Endocrine therapy for early breast cancer in the era of oral selective estrogen receptor degraders: challenges and future perspectives.

PURPOSE OF REVIEW: Growth and survival of hormone receptor positive breast cancer cells are dependent on circulating hormones (e.g., estrogen and progesterone). Endocrine therapy improved outcomes in both early and advanced hormone receptor positive breast cancer. These treatments include drugs with different mechanisms of action, namely selective estrogen receptor modulators (SERM), aromatase inhibitors, and selective estrogen receptor degraders (SERDs). SERDs represent estrogen receptor antagonists, favoring its degradation and thus interfering with proliferation genes transcription and activation. Fulvestrant is the first approved SERD, administered intramuscularly for treating advanced breast cancer. RECENT FINDINGS: Oral SERDs have been tested to overcome the limitation of the intramuscular administration, and to increase SERD bioavailability. Recently, an oral SERD, Elacestrant, has been approved by the Food and Drug Administration (FDA) for patients carrying an ESR1 mutation. In fact, oral SERDs seem to be effective in tumors harboring ESR1 mutations, a well known mechanism of resistance to endocrine therapy (especially aromatase inhibitors). SUMMARY: More recently, oral SERDs have been tested in patients with early hormone receptor positive breast cancer, although their impact on survival and in this curative setting compared to standard endocrine therapy still needs to be elucidated. The best timing and duration of SERD administration and specific biomarkers in (neo)adjuvant setting remain largely unknown.

Efficacy and safety of endoxifen in bipolar disorder: A systematic review.

BACKGROUND: Endoxifen, a protein kinase C inhibitor and selective estrogen receptor modulator, primarily used in breast cancer treatment, has recently emerged as a potential therapeutic option for managing manic episodes associated with bipolar disorder (BD). This review aims to assess the existing evidence base for endoxifen in BD treatment and evaluate the strengths and limitations of current research findings. METHODS: A systematic search was conducted on Medline, Embase, and Web of Science databases. We included studies published in English that used endoxifen in BD, alongside any relevant studies identified through manual searching and conference papers with full-text availability. Information pertaining to dose, duration, clinical effects, and safety profiles was extracted from the included studies. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in clinical trials. RESULTS: The final review included seven case reports (including two conference presentations), two clinical trials, and one prospective study. Most studies administered endoxifen 8 mg and reported an improvement in manic symptoms. Several case reports included patients with comorbid substance use, and most patients received mood stabilizers concurrently. Few reports lacked any structured outcome measures. The clinical trials used divalproex 1000 mg as an active comparator, which was deemed sub-therapeutic. Despite being multicentric, the first trial lacked data on center-wise recruitment, and certain methodological concerns were observed across the included trials. There were no serious adverse effects noted, except for a significant elevation in lipid profile within a 3-week period. Limited data were available regarding endoxifen efficacy and safety in mixed episodes, depressive episodes, and maintenance treatment. CONCLUSION: There is a paucity of research on the efficacy and safety of endoxifen in BD. While existing evidence suggests short-term efficacy in manic episodes, significant limitations were identified in most of the included studies. Further research is imperative to establish the efficacy and safety of endoxifen in BD before considering its recommendation as a viable treatment option.

An inducible glycogen synthase-1 knockout halts but does not reverse Lafora disease progression in mice.

Malstructured glycogen accumulates over time in Lafora disease (LD) and precipitates into Lafora bodies (LBs), leading to neurodegeneration and intractable fatal epilepsy. Constitutive reduction of glycogen synthase-1 (GYS1) activity prevents murine LD, but the effect of GYS1 reduction later in disease course is unknown. Our goal was to knock out Gys1 in laforin (Epm2a)-deficient LD mice after disease onset to determine whether LD can be halted in midcourse, or even reversed. We generated Epm2a-deficient LD mice with tamoxifen-inducible Cre-mediated Gys1 knockout. Tamoxifen was administered at 4 months and disease progression assessed at 12 months. We verified successful knockout at mRNA and protein levels using droplet digital PCR and Western blots. Glycogen determination and periodic acid-Schiff-diastase staining were used to analyze glycogen and LB accumulation. Immunohistochemistry using astrocytic (glial fibrillary acidic protein) and microglial (ionized calcium-binding adapter molecule 1) markers was performed to investigate neuroinflammation. In the disease-relevant organ, the brain, Gys1 mRNA levels were reduced by 85% and GYS1 protein depleted. Glycogen accumulation was halted at the 4-month level, while LB formation and neuroinflammation were significantly, though incompletely, prevented. Skeletal muscle analysis confirmed that Gys1 knockout inhibits glycogen and LB accumulation. However, tamoxifen-independent Cre recombination precluded determination of disease halting or reversal in this tissue. Our study shows that Gys1 knockdown is a powerful means to prevent LD progression, but this approach did not reduce brain glycogen or LBs to levels below those at the time of intervention. These data suggest that endogenous mechanisms to clear brain LBs are absent or, possibly, compromised in laforin-deficient murine LD.

Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2-3 years of letrozole in postmenopausal patients with breast cancer who have already received 2-3 years of tamoxifen. METHODS: This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I-III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2-3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635. FINDINGS: Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2-3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5-13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57-66) in the control group and 67% (62-71) in the extended group (hazard ratio 0·78, 95% CI 0·65-0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed. INTERPRETATION: In postmenopausal patients with breast cancer who received 2-3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2-3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2-3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer. FUNDING: Novartis and the Italian Ministry of Health. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FINDINGS: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. INTERPRETATION: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FUNDING: Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Accelerating drug access from advanced to early breast cancer: the special case of oral selective estrogen receptor degraders.

PURPOSE OF REVIEW: For hormone receptor positive breast cancer, the development of endocrine resistance commonly occurs, presenting as either disease progression in the metastatic setting or recurrence during or following adjuvant endocrine therapy. Various mechanisms of resistance have been described. In order to reduce or overcome endocrine resistance, there has been substantial interest in developing potent and orally bioavailable selective estrogen receptor degraders (SERDs) for metastatic disease and select patients with early-stage estrogen receptor positive breast cancer. RECENT FINDINGS: At least 11 oral SERDs have entered clinical development. We review current studies in both the metastatic and neoadjuvant/adjuvant setting and present the available evidence of benefit and toxicity for these novel agents. Further characterization of changes to tissue-based biomarkers such as estrogen receptor, progesterone receptor and Ki67 expression and blood-based biomarkers such as ctDNA and estrogen receptor 1 mutation may help to refine therapeutic strategies, combinations, and patient selection to identify women who are most likely to benefit from these novel endocrine agents. SUMMARY: Although SERDs have clear therapeutic potential based on nonclinical studies and have demonstrated early signs of activity in phase I and II studies in the metastatic setting, ongoing research is needed to clarify when and in whom these agents may have greatest clinical benefit.

Design and Characterization of Maltoheptaose-b-Polystyrene Nanoparticles, as a Potential New Nanocarrier for Oral Delivery of Tamoxifen.

Tamoxifen citrate (TMC), a non-steroidal antiestrogen drug used for the treatment of breast cancer, was loaded in a block copolymer of maltoheptaose-b-polystyrene (MH-b-PS) nanoparticles, a potential drug delivery system to optimize oral chemotherapy. The nanoparticles were obtained from self-assembly of MH-b-PS using the standard and reverse nanoprecipitation methods. The MH-b-PS@TMC nanoparticles were characterized by their physicochemical properties, morphology, drug loading and encapsulation efficiency, and release kinetic profile in simulated intestinal fluid (pH 7.4). Finally, their cytotoxicity towards the human breast carcinoma MCF-7 cell line was assessed. The standard nanoprecipitation method proved to be more efficient than reverse nanoprecipitation to produce nanoparticles with small size and narrow particle size distribution. Moreover, tamoxifen-loaded nanoparticles displayed spherical morphology, a positive zeta potential and high drug content (238.6 ± 6.8 µg mL-1) and encapsulation efficiency (80.9 ± 0.4 %). In vitro drug release kinetics showed a burst release at early time points, followed by a sustained release profile controlled by diffusion. MH-b-PS@TMC nanoparticles showed higher cytotoxicity towards MCF-7 cells than free tamoxifen citrate, confirming their effectiveness as a delivery system for administration of lipophilic anticancer drugs.

Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors.

A significant unmet need for patients with multiple sclerosis (MS) is the lack of U.S. Food and Drug Administration (FDA)-approved remyelinating therapies. We have identified a compelling remyelinating agent, bazedoxifene (BZA), a European Medicines Agency (EMA)-approved (and FDA-approved in combination with conjugated estrogens) selective estrogen receptor (ER) modulator (SERM) that could move quickly from bench to bedside. This therapy stands out as a tolerable alternative to previously identified remyelinating agents and other candidates within this family. Using an unbiased high-throughput screen, with subsequent validation in both murine and human oligodendrocyte precursor cells (OPCs) and coculture systems, we find that BZA enhances differentiation of OPCs into functional oligodendrocytes. Using an in vivo murine model of focal demyelination, we find that BZA enhances OPC differentiation and remyelination. Of critical importance, we find that BZA acts independently of its presumed target, the ER, in both in vitro and in vivo systems. Using a massive computational data integration approach, we independently identify six possible candidate targets through which SERMs may mediate their effect on remyelination. Of particular interest, we identify EBP (encoding 3ß-hydroxysteroid-Δ8,Δ7-isomerase), a key enzyme in the cholesterol biosynthesis pathway, which was previously implicated as a target for remyelination. These findings provide valuable insights into the implications for SERMs in remyelination for MS and hormonal research at large.SIGNIFICANCE STATEMENT Therapeutics targeted at remyelination failure, which results in axonal degeneration and ultimately disease progression, represent a large unmet need in the multiple sclerosis (MS) population. Here, we have validated a tolerable European Medicines Agency-approved (U.S. Food and Drug Administration-approved in combination with conjugated estrogens) selective estrogen receptor (ER) modulator (SERM), bazedoxifene (BZA), as a potent agent of oligodendrocyte precursor cell (OPC) differentiation and remyelination. SERMs, which were developed as nuclear ER-α and ER-ß agonists/antagonists, have previously been implicated in remyelination and neuroprotection, following a heavy focus on estrogens with underwhelming and conflicting results. We show that nuclear ERs are not required for SERMs to mediate their potent effects on OPC differentiation and remyelination in vivo and highlight EBP, an enzyme in the cholesterol biosynthesis pathway that could potentially act as a target for SERMs.

A prospective, randomized study of Toremifene vs. tamoxifen for the treatment of premenopausal breast cancer: safety and genital symptom analysis.

BACKGROUND: Toremifene (TOR) is a selective oestrogen receptor modulator (SERM) and has comparable efficacy to that of tamoxifen (TAM) in breast cancer patients. Herein, we compared the safety of TOR to that of TAM in the adjuvant treatment of premenopausal breast cancer. METHODS: This was a prospective randomized and open-label clinical study. Premenopausal patients with hormonal receptor (HR)-positive early breast cancer were randomly assigned (1:1) to receive TOR) or TAM treatment. The follow-up period was 1 year. The primary end point was the incidence of ovarian cysts, and secondary end points were the incidence of endometrial thickening, changes in female hormones, the incidence of fatty liver, changes in the modified Kupperman index (mKMI) and changes in quality of life. RESULTS: There were 92 patients in the final analysis. The incidences of ovarian cysts were 42.6% in the TOR group and 51.1% in the TAM group (p = 0.441). Forty-one patients (87.2%) in the TOR group and 36 patients (80.0%) in the TAM group experienced endometrial thickening (p = 0.348). The proportions of patients with fatty liver were 31.9% in the TOR group and 26.7% in the TAM group (p = 0.581). No significant differences in the mKMI or quality of life were observed between the two groups. CONCLUSIONS: TOR and TAM have similar side effects on the female genital system and quality of life in premenopausal early breast cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02344940. Registered 26 January 2015 (retrospectively registered).

Nanostructured lipid carrier potentiated oral delivery of raloxifene for breast cancer treatment.

Nanotherapeutics in cancer treatment are dominating global science and research, and have been recognized as the pioneering medical care regimen. Raloxifene (RLN) has been used for its anti-proliferative action on mammary tissue, however, it suffers from poor oral bioavailability. This investigation gives an account of the design and development of RLN-loaded nanostructured lipid carriers (RLN-NLCs) using a simple and scalable ultrasonication method for improved oral efficacy and limited offsite toxicity using Compritol® 888 ATO as a solid lipid and Transcutol® HP as a liquid lipid. In addition, the optimized RLN-NLCs were in the nanometric range (121 nm) with high % entrapment efficiency (%EE) (81%) for RLN, and were further freeze-dried in the presence of mannitol to enhance the stability of RLN-NLCs in the dry state for long-term use. Morphological observation under a transmission electron microscope and scanning electron microscope revealed the spherical smooth surface nanometric size of RLN-NLCs. Powder x-ray diffraction confirmed the encapsulation of RLN into the RLN-NLC's matrix with reduced crystallinity of the drug. The in vitro release study showed a burst release for an initial 4 h, and sustained release for up to 24 h. Furthermore, the RLN-NLCs showed higher cytotoxicity towards MCF-7 cells in vitro in comparison to RLN suspension, and an ex vivo intestinal permeation study demonstrated improved intestinal permeability of RLN-NLCs. Moreover, the in vivo pharmacokinetic study in female Wistar rats showed a 4.79-fold increment in oral bioavailability of RLN from RLN-NLCs compared to RLN suspension. Taken together, our results pave the way for a new nanotherapeutic approach towards breast cancer treatment.

Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial.

We assessed the utility of raloxifene (60 mg/day) as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 24-week, double-blind, randomized, placebo-controlled study. Patients were recruited from the inpatient and outpatient services of Parc Sanitari Sant Joan de Déu, Hospital Universitari Institut Pere Mata, and Corporació Sanitària Parc Taulí. Seventy eight postmenopausal women with schizophrenia were randomized to either adjunctive raloxifene or placebo. Sixty-eight began the clinical trial (37 women on raloxifene adjunct) and 31 on placebo adjunct. The outcome measures were: memory, attention and executive function. Assessment was conducted at baseline and at week 24. Between groups homogeneity was tested with the Student's t test for continuous variables and/or the Mann-Whitney U test for ordinal variables and the χ2 test or Fisher's exact test for categorical variables. The differences between the two groups in neuropsychological test scores were compared using the Student's t test. The sample was homogenous with respect to age, formal education, illness duration and previous pharmacological treatment. The addition of raloxifene to antipsychotic treatment as usual showed no differences in cognitive function. The daily use of 60 mg raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia has no appreciable effect.ClinicalTrials.gov Identifier: NCT01573637.

Anti-Müllerian hormone is correlated with cumulative live birth in minimal ovarian stimulation with clomiphene citrate: a retrospective cohort study.

BACKGROUND: Several studies have investigated the correlation between the serum anti-Müllerian hormone (AMH) level and in vitro fertilization (IVF) outcomes in controlled ovarian stimulation cycles; however, studies regarding the correlation of the serum AMH level with IVF outcomes in minimal ovarian stimulation cycles remain limited. In this study, we aimed to analyze the correlation of the serum AMH level with ovarian responsiveness, embryonic outcomes, and cumulative live birth rates in clomiphene citrate (CC)-based minimal ovarian stimulation cycles. METHODS: Clinical records of 689 women whose entire ovarian stimulation regimen consisted solely of minimal stimulation cycle IVF using CC alone from November 2017 to October 2019 were retrospectively reviewed. The association between IVF outcomes and the serum AMH level before the initiation of the first fertility treatment was analyzed. Furthermore, the correlation of the serum AMH level with cumulative live birth rates after IVF treatment was assessed. The Cochran-Armitage test, Pearson's chi-squared test, Spearman rank correlation test, Student's t-test, one-way analysis of variance, logistic regression analysis, Kaplan-Meier method and Cox proportional hazards model were used to analyze the data. RESULTS: The serum AMH level positively correlated with the number of retrieved oocytes, blastocyst formation rate, blastocyst cryopreservation rate, and live birth rate per oocyte retrieval in CC-based minimal ovarian stimulation cycles without any exogenous gonadotropin administration. Furthermore, the cumulative live birth rate and treatment period required for conceiving were strongly associated with the serum AMH level at the initiation of fertility treatment. CONCLUSIONS: A low serum AMH level correlated with low ovarian responsiveness, impaired pre-implantation embryonic development, and decreased cumulative live birth rate in CC-based minimal ovarian stimulation cycles. Therefore, the cycle success rate would be predicted by measuring the serum AMH level in minimal ovarian stimulation with CC alone.

Ospemifene: A Novel Oral Therapy for Vulvovaginal Atrophy of Menopause.

Vulvovaginal atrophy (VVA) resulting from estrogen deprivation at menopause often results in distressing vaginal dryness and dyspareunia. Fewer than 25% of affected women seek help for this condition citing embarrassment, cultural values, an aging or unavailable partner and concerns about use of estrogens following the Women's Health Initiative. Available non-hormonal treatments, such as moisturizers, while affording some relief can be messy to apply and do not prevent disease progression. A new oral selective estrogen receptor modulator, ospemifene, has been found to have strong estrogenic activity in vaginal tissues without adverse estrogenic effects at other sites.

A matrix dispersion based on phospholipid complex system: preparation, lymphatic transport, and pharmacokinetics.

Raloxifene hydrochloride (RH) suffers from low oral bioavailability due to its low water-solubility and first-pass metabolism. Therefore, a novel phospholipid complex of RH (RHPC) and a matrix dispersion based on phospholipid complex (RHPC-MD) were successfully prepared and optimized. Several methods were used to validate the formation of RHPC and RHPC-MD, such as differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, infrared spectroscopy, particle size, and zeta potential, meanwhile, their octanol-water partition coefficient, solubility, and dissolution in vitro were also evaluated. To investigate the absorption mechanism of RHPC in vivo, the RHPC was administered to the chylomicron flow blockage rat model. Interestingly, as we expected, a significant reduction in RHPC absorption (67%) (**p< .01) in presence of cycloheximide (CXI) inhibitor was observed, thus confirming the RHPC could be absorbed by lymphatic transport in vivo. Pharmacokinetic studies revealed that the relative oral bioavailability of RHPC as well as RHPC-MD was 223% and 329%, respectively, when comparing with the commercial RH tablets. These outcomes suggested that the current study provided an attractive formulation to enhance the oral bioavailability of RH and stimulated to further research the absorption mechanism of RHPC in vivo.

Efficacy of combined medication of risedronate sodium and selective estrogen receptor modulator on the postmenopausal osteoporosis.

To evaluate the efficacy of combined medication of risedronate sodium and raloxifene, a selective estrogen receptor modulator (SERM) on the postmenopausal osteoporosis (PMOP). PMOP patients underwent the combined medication of risedronate sodium and raloxifene (SERM, Treatment group), or only medication of risedronate sodium (Control group). After medication, more significant increases were observed in the bone densities of the lumber vertebra (L1-4) and the neck of left femur of patients in the treatment group. Simultaneously, the levels of estrogen and progesterone in serum decreased sharply in the treatment group. After treatment, P1NP and ß-CTX levels in serum decreased significantly in two groups in comparison with the levels prior to treatment, with evident elevations in the levels of BAP and BGP; similarly, ameliorations in the treatment group were much more evident than those in the control group. In addition, significant declines were identified in the VAS scores of two groups after treatment when comparing to the scores prior to the treatment, and the decline in the treatment group was more evident than that in the control group. Combined medication of risedronate sodium and SERM (raloxifene) performs better in treatment of osteoporosis than the single use of risedronate sodium, without the deterioration of adverse effect of medication.

Selective oestrogen receptor degraders in breast cancer: a review and perspectives.

PURPOSE OF REVIEW: Estrogen receptor-positive breast cancer accounts for 70% of all breast cancers. Sequential endocrine treatment in monotherapy or in combination with CDK 4/6 or m-TOR inhibitors is the mainstay of recommended treatment options in the management of metastatic breast cancer even in the presence of visceral metastasis. There is an emerging need to address endocrine resistance, which despite highly efficacious treatment combinations still can develop. RECENT FINDINGS: One of the mechanisms of endocrine resistance is molecular alteration of the oestrogen receptor itself, such as ESR1 mutations affecting the ligand-binding domain. These mutations emerge under the selective pressure of aromatase inhibitors. The efficacy of selective oestrogen receptor degraders (SERDs) might not be affected by the presence of molecular alterations of oestrogen receptor. Fulvestrant is the only SERD used in current clinical practice. Numerous novel, nonsteroidal orally available SERDs are currently in clinical development. Efficacious oestrogen receptor target engagement and promising clinical activity was shown in early phase clinical trials. SUMMARY: Therefore, a new class of orally available nonsteroidal SERDs gains high interest in tackling endocrine resistance in oestrogen receptor-positive (ER+) advanced breast cancer. Clinical efficacy needs to be confirmed in larger patient populations.

Key metabolic parameters change significantly in early breast cancer survivors: an explorative PILOT study.

BACKGROUND: With increasing number of breast cancer survivors, more attention is drawn to long-term consequences of curative cancer treatment. Adjuvant treatment of breast cancer patients is associated with several unfavorable medical conditions, including dyslipidemia, insulin resistance, and obesity, potentially leading to cardiovascular disease and/or the metabolic syndrome. The aim of this explorative study is to investigate metabolic side effects of adjuvant treatment in breast cancer patients. METHODS: A cohort of 13 premenopausal and 20 postmenopausal women with early stage breast cancer were extensively examined prior to, immediately after and 1 year after ended adjuvant chemotherapy and compared with healthy controls (N = 36) matched by age and menopausal status. Repeated examinations included: anthropometric measures, DEXA scans, 24-h blood pressure measurements, and blood samples [high sensitivity CRP, lipid profile and glucose metabolism, including homeostatic model assessment (HOMA)]. RESULTS: At baseline, breast cancer patients were similar to healthy controls regarding all measures. From baseline to 1-year post-treatment specific components of the metabolic syndrome increased significantly in premenopausal breast cancer patients; body fat (P = 0.01), triglycerides (P = 0.03), waist circumference (P = 0.008) and diastolic blood pressure (P = 0.04). In postmenopausal patients, waist circumference also increased significantly (P = 0.03), and High density lipoprotein (HDL) cholesterol decreased significantly (P = 0.05). CONCLUSIONS: Specific components of the metabolic syndrome changed significantly during chemotherapy in early stage breast cancer patients. After 1 year, several key parameters remained pathologically changed. Premenopausal breast cancer patients seemed to be especially prone to develop these unfavorable changes. Trial registration ClinicalTrial.gov, registration number NCT02652975. Registered 15 December 2015-Retrospectively registered, https://clinicaltrials.gov/ .

Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism.

PURPOSE: Clomiphene citrate may be used as an off label treatment of hypogonadism. There are few long-term data on clomiphene citrate efficacy and safety when administered for more than 3 years. We assessed improvements in testosterone and hypogonadal symptoms while on clomiphene citrate for extended periods. MATERIALS AND METHODS: We performed a retrospective review to identify patients treated with clomiphene citrate for hypogonadism (baseline testosterone less than 300 ng/dl) at a total of 2 institutions from 2010 to 2018. We assessed the duration of clomiphene citrate therapy, serum testosterone levels, symptom improvement and clomiphene citrate side effects. RESULTS: A total of 400 patients underwent clomiphene citrate treatment for a mean ± SD of 25.5 ± 20.48 months (range 0 to 84). Of the patients 280 received clomiphene citrate for 3 years or less (mean 12.75 ± 9.52 months) and 120 received it for more than 3 years (mean 51.93 ± 10.52 months). Of men on clomiphene citrate for more than 3 years 88% achieved eugonadism, 77% reported improved symptoms and 8% reported side effects. Estradiol was significantly increased following clomiphene citrate treatment. Results did not significantly differ between patients treated for more than 3, or 3 or fewer years. The most common side effects reported by patients treated more than 3 years included changes in mood in 5, blurred vision in 3 and breast tenderness in 2. There was no significant adverse event in any patient treated with clomiphene citrate. CONCLUSIONS: Clomiphene citrate is not typically offered as primary treatment of hypogonadism in men who do not desire fertility preservation. These data demonstrate that clomiphene citrate is safe and effective with few side effects when used as long-term treatment of hypogonadism.

Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies.

OBJECTIVE: Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially aromatase inhibitors (AIs). The purpose of this study was to evaluate the frequency and clinical relevance of ESR1 genomic alterations in gynecologic malignancies. METHODS: DNA from FFPE tumor tissue obtained during routine clinical care for 9645 gynecologic malignancies (ovary, fallopian tube, uterus, cervix, vagina, vulvar, and placenta) was analyzed for all classes of genomic alterations (base substitutions (muts), insertions, deletions, rearrangements, and amplifications) in ESR1 by hybrid capture next generation sequencing. A subset of alterations was characterized in laboratory-based transcription assays for response to endocrine therapies. RESULTS: A total of 295 ESR1 genomic alterations were identified in 285 (3.0%) cases. mutESR1 were present in 86 (0.9%) cases and were more common in uterine compared to other cancers (2.0% vs <1%, respectively p < 0.001). mutESR1 were enriched in carcinomas with endometrioid versus serous histology (4.4% vs 0.2% respectively, p < 0.0001 in uterine and 3.5% vs 0.3% respectively, p = 0.0004 in ovarian carcinomas). In three of four patients with serial sampling, mutESR1 emerged under the selective pressure of AI therapy. Despite decreased potency of estrogen receptor (ER) antagonists in transcriptional assays, clinical benefit was observed following treatment with selective ER-targeted therapy, in one case lasting >48 months. CONCLUSIONS: While the prevalence of ESR1 mutations in gynecologic malignancies is low, there are significant clinical implications useful in guiding therapeutic approaches for these cancers.

The use of selective estrogen receptor modulators on bone health in men.

Selective estrogen receptor modulators (SERMs) represent a class of drugs that act as agonist or antagonist for estrogen receptor in a tissue-specific manner. The SERMs drugs are initially used for the prevention and treatment of osteoporosis in postmenopausal women. Bone health in prostate cancer patients has become a significant concern, whereby patients undergo androgen deprivation therapy is often associated with deleterious effects on bone. Previous preclinical and epidemiological findings showed that estrogens play a dominant role in improving bone health as compared to testosterone in men. Therefore, this evidence-based review aims to assess the available evidence derived from animal and human studies on the effects of SERMs on the male skeletal system. The effects of SERMs on bone mineral density (BMD)/content (BMC), bone histomorphometry, bone turnover, bone strength and fracture risk have been summarized in this review.