ways for targeting calcium integrin-binding protein1, which is an important target that could be useful to scientists., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Progesterone receptors (PR) play a pivotal role in many female reproductive tissues such as the uterus, the ovary, and the mammary gland (MG). Moreover, PR play a key role in breast cancer growth and progression. This has led to the development and study of different progestins and antiprogestins, many of which are currently being tested in clinical trials for cancer treatment. Recent reviews have addressed the role of PR in MG development, carcinogenesis, and breast cancer growth. Thus, in this review, in addition to making an overview on PR action in normal and tumor breast, the focus has been put on highlighting the still unresolved topics on hormone treatment involving PR isoforms and breast cancer prognosis., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Objective: To analyze the application, efficacy, and safety of palbociclib in hormone receptor positive (HR+) and HER2 negative (HER2-) advanced breast cancer in the real world. Methods: The information of patients who received palbociclib treatment from September 2018 to September 2020 was collected, and the general medical history data and disease characteristics were summarized. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and safety were analyzed. Results: A total of 55 patients with HR+/HER2-advanced breast cancer who received a treatment regimen containing palbociclib were enrolled. The ORR was 48.8%, and DCR was 88.4%. The median PFS was 12.0 months (95% CI , 11.1-13.0 months), and the median TTF was 8.50 months (95% CI , 2.5-14.5 months). Among them, palbociclib was superior to multi-line therapy in the first line ( P =0.000 1). The prognosis of patients with non-liver metastases was better ( P =0.01). Hematological toxicity was the focus of observation of adverse events, including leukopenia, neutropenia, and thrombocytopenia. The incidence rates of them were 78.2%, 85.5%, and 34.5%, respectively. No other grade 3-4 nonhematological toxicity was found. Conclusions: Palbociclib combined with endocrine therapy in patients with HR+/HER2-advanced breast cancer has good efficacy and controllable adverse reactions. It can be used as a first-line or multi-line treatment option for HR+/HER2-advanced breast cancer.

Background: A retrospective study of the real-world use of neoadjuvant endocrine therapy (NET) is important for standardizing the role of NET in breast cancer care., Methods: In a consecutive series of women with operable breast cancer who received NET for ≥28 days, associations of NET objectives, NET outcomes, adjuvant chemotherapy use after NET, and survival with clinicopathological factors were examined., Results: NET objectives were reduction in surgical extent in 49 patients, avoidance of surgery in 31, and treatment until scheduled surgery in 8. The mean duration of NET was 349.5 (range, 34-1,923), 869.8 (range, 36-4,859), and 55.8 (range, 39-113) days, respectively, in these cohorts (success rate: 79.6%, 64.5%, and 100%, respectively), and the differences were significant. Among patients in the former two cohorts, progression-free survival was significantly better in patients with stage 0 or I disease, ductal carcinoma in situ or invasive ductal carcinoma, ≥71% estrogen receptor (ER) positivity, and the surgical extent reduction cohort than the other counterparts. Postoperative chemotherapy use was significantly associated with lymph node metastasis, a high Ki67 labeling index, lymphovascular invasion, and a high preoperative endocrine prognostic index at the time of surgery after NET. Better recurrence-free survival after surgery was significantly associated with high ER expression after NET or high progesterone receptor expression before or after NET., Conclusions: NET can help reduce surgical extent or avoid surgery in women with early breast cancer, ductal carcinoma, or high ER expression. NET may also aid in decisions related to postoperative systemic therapy to improve survival.

Objective: To evaluate the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy (ET) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER-2-) advanced breast cancer (ABC) patients., Methods: We searched clinical trials of CDK4/6 inhibitors combined with ET and calculated the clinical outcomes., Results: HR+/HER-2- ABC patients treated with CDK4/6 inhibitors combined with ET had significantly prolonged progression-free survival (PFS) and improved objective response rate (ORR) and clinical benefit rate (CBR)., Conclusions: CDK4/6 inhibitors combined with ET can bring more clinical benefits to ABC patients, and the safety profile is acceptable.

Indication for neoadjuvant chemotherapy (NACT) in HR+/HER2-negative tumors is controversial. Pathological complete response (pCR) rates range from 0 to 18 % while breast-conserving surgery (BCS) is achievable in up to 60 % of tumors. No pathological feature definitely predicts pCR; lobular and molecular luminal A tumors are less likely to achieve pCR although experiencing better outcomes. Luminal B subtype, high proliferation, lack of progesterone receptor, high tumor-infiltrating lymphocytes are positively associated with increased pCR rates but worse outcomes and the prognostic role of pCR is inconsistent across studies. Molecular intrinsic subtyping and genomic signatures appear as more accurate predictors of benefit from NACT, but larger studies are needed. Anthracycline and taxane-based chemotherapy remains the standard NACT; however, CDK 4/6 inhibitors and immune checkpoint inhibitors are under evaluation. In conclusion, NACT may be proposed for luminal tumors requiring downsizing for BCS after multidisciplinary evaluation, provided that other contraindications to BCS are excluded., (Copyright © 2021 Elsevier B.V. All rights reserved.)

ER+/PR- (estrogen receptor positive and progesterone receptor negative) tumors constitute only a small portion of the breast cancer population. Patients with ER+/PR- tumors, however, are characterized by worse survival compared to patients with ER+/PR+ (estrogen receptor positive and progesterone receptor positive) tumors. Controversy exists regarding the efficacy of hormone blocking therapy for patients with ER+/PR- tumors. The NCDB was queried between 2004 and 2015, and patients with invasive ER+/PR- tumors were identified. We employed univariate Cox proportional hazards to compare outcomes among patients that did or did not receive hormone blocking therapy. We identified 138,398 patients with invasive ER+/PR- tumors, 32,044 (23%) of whom did not receive hormone blocking therapy. The reasons for not receiving hormone blocking therapy included contraindications to treatment, death, patient refusal, and unknown. There were no significant differences in race, income quartile, or education quartile between patients who did and did not receive hormone blocking therapy. Patients who did not receive hormone blocking therapy underwent surgical assessment of the axilla more frequently than those who did receive hormone therapy. Our analysis demonstrated that hormone blocking therapy administration was associated with increased overall survival for up to 10 years of follow up (HR: 0.58; 95% CI: 0.56-0.59, p < 0.001). Hormone blocking therapy may be associated with increased survival for breast cancer patients with ER+/PR- tumors. Although this benefit may last for years after completion of the course, up to 25% of patients do not receive this treatment. Strategies to increase the utilization and adherence to hormone blocking therapy regimens may improve patient survival outcomes.

Background: Vilaprisan (VPR) is a new orally available selective progesterone receptor modulator (SPRM), with anti-proliferative activity against uterine fibroids (UFs). It definitively causes suppression of ovulation and inhibition of proliferation of endometrial, myometrial and UF cells., Purpose: This review aims to summarize current knowledge on VPR from all studies, including clinical trials, conducted to date and to contextualize the potential role of VPR in future medical regimens for the treatment of UFs., Methods: We performed a literature search in PubMed US National Library of Medicine and Google Scholar databases. Both databases were extensively searched for all original and review articles/book chapters as well as congress abstracts published in English until July 2019. The use of VPR for UF therapy was identified by using the keywords: "uterine fibroids" and "vilaprisan"., Results: In phase I and II clinical trials, VPR was shown to be effective in ameliorating UF-related clinical symptoms, especially abnormal or excessive uterine bleeding and in shrinking UFs. The tolerability of VPR is roughly similar to that of ulipristal acetate (UPA) and it tends to be more favorable than that of GnRH-agonists., Conclusion: Presently, all trials examining the utility of VPR for the treatment of UF are halted; likely, due to the recently reported cases of hepato-toxicity with UPA, in addition to non reassuring toxicology results from preclinical long-term testing on rodents, carried out in parallel with late stage testing on humans. An accurate summary of robust data related to the safety of VPR is urgently needed to draw definitive conclusions on the future clinical development of this drug for UF therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Endometriosis is a chronic disease, and a lifelong management plan should be developed by using pharmacological treatment and surgical procedures. The pathogenesis of endometriosis is complicated and has not been definitively established. The mechanisms involved are numerous, and their understanding is constantly evolving. Currently, the first-line drugs act by blocking ovarian function, creating an hypoestrogenic environment. The blockade of estrogen secretion and receptor activity and the activation of progesteron receptors are the main target of several current drugs, as well as those under development. The oral GnRH antogonists, the aromatase inhibitors, SERMs, and SPRMs are the hormonal drugs currently studied for treating endometriosis. The increasing knowledge of the pathogenesis has allowed the development of new treatments. The most studied are the anti-inflammatory drugs, starting from the new NSAIDs to the monoclonal antibodies and the statins. Among the antiangiogenic compounds, a role is suggested for Icon, PPARs, and HDACIs. A new class of drugs is the cannabinoids. The aim of this review was to investigate the new therapeutic hormonal and non-hormonal alternatives to standard treatments., (Copyright © 2018. Published by Elsevier Ltd.)

Uterine fibroids are the most frequent benign tumours in women of child-bearing age. Their symptoms are diverse and the quality of life of the women affected can be significantly impaired. While treatment to date has been primarily by means of surgical intervention, selective progesterone receptor modulators (SPRMs) open up new medication-based treatment options. EMA's Pharmacovigilance Risk Assessment Committee (PRAC) has recently completed its review of ESMYA® (ulipristal acetate, 5 mg), following reports of serious liver injury, including liver failure leading to transplantation in postmarketing settings. We will provide some information on the PRAC's recommendations to minimize this risk. Nevertheless, the effectiveness and safety of the SPRM ulipristal acetate (UPA), both with regard to preoperative administration and with regard to an intermittent administration as long-term treatment for patients with symptomatic uterine fibroids, have been shown in several clinical studies (PEARL I-IV).

Objective: To investigate whether ulipristal acetate (UPA) treatment modifies the expression of progesterone receptor (PR), its nuclear cofactors steroid receptor coactivator-1 (SRC1) and nuclear corepressor-1 (NCoR1), prosurvival factor B-cell lymphoma 2 (Bcl-2), and Akt in uterine myomas., Patients: Prospective study of 59 women with symptomatic myomas undergoing myomectomy. Forty-two patients were treated preoperatively with UPA; the remaining 17 were not and they served as controls., Method: Tissue microarrays were obtained from surgical specimens and immunohistochemistry was performed. Blinded quantification of expression of PR (PR-A vs. PR-B), coactivator SRC1 and corepressor NCoR1, and prosurvival factor Bcl-2, and Akt and evaluation of Akt phosphorylation levels., Results: Compared with the control group, UPA does not alter PR protein levels or expression patterns in myomas, and the PR-A/PR-B ratio was similar, as well as cytoplasmic or nuclear expression of cofactors SRC1 and NCoR1. Bcl-2 was heterogeneously expressed throughout the samples and no significant modification in expression was evidenced. No significant difference was found in Akt expression and phosphorylation between treated and untreated myomas., Conclusion: This study did not find any significant change in the expression of the studied factors in myomas after UPA exposure. In conclusion, various theories on myomas cells proposed on the basis of in vitro studies are not supported in vivo., (© 2017 S. Karger AG, Basel.)

Breast cancer is a heterogenous disease, comprised of at least 3 major subtypes: hormone receptor-positive/HER2-(HR+), HER2+, and HR-/HER2-(triple negative) breast cancers. The medical management of each subype is distinct. In this article, we review contemporary data supporting the use of chemotherapy, endocrine therapy and biologic therapies, especially HER2-directed agents, in the adjuvant and neoadjuvant setting in patients with newly diagnosed nonmetastatic (stage I-III) breast cancer.

The majority of breast cancer expresses the estrogen and or progesterone receptors (ER and PR). In tumors without concomitant HER2 amplification, hormone therapy is a major treatment option for all disease stages. Resistance to hormonal therapy is associated with disease recurrence and progression. Recent studies have identified a number of resistance mechanisms leading to estrogen-independent growth of hormone receptor-positive (HR+) breast cancer as a result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. These include acquired mutations in ER-alpha (ESR1) in response to endocrine deprivation; constitutive activation of cyclin-dependent kinases (CDK) 4 and 6; cross talk between ER and growth factor receptor signaling such as HER family members, fibroblast growth factor receptor (FGFR) pathways, intracellular growth, and survival signals PI3K/Akt/mTOR; and epigenetic modifications by histone deacetylase (HDAC) as well as interactions with tumor microenvironment and host immune response. Inhibitors of these pathways are being developed to improve efficacy of hormonal therapy for treatment of both metastatic and early-stage disease. Two agents are currently approved in the United States for the treatment of metastatic HR+ breast cancer, including the mTOR inhibitor everolimus and the CDK4/6 inhibitor palbociclib. Management of toxicity is a critical aspect of treatment; the primary toxicity of everolimus is stomatitis (treated with topical steroids) and of palbociclib is neutropenia (treated with dose reduction/delay). Many agents are in clinical trials, primarily in combination with hormone therapy; novel combinations are under active investigation.

Purpose of Review: Review of recent data from clinical trials and descriptions of endometrial morphology with administration of selective progesterone receptor modulators (SPRMs)., Recent Findings: Recent reports concerning administration of SPRMs, specifically the efficacy of ulipristal acetate in reducing fibroid size and rapid control of menstrual blood loss, have renewed clinical interest in this class of compound. Histological data from studies with SPRMs report that this class of drugs is associated with progesterone receptor modulator-associated endometrial changes. Data on mechanisms of action are lacking. The antagonistic progesterone effect of SPRMs has shown promising results in animal studies with endometriosis. Sex steroid receptor effects of PRMs outside the reproductive tract raise the potential for use in neurology and oncology, and although there are several randomized trials in these areas, there are limited small studies published to date., Summary: The SPRM ulipristal acetate is an effective treatment for preoperative treatment of fibroids and a reliable emergency contraceptive. This class of compounds holds the potential for long-term effective medical management of fibroids and may have utility in the management of other sex steroid-dependent conditions.

Purpose of Review: Efficient treatment options for the increasing complaint of heavy menstrual bleeding are required to avoid the morbidity associated with major surgery. This review summarizes recent developments in the nonsurgical approach to treating menorrhagia., Recent Findings: Even though the mechanism of menstruation has still not been fully elucidated, there have been promising developments in the attempt to reduce menstrual blood loss. The levonorgestrel-releasing intrauterine system has proven very efficient, and there is a frameless device suitable for enlarged uterine cavities. The side effect of breakthrough bleeding has been the main reason for discontinuing treatment. Recent studies have investigated options of concomitant therapy with antiprogestogens to counter this effect. Another group of novel compounds are selective progesterone receptor modulators, which thus far have been shown to reduce menstrual bleeding without the unwanted effect of unscheduled bleeding episodes., Summary: As menorrhagia is largely a subjective complaint, it is important for successful therapy to be based on an informed patient's choice. Currently, lack of evidence-based practice, poor compliance and unpleasant side effects limit the success of medical therapies contributing to the amount of major surgery performed for this indication. If concomitant therapies succeeded in minimizing the episodes of breakthrough bleeding with the levonorgestrel-releasing intrauterine system, its recommendation as a first choice treatment may be confounded. Further research is needed into efficiency and safety of selective progesterone receptor modulators, which appear to have great potential in reducing menstrual blood loss.

Data regarding the effects of progesterone and a progestagen on human normal breast epithelial cell proliferation and apoptosis are presented here. In postmenopausal women, adding progesterone to percutaneously administrated oestradiol significantly reduces the proliferation induced by oestradiol. In vitro and in premenopausal women, stopping the administration of nomegestrol acetate triggers a peak of apoptosis. Fibro-adenoma and cancerous cells do not show this regulation of apoptosis. Progesterone seems to be important in normal breast homeostasis.