Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Effectiveness of gonadotropin-releasing hormone agonists for ovarian function suppression in premenopausal patients with hormone receptor-positive breast cancer: a retrospective single-center real-world study.

PURPOSE: This study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed. PATIENTS AND METHODS: Premenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30 pg/ml. Patient data was gathered from medical records for this comparison. RESULTS: Of the 264 patients enrolled in this study, 117 were administered 3.6 mg of goserelin monthly (goserelin 1 M group), 63 received 3.75 mg of leuprorelin monthly (leuprorelin 1 M group) and 84 were given 11.25 mg of leuprorelin every three months (leuprorelin 3 M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824-0.982), P = 0.018]. CONCLUSION: Insufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS.

Comparison of goserelin and leuprorelin for ovarian protection during chemotherapy in young patients with breast cancer.

PURPOSE: Although different gonadotropin-releasing hormone (GnRH) agonists may have different effects, their effect of ovarian protection during chemotherapy for breast cancer has not been compared. This study aimed to compare the effects of goserelin and leuprorelin for ovarian protection during chemotherapy in young patients with breast cancer. METHODS: This prospective study analyzed 193 patients with breast cancer aged ≤ 40 years who had regular menstruation and serum anti-Müllerian hormone (AMH) levels ≥ 1 ng/mL before treatment. Patients received either goserelin or leuprorelin for ovarian protection during doxorubicin/cyclophosphamide-based chemotherapy. Resumption of menstruation and changes in serum levels of AMH were compared between the two groups at 12 months after completion of chemotherapy. RESULTS: The mean age and the pretreatment serum AMH level were 33.2 years and 4.4 ng/mL in goserelin group and 34.2 years and 4.0 ng/mL in leuprorelin group. The proportion of patients who resumed menstruation was not different between the goserelin (94.4%) and leuprorelin (95.3%) groups at 12 months after chemotherapy completion. Serum AMH levels decreased significantly in both the goserelin (from 4.4 to 1.2 ng/mL) and leuprorelin (from 4.0 to 1.2 ng/mL) groups, with no statistical significance. In addition, no difference was found in the proportion of patients with serum AMH levels ≥ 1 ng/mL between the goserelin (49.5%) and leuprorelin (44.2%) groups at 12 months after chemotherapy. CONCLUSION: Goserelin and leuprorelin were comparable in terms of ovarian protection during doxorubicin/cyclophosphamide-based chemotherapy in young patients with breast cancer.

Systematic risk analysis of radiation pneumonitis in breast cancer: role of cotreatment with chemo-, endocrine, and targeted therapy.

PURPOSE: A major complication of sequential and concomitant chemoradiation in breast cancer treatment is interstitial pneumonitis induced by radiation therapy (RT), systemic therapy, or a combination of both. Dose and volume of co-irradiated lung tissue directly correlate with the risk of radiation pneumonitis. Especially in case of combined treatment, it is often unclear which of the used therapeutic agents promote pneumonitis. METHODS: This was a prospective monocentric study including 396 breast cancer patients. A systematic analysis of single and combined therapeutic measures was performed in order to identify treatment-related factors enhancing the risk of pneumonitis post RT. RESULTS: Overall incidence of pneumonitis of any grade was 38%; 28% were asymptomatic (grade 1) and 10% were symptomatic (> grade 1). Pneumonitis > grade 2 did not occur. Beside age, smoking status, and mean lung dose, the combined treatment with goserelin and tamoxifen significantly enhanced the risk of pneumonitis in a supra-additive pattern (odds ratio [OR] 4.38), whereas each agent alone or combined with other drugs only nonsignificantly contributed to a higher pneumonitis incidence post RT (OR 1.52 and OR 1.16, respectively). None of the other systemic treatments, including taxanes, increased radiation pneumonitis risk in sequential chemoradiation. CONCLUSION: Common treatment schedules in sequential chemoradiation following breast-conserving surgery only moderately increase lung toxicity, mainly as an asymptomatic complication, or to a minor extent, as transient pneumonitis ≤ grade 2. However, combined treatment with tamoxifen and the LHRH analog goserelin significantly increased the risk of pneumonitis in breast cancer patients after chemoradiation. Thus, closer surveillance of involved patients is advisable.

Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System.

AIMS: To investigate interstitial lung disease (ILD) in men with prostate cancer receiving hormone therapy. METHODS: We gathered cases diagnosed with prostate cancer based on the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2004 to 2020. We divided the included cases into 3 groups based on the primary suspected drugs: a hormone therapy group, a positive control group (taxanes), and a negative control group. We employed reporting odds ratio, a disproportionality method, to detect the association between ILD events and target drugs. RESULTS: We finally included a total of 85 403 cases, 69 894 cases (628 ILD event cases) in the hormone therapy group, 2302 cases (158 ILD event cases) in the positive control group and 13 207 cases (72 ILD event cases) in the negative control group. There were 394 ILD event cases (62.74%) in the hormone therapy group in Japan; 78.68% of the ILD events occurred within the first year after hormone treatment. Disproportionality analysis indicated that ILD events were significantly associated with nilutamide, flutamide, bicalutamide, goserelin, degarelix and apalutamide; the reporting odds ratios (95% confidence interval) were 32.14 (11.03-93.63), 9.93 (3.62-27.21), 8.19 (6.01-11.16), 3.74 (2.61-5.37), 2.41 (1.55-3.75) and 1.94 (1.01-3.75), respectively. CONCLUSION: Based on this FAERS pharmacovigilance analysis, the association between ILD events and hormone therapy drugs, including bicalutamide, flutamide, nilutamide, goserelin, degarelix and apalutamide, should not be ignored, especially in the Japanese population. Lung function of prostate cancer patients should be monitored when receiving the hormone therapy drugs mentioned above, especially for the first year post medication.

Clinical efficacy and safety of trimonthly administration of goserelin acetate 10.8 mg in premenopausal Chinese females with symptomatic adenomyosis: a prospective cohort study.

OBJECTIVE: This prospective cohort study aimed to compare the clinical efficacy and safety of goserelin 10.8 mg administered trimonthly with goserelin 3.6 mg administered monthly in premenopausal females with symptomatic adenomyosis. METHODS: We recruited 139 premenopausal females with adenomyosis who complained of dysmenorrhea and/or menorrhagia. The first group (n = 70) received a single subcutaneous injection of goserelin 10.8 mg, and the second group (n = 69) received monthly subcutaneous goserelin 3.6 mg administered for 3 months. Follow-up was performed at the outpatient department after 12 weeks. RESULTS: Ultimately, 130 patients completed the study, including 68 and 62 patients in the goserelin 10.8 mg (n = 70) and 3.6 mg (n = 69) groups, respectively. We observed a significant decrease in the dysmenorrhea (NRS) score, uterine volume, and cancer antigen 125 (CA125) levels, and a significant increase in hemoglobin (HGB) levels in both treatment groups. There was no significant difference between the two groups. The sum of the adverse event scores was slightly higher in the goserelin 3.6 mg than in the 10.8 mg group. CONCLUSIONS: The clinical efficacy of trimonthly administration of goserelin 10.8 mg was equivalent to monthly 3.6 mg dosing and was non-inferior regarding safety and tolerability. Hence, it can be a more cost-effective and convenient alternative treatment option in premenopausal females with symptomatic adenomyosis. TRIAL REGISTRATION: ChiCTR2200059548.

[Follow-up analysis of sex hormone levels and prognosis in women after hematopoietic stem cell transplantation].

Objective: To investigate the levels of sex hormone and fertility in female patients after hematopoietic stem cell transplantation (HSCT), as well as their correlation with conditioning regimens, and analyse the effect of hormone replacement therapy (HRT) in young women after HSCT. Methods: Retrospective case series study. The clinical data of 147 women who underwent HSCT in the First Affiliated Hospital of Soochow University from January 2010 to January 2021 were retrospectively analyzed. The sex hormone levels were measured and followed-up, and the survival, menstrual fertility and the use of HRT of the patients were also followed-up. The sex hormone levels were measured after transplantation, and the ovarian function was evaluated. Independent sample t test and χ2 test were used for comparison between the two groups. Results: The median age of the 147 patients was 26 (range, 10-45) years. Of them, 135 patients received allogeneic HSCT and 12 patients received autologous HSCT. Furthermore, 129 patients received myeloablative conditioning, and 18 patients received reduced conditioning dose. The median follow-up time was 50 months (range, 18-134 months). Five patients died of disease recurrence during follow-up. Of the 54 patients with subcutaneous injection of zoladex, three recovered menstruation spontaneously after transplantation, and all of them were myeloablative conditioning patients, one patient gave birth to twins through assisted reproductive technology. Ninety-three patients did not use zoladex before conditioning, two patients with aplastic anemia with non-myeloablative transplantation resumed menstruation spontaneously, and conceived naturally. The level of follicle stimulating hormone after transplantation in patients receiving myeloablative conditioning regimen was significantly higher than that in patients receiving reduced-dose conditioning regimen [(95.28±3.94) U/L vs. (71.85±10.72) U/L, P=0.039]. Among 147 patients, 122 patients developed premature ovarian failure, 83 patients received sex hormone replacement therapy after transplantation, and 76 patients recovered menstruation and improved endocrine function. Conclusions: The incidence of premature ovarian failure is high in female patients after HSCT, and patients have a chance at natural conception. Reducing the dose of conditioning regimen and the application of zoladex before transplantation can reduce ovarian of conditioning drugs. HRT after transplantation can partially improve the endocrine function of patients.

High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial.

BACKGROUND: The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial. METHODS: This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36). FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed. INTERPRETATION: After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process. FUNDING: Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.

Quantitative proteomic analysis of GnRH agonist treated GBM cell line LN229 revealed regulatory proteins inhibiting cancer cell proliferation.

BACKGROUND: Gonadotropin-releasing hormone (GnRH) receptor, a rhodopsin-like G-protein coupled receptor (GPCR) family member involved in GnRH signaling, is reported to be expressed in several tumors including glioblastoma multiforme (GBM), one of the most malignant and aggressive forms of primary brain tumors. However, the molecular targets associated with GnRH receptor are not well studied in GBM or in other cancers. The present study aims at investigating the effect of GnRH agonist (Gosarelin acetate) on cell proliferation and associated signaling pathways in GBM cell line, LN229. METHODS: LN229 cells were treated with different concentrations of GnRH agonist (10-10 M to 10-5 M) and the effect on cell proliferation was analyzed by cell count method. Further, total protein was extracted from control and GnRH agonist treated cells (with maximum reduction in cell proliferation) followed by trypsin digestion, labeling with iTRAQ reagents and LC-MS/MS analysis to identify differentially expressed proteins. Bioinformatic analysis was performed for annotation of proteins for the associated molecular function, altered pathways and network analysis using STRING database. RESULTS: The treatment with different concentrations of GnRH agonist showed a reduction in cell proliferation with a maximum reduction of 48.2% observed at 10-6 M. Quantitative proteomic analysis after GnRH agonist treatment (10-6 M) led to the identification of a total of 29 differentially expressed proteins with 1.3-fold change (23 upregulated, such as, kininogen-1 (KNG1), alpha-2-HS-glycoprotein (AHSG), alpha-fetoprotein (AFP), and 6 downregulated, such as integrator complex subunit 11 (CPSF3L), protein FRG1 (FRG1). Some of them are known [KNG1, AHSG, AFP] while others such as inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2), ITIH4, and LIM domain-containing protein 1 (LIMD1) are novel to GnRH signaling pathway. Protein-protein interaction analysis showed a direct interaction of KNG1, a hub molecule, with GnRH, GnRH receptor, EGFR and other interactors including ITIH2, ITIH4 and AHSG. Overexpression of KNG1 after GnRH agonist treatment was validated using Western blot analysis, while a significant inhibition of EGFR was observed after GnRH agonist treatment. CONCLUSIONS: The study suggests a possible link of GnRH signaling with EGFR signaling pathways likely via KNG1. KNG1 inhibitors may be investigated independently or in combination with GnRH agonist for therapeutic applications.

A cohort study of the efficacy of the dienogest and the gonadotropin-releasing hormone agonist in women with adenomyosis and dysmenorrhea.

PURPOSE: To study the efficacy and safety of the dienogest and the gonadotropin-releasing hormone agonist (GnRH-a) in symptomatic females with uterine adenomyosis. METHODS: A total of 127 patients with adenomyosis with a chief complaint of dysmenorrhea were recruited. The first group received 2 mg of dienogest (DNG) daily, whereas the second group received goserelin acetate (GS) (3.6 mg/4 weeks) for 12 weeks. Outpatient follow-up was undertaken after 12 weeks. RESULTS: Among 127 women, 56/63 (88.9%) patients completed the treatment in the DNG group, whereas 62/64 (96.9%) patients completed the treatment in the GS group. A significant decrease in dysmenorrhea symptoms as measured by the visual analog scale (VAS) and Carcinoma antigen125 (CA125) after 12 weeks of treatment was observed in both groups (p < .001). The hemoglobin of anemic patients did not significantly improve after 12 weeks of treatment (p＝0.21) and the uterine volume slightly increased without statistical significance (p＝0.10) in the DNG group. Simultaneously, The hemoglobin of anemic patients significantly improved (p < .001) and the uterine volume significantly decreased (p < .001) in the GS group. CONCLUSIONS: Dienogest effectively alleviates the symptoms of dysmenorrhea in patients with adenomyosis, but it cannot improve the anemia or reduce the size of the uterus. GnRH-a is more effective in improving anemia and reducing the uterine volume in patients with adenomyosis. TRIAL REGISTRATION: ChiCTR1900024958.

Patient preferences and adherence to adjuvant GnRH analogs among premenopausal women with hormone receptor positive breast cancer.

PURPOSE: Adjuvant ovarian function suppression (OFS) in premenopausal hormone receptor (HR) positive breast cancer (BC) improves survival. Adherence to adjuvant gonadotropin-releasing hormone analogs (GnRHa) remains a challenge and is associated with toxicities and inconvenient parenteral administration. The goal of this study was to describe real-world adherence patterns and patient preferences surrounding adjuvant GnRHa. METHODS: We analyzed the medical records of premenopausal women with non-metastatic HR positive BC from January 2000 to December 2017; participants received adjuvant monthly goserelin or leuprolide at The Ohio State University. Data collected included demographics, clinicopathologic characteristics, and OFS adherence/side effects. We defined non-adherence as discontinuation of GnRHa within 3 years for a reason other than switching to an alternate OFS, delay > 7 days from a dose, or a missed dose. Chi-square tests assessed associations between clinical characteristics and outcomes. RESULTS: A total of 325 patients met eligibility. Of these, 119 (37%) patients were non-adherent to GnRHa; 137 (42%) underwent elective bilateral salpingo-oophorectomy after initial GnRHa. Those opting for surgery reported significantly more hot flashes (74% vs 48%, p < 0.001), arthralgias (46% vs 30%, p = 0.003), and vaginal dryness (37% vs 21%, p = 0.001) compared with patients remaining on GnRHa. CONCLUSION: Non-adherence to adjuvant GnRHa occurred in over a third of patients and almost half the patients initiating GnRHa underwent subsequent surgical ablation. These high frequencies highlight real-world patterns of OFS. Additionally, treatment toxicities may impact personal preference of OFS modality. Personalized practices to target predictors of adjuvant GnRHa non-adherence are critical to optimize symptoms, adherence, and survivorship.

Protective effect of goserelin on ovarian reserve during (neo)adjuvant chemotherapy in young breast cancer patients: a prospective cohort study in China.

STUDY QUESTION: Does goserelin, a GnRH agonist, have a protective effect in young breast cancer patients in terms of ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) during chemotherapy? SUMMARY ANSWER: Compared with chemotherapy alone, concurrent goserelin is associated with a higher probability of ovarian reserve recovery at 1 year after chemotherapy. WHAT IS KNOWN ALREADY: Previous studies on the administration of goserelin to protect ovarian function during chemotherapy have produced conflicting results because of the endpoint used, namely, chemotherapy-induced amenorrhoea. Reproductive medicine specialists consider AMH and AFC as the most sensitive ovarian reserve markers; however, they have never been used as biomarkers to assess the potential protective effects on ovarian reserve of goserelin during chemotherapy. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study in which patients were assigned to receive (neo)adjuvant chemotherapy with goserelin (the goserelin group) or without goserelin (the control group) according to each patient's preference. Of 242 breast cancer patients enrolled between December 2015 and November 2019, 76 in control group and 73 in goserelin group were able to be assessed at 1 year after chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal patients with a regular menstrual cycle and aged 18-45 years were eligible for enrolment if they were newly diagnosed with stages I-III breast cancer for which treatment with adjuvant or neoadjuvant chemotherapy was planned. Each patient in the goserelin group was given a subcutaneous dose of 3.6 mg at least 1 week before the first cycle of chemotherapy and then every 4 weeks for the duration of chemotherapy. Ovarian reserve markers and menstrual status were evaluated before and after chemotherapy in the two treatment groups. The primary endpoint was the AMH recovery rate, the secondary endpoints were the recovery rates of AFC, estradiol (E2), follicle-stimulating hormone (FSH) and menstruation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 149 patients (76 in the control group and 73 in the goserelin group) with complete data at 1 year after chemotherapy, the adjusted recovery rate of AMH was 46.5% and 21.8% in the goserelin group and control group, respectively (odds ratio: 3.08; P = 0.002). The trends in AFC and FSH recovery rates were consistent with that in AMH recovery rate. Notably, AMH levels remained low in 41.3% of patients whose menstrual activity had resumed. LIMITATIONS, REASONS FOR CAUTION: Randomisation was not performed because of ethical considerations, so selection bias was inevitable, although propensity score weighting was done. The study was also underpowered because 21.5% (52/242) of enrolled patients received GnRH agonist-containing endocrine therapy and could not be analysed at 1 and 2 years after chemotherapy. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that co-administration of goserelin with chemotherapy provides obvious ovarian reserve protection in these young breast cancer patients. We expect that these results will be applicable in clinical practice for young breast cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Key R&D Program of China No. 2016YFC0901302, by the Research and Development Fund of Peking University People's Hospital No. RD2014-13, RDY2017-19 and by AstraZeneca. The authors have no disclosures. TRIAL REGISTRATION NUMBER: NCT02430103.

Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer.

INTRODUCTION: Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer. PATIENTS AND METHODS: In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints. RESULTS: A total of 187 patients were assigned to receive NCT (n = 95) or NET (n = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI 17.6-44.0, p < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4-24.9, p = 0.046). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (p < 0.005). No difference existed in the conversion rate of BCS (13.8% for NCT vs. 11.5% for NET, p = 0.531) and Ki-67 change (p = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group. CONCLUSIONS: Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01622361. Registration June 19, 2012.

Association between immunosuppressive cytokines and PSA progression in biochemically recurrent prostate cancer treated with intermittent hormonal therapy.

BACKGROUND: Immunosuppressive cytokines have the potential to promote prostate cancer progression. Assessing their longitudinal changes may implicate mechanisms of progression, treatment resistance, and suggest new therapeutic targets. METHODS: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time to prostate-specific antigen progression (TTPP) were identified from a completed phase III trial (NCT00020085). Serum samples were archived at baseline, 3 months after ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay. The Wilcoxon signed-rank sum test was used to compare observations between time points. Kaplan-Meier analysis was used to calculate TTPP dichotomized by cytokine values above or below the median. Pearson's rank correlation coefficient was used to compare continuous variables. RESULTS: Median TTPP was 399 days (range, 114-1641). Median prostate-specific antigen (PSA) at baseline and progression were 8.5 and 5.3 ng/mL, respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. Castrate levels of testosterone (<50 ng/dL) after 3 months of ADT occurred in 35 patients (95%). TNF-α (P = .002), IL-23 (P = .002), and CXCL10 (P = .001) significantly increased from baseline to post ADT. Certain cytokines correlated longitudinally: TNF-α correlated with IL-23 (r = .72; P < .001) and IL-8 (r = .59; P < .001) from baseline to post ADT and to PSA progression. Neutrophil-to-lymphocyte ratio correlated with IL-27 (r = .57; P < .001) and MIP-3α (r = .56; P < .001). Patients with a detectable PSA after ADT had elevated levels of IL-6 (P = .049) and IL-8 (P = .013) at PSA progression as compared with those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = .042). CONCLUSIONS: Several innate cytokines were associated with biochemically recurrent prostate cancer.

Pharmacological sex hormone manipulation as a risk model for depression.

Sex hormone transition may trigger severe depressive episodes in some women. In order to map mechanisms related to such phenomena we developed a pharmacological preclinical human model using sex hormone manipulation with gonadotropin releasing hormone agonist (GnRHa) in a placebo-controlled design. Here the findings from this model is synthesized and discussed in the context of related literature on hormonal contributions to reproductive mental health disorders. The GnRha model work points to an estradiol-dependent depressive response in healthy women undergoing short-term sex hormone manipulation with GnRHa, which is linked to serotonin transporter changes (a key regulator of synaptic serotonin), a disengagement of hippocampus, and overengagement of brain networks recruited when processing emotional salient information. Further, the GnRHa model suggest that key brain regions in the reward circuit are less engaged in positive stimuli when undergoing sex hormone manipulation, which may underlie anhedonia. Also, the work supports that enhanced sensitivity to estrogen signaling at the level of gene expression may drive increased risk for depressive symptoms when exposed to sex steroid hormone fluctuations. In conclusion, the GnRHa model work highlights the brain signatures of rapid and profound changes in sex steroid hormone milieu, which reflect plausible mechanisms by which risk for mood disorders works. This model points to the role of estrogen dynamics and sensitivity, and offers a rationale for personalized prevention in hormonal transition phases, for example pregnancy to postpartum transition, perimenopause, and hormone treatments, which now can move into clinical translation and ideally pave the way for protecting mental and cognitive health.

Failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer.

We report the failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer. A 76-year-old man was admitted to our hospital for evaluation of an elevated serum prostate specific antigen (PSA) level (191.10 ng/ml) in August 2011. He was diagnosed with T3aN0M1b prostate adenocarcinoma. A combined androgen blockade using luteinizing hormone-releasing hormone agonist (the 1-month depot of leuprorelin acetate) and antiandrogen was administered. Due to liver dysfunction, antiandrogens, both bicalutamide and flutamide, were stopped. The 1-month depot was switched to the 3-month depot in May 2013, but the patient complained of induration and abscess at the infection site. Leuprorelin acetate was replaced by goserelin acetate. Because no adverse event appeared after injection of the 1-month depot of goserelin acetate, the 3-month depot was administered in October 2013. The PSA level increased gradually, and the testosterone level was greater than 50 ng/dl, that is, above castrate range. The 3-month depot of both leuprorelin acetate and goserelin acetate was not effective for this patient. For this reason, the 1-month depot of leuprorelin acetate was started resulting in a rapid decrease in PSA and testosterone levels. Thereafter, androgen depriving therapy could be continued. Androgen deprivation therapy is the standard treatment for patients with advanced prostate cancer and luteinizing hormone-releasing hormone aims to suppress serum testosterone to castrate range. We recommend assessing the serum testosterone levels during luteinizing hormone-releasing hormone agonist therapy for monitoring treatment efficacy and verifying progression when the PSA level increases.

Laparoscopic surgery for endometriosis.

BACKGROUND: Endometriosis is associated with pain and infertility. Surgical interventions aim to remove visible areas of endometriosis and restore the anatomy. OBJECTIVES: To assess the effectiveness and safety of laparoscopic surgery in the treatment of pain and infertility associated with endometriosis. SEARCH METHODS: This review has drawn on the search strategy developed by the Cochrane Gynaecology and Fertility Group including searching the Cochrane Gynaecology and Fertility Group's specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, reference lists for relevant trials, and trial registries from inception to April 2020. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) that compared the effectiveness and safety of laparoscopic surgery with any other laparoscopic or robotic intervention, holistic or medical treatment, or diagnostic laparoscopy only. DATA COLLECTION AND ANALYSIS: Two review authors independently performed selection of studies, assessment of trial quality and extraction of relevant data with disagreements resolved by a third review author. We collected data for the core outcome set for endometriosis. Primary outcomes included overall pain and live birth. We evaluated the quality of evidence using GRADE methods. MAIN RESULTS: We included 14 RCTs. The studies randomised 1563 women with endometriosis. Four RCTs compared laparoscopic ablation or excision with diagnostic laparoscopy only. Two RCTs compared laparoscopic excision with diagnostic laparoscopy only. One RCT compared laparoscopic ablation or excision with laparoscopic ablation or excision and uterine suspension. Two RCTs compared laparoscopic ablation and uterine nerve transection with diagnostic laparoscopy only. One RCT compared laparoscopic ablation with diagnostic laparoscopy and gonadotropin-releasing hormone (GnRH) analogues. Two RCTs compared laparoscopic ablation with laparoscopic excision. One RCT compared laparoscopic ablation or excision with helium thermal coagulator with laparoscopic ablation or excision with electrodiathermy. One RCT compared conservative laparoscopic surgery with laparoscopic colorectal resection of deep endometriosis infiltrating the rectum. Common limitations in the primary studies included lack of clearly described blinding, failure to fully describe methods of randomisation and allocation concealment, and poor reporting of outcome data. Laparoscopic treatment versus diagnostic laparoscopy We are uncertain of the effect of laparoscopic treatment on overall pain scores compared to diagnostic laparoscopy only at six months (mean difference (MD) 0.90, 95% confidence interval (CI) 0.31 to 1.49; 1 RCT, 16 participants; very low quality evidence) and at 12 months (MD 1.65, 95% CI 1.11 to 2.19; 1 RCT, 16 participants; very low quality evidence), where a positive value means pain relief (the higher the score, the more pain relief) and a negative value reflects pain increase (the lower the score, the worse the increase in pain). No studies looked at live birth. We are uncertain of the effect of laparoscopic treatment on quality of life compared to diagnostic laparoscopy only: EuroQol-5D index summary at six months (MD 0.03, 95% CI -0.12 to 0.18; 1 RCT, 39 participants; low quality evidence), 12-item Short Form (SF-12) mental health component (MD 2.30, 95% CI -4.50 to 9.10; 1 RCT, 39 participants; low quality evidence) and SF-12 physical health component (MD 2.70, 95% CI -2.90 to 8.30; 1 RCT, 39 participants; low quality evidence). Laparoscopic treatment probably improves viable intrauterine pregnancy rate compared to diagnostic laparoscopy only (odds ratio (OR) 1.89, 95% CI 1.25 to 2.86; 3 RCTs, 528 participants; I2 = 0%; moderate quality evidence). We are uncertain of the effect of laparoscopic treatment compared to diagnostic laparoscopy only on ectopic pregnancy (MD 1.18, 95% CI 0.10 to 13.48; 1 RCT, 100 participants; low quality evidence) and miscarriage (MD 0.94, 95% CI 0.35 to 2.54; 2 RCTs, 112 participants; low quality evidence). There was limited reporting of adverse events. No conversions to laparotomy were reported in both groups (1 RCT, 341 participants). Laparoscopic ablation and uterine nerve transection versus diagnostic laparoscopy We are uncertain of the effect of laparoscopic ablation and uterine nerve transection on adverse events (more specifically vascular injury) compared to diagnostic laparoscopy only (OR 0.33, 95% CI 0.01 to 8.32; 1 RCT, 141 participants; low quality evidence). No studies looked at overall pain scores (at six and 12 months), live birth, quality of life, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy and miscarriage. Laparoscopic ablation versus laparoscopic excision There was insufficient evidence to determine whether there was a difference in overall pain, measured at 12 months, for laparoscopic ablation compared with laparoscopic excision (MD 0.00, 95% CI -1.22 to 1.22; 1 RCT, 103 participants; very low quality evidence). No studies looked at overall pain scores at six months, live birth, quality of life, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy, miscarriage and adverse events. Helium thermal coagulator versus electrodiathermy We are uncertain whether helium thermal coagulator compared to electrodiathermy improves quality of life using the 30-item Endometriosis Health Profile (EHP-30) at nine months, when considering the components: pain (MD 6.68, 95% CI -3.07 to 16.43; 1 RCT, 119 participants; very low quality evidence), control and powerlessness (MD 4.79, 95% CI -6.92 to 16.50; 1 RCT, 119 participants; very low quality evidence), emotional well-being (MD 6.17, 95% CI -3.95 to 16.29; 1 RCT, 119 participants; very low quality evidence) and social support (MD 5.62, 95% CI -6.21 to 17.45; 1 RCT, 119 participants; very low quality evidence). Adverse events were not estimable. No studies looked at overall pain scores (at six and 12 months), live birth, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy and miscarriage. AUTHORS' CONCLUSIONS: Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. No data were reported on live birth. There is moderate quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only. No studies were found that looked at live birth for any of the comparisons. Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety.

Progestogens or progestogen-releasing intrauterine systems for uterine fibroids (other than preoperative medical therapy).

BACKGROUND: Uterine fibroids can cause heavy menstrual bleeding. Medical treatments are considered to preserve fertility. It is unclear whether progestogens or progestogen-releasing intrauterine systems can reduce fibroid-related symptoms. This is the first update of a Cochrane Review published in 2013. OBJECTIVES: To determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and PsycINFO databases to July 2020. We also searched trials registers for ongoing and registered trials, and checked references of relevant trials. SELECTION CRITERIA: All identified published or unpublished randomised controlled trials (RCTs) assessing the effect of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias, and assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: This updated review included four studies with 221 women with uterine fibroids. The evidence was very low quality, downgraded for serious risk of bias, due to poor reporting of study methods, and serious imprecision. Levonorgestrel-releasing intrauterine device (LNG-IUS) versus hysterectomy There was no information on the outcomes of interest, including adverse events. LNG-IUS versus low dose combined oral contraceptive (COC) At 12 months, we are uncertain whether LNG-IUS reduced the percentage of abnormal uterine bleeding, measured with the alkaline hematin test (mean difference (MD) 77.50%, 95% confidence interval (CI) 70.44 to 84.56; 1 RCT, 44 women; very low-quality evidence), or the pictorial blood assessment chart (PBAC; MD 34.50%, 95% CI 11.59 to 57.41; 1 RCT, 44 women; very low-quality evidence); increased haemoglobin levels (MD 1.50 g/dL, 95% CI 0.85 to 2.15; 1 RCT, 44 women; very low-quality evidence), or reduced fibroid size more than COC (MD 1.90%, 95% CI -12.24 to 16.04; 1 RCT, 44 women; very low-quality evidence). The study did not measure adverse events. LNG-IUS versus oral progestogen (norethisterone acetate (NETA)) Compared to NETA, we are uncertain whether LNG-IUS reduced abnormal uterine bleeding more from baseline to six months (visual bleeding score; MD 23.75 points, 95% CI 1.26 to 46.24; 1 RCT, 45 women; very low-quality evidence); increased the percentage of change in haemoglobin from baseline to three months (MD 4.53%, 95% CI 1.46 to 7.60; 1 RCT, 48 women; very low-quality evidence), or from baseline to six months (MD 10.14%, 95% CI 5.57 to 14.71; 1 RCT, 45 women; very low-quality evidence). The study did not measure fibroid size. Spotting (adverse event) was more likely to be reported by women with the LNG-IUS (64.3%) than by those taking NETA (30%; 1 RCT, 45 women; very low-quality evidence). Oral progestogen (dienogest, desogestrel) versus goserelin acetate Compared to goserelin acetate, we are uncertain whether abnormal uterine bleeding was reduced at 12 weeks with dienogest (PBAC; MD 216.00 points, 95% CI 149.35 to 282.65; 1 RCT, 14 women; very low-quality evidence) or desogestrel (PBAC; MD 78.00 points, 95% CI 28.94 to 127.06; 1 RCT, 16 women; very low-quality evidence). Vasomotor symptoms (adverse events, e.g. hot flashes) are only associated with goserelin acetate (55%), not with dienogest (1 RCT, 14 women; very low-quality evidence) or with desogestrel (1 RCT, 16 women; very low-quality evidence). The study did not report fibroid size. AUTHORS' CONCLUSIONS: Because of very low-quality evidence, we are uncertain whether the LNG-IUS reduces abnormal uterine bleeding or increases haemoglobin levels in premenopausal women with uterine fibroids, compared to COC or norethisterone acetate. There was insufficient evidence to determine whether the LNG-IUS reduces the size of uterine fibroids compared to COC. We are uncertain whether oral progestogens reduce abnormal uterine bleeding as effectively as goserelin acetate, but women reported fewer adverse events, such as hot flashes.

Androgen deprivation therapy improves the in vitro capacity of high-density lipoprotein (HDL) to receive cholesterol and other lipids in patients with prostate carcinoma.

BACKGROUND: Androgen deprivation therapy (ADT) is widely used in the treatment of testosterone-dependent prostate carcinomas. ADT often increases plasma LDL and HDL cholesterol and triglycerides. The aim was to test whether ADT changes the transfer of lipids to HDL, an important aspect of this metabolism and HDL protective functions, and related parameters. METHODS: Sixteen volunteers with advanced prostate carcinoma submitted to pharmacological ADT or orchiectomy had plasma collected shortly before and after 6 months of ADT. In vitro transfer of lipids to HDL was performed by incubating plasma with donor emulsion containing radioactive lipids by 1 h at 37 °C. After chemical precipitation of apolipoprotein B-containing lipoprotein, the radioactivity of HDL fraction was counted. RESULTS: ADT reduced testosterone to nearly undetectable levels and markedly diminished PSA. ADT increased the body weight but glycemia, triglycerides, LDL and HDL cholesterol, HDL lipid composition and CETP concentration were unchanged. However, ADT increased the plasma unesterified cholesterol concentration (48 ± 12 vs 56 ± 12 mg/dL, p = 0.019) and LCAT concentration (7.15 ± 1.81 vs 8.01 ± 1.55µg/mL, p = 0.020). Transfer of unesterified (7.32 ± 1.09 vs 8.18 ± 1.52%, p < 0.05) and esterified cholesterol (6.15 ± 0.69 vs 6.94 ± 1.29%, p < 0.01) and of triglycerides (6.37 ± 0.43 vs 7.18 ± 0.91%, p < 0.001) to HDL were increased after ADT. Phospholipid transfer was unchanged. CONCLUSION: Increase in transfer of unesterified and esterified cholesterol protects against cardiovascular disease, as shown previously, and increased LCAT favors cholesterol esterification and facilitates the reverse cholesterol transport. Thus, our results suggest that ADT may offer anti-atherosclerosis protection by improving HDL functional properties. This could counteract, at least partially, the eventual worse effects on plasma lipids.

Recurrence of uterine adenomyosis after administration of gonadotropin-releasing hormone agonist and the efficacy of dienogest.

This study elucidated the degree of adenomyosis recurrence following gonadotropin-releasing hormone agonist (GnRHa) discontinuation and dienogest efficiency for recurrent adenomyosis. This retrospective cohort study included 30 patients, divided into a group of patients whose progress was observed without providing additional therapy following GnRHa administration for six months (Group G) and a group of patients administered dienogest for six months following six months of GnRHa administration (Group D). Menorrhagia, dysmenorrhea, chronic pelvic pain, abdominal fullness, and uterine volume were recorded prior to treatment, six months after the start of therapy (6 M), and 12 months after the start of therapy (12 M). In Group G (n = 15), although all subjective symptoms disappeared at 6 M, nearly all symptoms recurred at 12 M. Uterine volume significantly decreased from 341.0 cm3 to 156.0 cm3 at 6 M (p = .001) and significantly increased again to 282.3 cm3 at 12 M (p = .003). In Group D (n = 15), all subjective symptoms disappeared at 6 M, and only abdominal fullness returned in a significant number of patients (5 of 5; p = .021) at 12 M. Uterine volume decreased significantly at 6 M (p = .003) and significantly increased again from 162.5 cm3 to 205.6 cm3 at 12 M (p = .006). Subjective symptoms, except for abdominal fullness, did not recur when dienogest was administered after GnRHa.