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The current study designed to evaluate the role of pluripotent stem cells (iPSc) on experimentally-induced ovarian ablation (OA) by evaluating of hematological parameters, FSH and E2 changes, molecular and histopathological examination. 50 female rats were divided into five groups with 10 in each group. Group (1): control group. Group (2): rats injected with Doxorubicin (DOX) (3 mg/kg) and Cyclophosphamide (CYP) (50mg/kg) dissolved in sterile physiological saline injected I/P once a week for 5 weeks. Group (3): 10 rats undergo chemoablasion then injected with 5 IU of pregnant mare serum gonadotropin (PMSG) single s/c injection. Group (4): 10 rats undergo chemoablasion, then iPSc injected i/v single injection for 2 months. Group (5): 10 rats undergo chemoablasion then iPSc injected i/v combined with single s/c injection of 5 IU PMSG. Results revealed that rats injected with Dox and CYP showed asignificant decrease in RBCs, Hb and PCV, WBCs, lymphocytes, neutrophil, eosinophil, E2 level and Oct 4 while there was significant increase in MCV, MCH, monocytes and FSH level compared with control (-ve) group. While, rats treated with PMSG or IPSc or PMSG and IPSc revealed significant increase in RBCs count as well as MCHC, E2 level and Oct 4 with non significant changes in Hb and PCV, WBCs, lymphocytes, eosinophil with asignificant increase of neutrophil IPSc or PMSG and IPSc groups and asignificant decrease in monocytes compared with OA group and control (-ve) group.

A b s t r a c t This experiment was designed to investigate the roles of induced pluripotent stem cells and hormonal therapy on experimentally-induced ovarian ablation (OA) by evaluating of hormonal, molecular, histopathological and immunohistochemical examinations. Fifty female rats classified into five main groups. Group (I):10 rats as control normal group. Group II (OA): 10 rats injecteded with (3 mg/kg) of DOX and (50 mg) CYP dissolved in clean physiological saline I/P once week for 5 weeks. Group (III): 10 rats go through chemoablasion, after that, rats were injected with 5 IU of PMSG single subcutaneous (S/C) injection. Group (IV): 10 rats undergo chemoablasion, after that induced pluripotent stem cells (iPSc) were injected intravenous (I/V) single injection for 2 months. Group (V): 10 rats undergo chemoablasion then iPSc were injected I/V combined with single S/C injection of 5 IU PMSG. Results revealed that rats injected with doxorubicin and cyclophosphamide showed a significant increase in FSH, LH levels while asignificant decrease in E2, PCNA, Oct4, Stra8 and Runx2 when compared with control (-ve) group. On the other hand, rats treated with PMSG or IPSc only or PMSG and IPSc revealed that there were increase in E2 level, PCNA, OCT4, Stra8 and Runx2 while there is decrease in FSH, LH levels when compared with chemoablated control group. Also, ovarian sections of chemoablated group showed degenerated surface epithelia, loss of secondary, and antral follicles. ovarian sections of group treated with PMSG and iPSc showed well observed primordial, primary and secondary follicles.

Background: Ovarian function suppression is being widely utilized as endocrine therapy to reduce estrogen release in premenopausal breast cancer patients and was achieved either by medical treatment with the Gonadotropin releasing hormone (GnRH) agonist or bilateral oophorectomy. This study aimed to examine the difference between GnRHa and ovarian ablation on depression, sexual dysfunction and quality of life.Methods: The premenopausal breast cancer patients who received ovarian function suppression were enrolled from seven hospital between June 2019 and February 2020. Our independent variable was the type of ovarian suppression, categorized as Ovarian Ablation (OA cohort, n=62) and medical GnRH agonist (GnRHa cohort, n=260). The self-administered questionnaire (OFS-Q5) developed and used in this study aimed to assess the depression (PHQ-9), sexual dysfunction (FSFI) and quality of life (EORTC QLQ-BR23), as well as the contributing factors.Results: In this cross-sectional study, 322 patients with ovarian function suppression completed surveys were collected. The mean sum score of the PHQ-9 in GnRHa cohort tend to be lower than that in ovarian ablation (OA) cohort (9.6 ±5.2 vs. 11.0 ±5.8, OR=1.495, P=0.080). Patients with major depression (PHQ-9≧15) was indicated significantly fewer in GnRHa cohort. Less patients met the criteria for sexual dysfunction (66.1%, FSFI< 26.55) in OA cohort compared with 81.5% of patients with GnRHa (P = 0.008). The ratio of sexual dysfunction remained lower for ovarian ablation women in long-term ovarian suppression (duration of ovarian suppression > 2 years: OA vs GnRHa, 36.7% vs 78.4%, P=2.4E-05). The differences of most subscales of QLQ-BR23 were insignificant in both cohorts.Conclusions: Our finding demonstrate here for the first time that ovarian ablation resulted in worse depression, favour sexual function than those with medical GnRHa, with similar quality of life. More attention need to paid on adverse effect in patients with diverse ovarian function suppression. Citation Format: Junnnan Xu, Tao Sun. Depression, sexual dysfunction and quality of life among breast cancer patients with ovarian function suppression: A cross sectional study between ovarian ablation verse GnRH agonists [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-48.

ObjectiveOvarian suppression is recommended to complement endocrine therapy in premenopausal women with breast cancer and high-risk features. It can be achieved by either medical ovarian suppression or therapeutic bilateral salpingo-oophorectomy. Our objective was to evaluate characteristics of patients with stage I–III hormone receptor positive primary breast cancer who underwent bilateral salpingo-oophorectomy at our institution.Materials and methodsPremenopausal women with stage I–III hormone receptor positive primary breast cancer diagnosed between January 2010 and December 2014 were identified from a database. Patients with confirmed BRCA1/2 mutations were excluded. Distribution of characteristics between treatment groups was assessed using χ2 test and univariate logistic regression. A multivariate model was based on factors significant on univariate analysis.ResultsOf 2740 women identified, 2018 (74%) received endocrine treatment without ovarian ablation, 516 (19%) received endocrine treatment plus ovarian ablation, and 206 (7.5%) did not receive endocrine treatment. Among patients undergoing ovarian ablation 282/516 (55%) received medical ovarian suppression, while 234 (45%) underwent bilateral salpingo-oophorectomy. By univariate logistic analyses, predictors for ovarian ablation were younger age (OR 0.97), histology (other vs ductal: OR 0.23), lymph node involvement (OR 1.89), higher International Federation of Gynecology and Obstetrics (FIGO) stage (stage II vs I: OR 1.48; stage III vs I: OR 2.86), higher grade (grade 3 vs 1: OR 3.41; grade 2 vs 1: OR 2.99), chemotherapy (OR 1.52), and more recent year of diagnosis (2014 vs 2010; OR 1.713). Only year of diagnosis, stage, and human epidermal growth factor receptor 2 (HER-2) treatment remained significant in the multivariate model. Within the cohort undergoing ovarian ablation, older age (OR 1.05) was associated with therapeutic bilateral salpingo-oophorectomy. Of 234 undergoing bilateral salpingo-oophorectomy, 12 (5%) mild to moderate adverse surgical events were recorded.ConclusionsBilateral salpingo-oophorectomy is used frequently as an endocrine ablation strategy. Older age was associated with bilateral salpingo-oophorectomy. Perioperative morbidity was acceptable. Evaluation of long-term effects and quality of life associated with endocrine ablation will help guide patient/provider decision-making.

A common side effect of chemotherapy in breast cancer is early menopause in premenopausal patients, which is mainly a result of an indirect form of ovarian ablation, and is associated with substantial impairment of quality of life. Suppressing the production of ovarian estrogen has been shown to reduce the recurrence of hormone receptor-positive early breast cancer in premenopausal women, but whether it has an added advantage over tamoxifen is being discussed. Types of permanent ablation of the ovarian function include surgical oophorectomy and radiation-induced ovarian failure. Both are associated with similar response rates in hormone receptor-positive metastatic breast cancer. Medical castration with luteinizing hormone-releasing hormone analogs (LHRHa) has the benefit of being a reversible approach. Another advantage that premenopausal patients who wish to reduce the risk of developing premature ovarian insufficiency induced by chemotherapy may be offered LHRHa irrespective of whether they desire pregnancy and their age at diagnosis. This also helps reduce the risk of menopausal signs and symptoms as well as the loss of bone density in the long-term, which are primary concerns for women. This is of utmost importance to premenopausal women who do not want to conceive after treatment or are not candidates for fertility preservation strategies because of age. It should be emphasized that for women who are interested in fertility preservation, gamete cryopreservation remains the first option, and LHRHa is not an alternative. During chemotherapy, however, temporary ovarian suppression with LHRHa may be given to women who either have no access to a fertility clinic or who have declined chemotherapy or have contraindications.

Breast cancer is the most prevalent cancer known worldwide in women. It is a heterogeneous, phenotypically diverse disease composed of several biologic subtypes that have distinct behavior and response to therapy. Hormone receptor-positive (i.e., estrogen [ER] and/or progesterone [PR] receptor-positive) breast cancers comprise the most common types of breast cancer, accounting for 75% of all cases. This makes endocrine therapy the standardized treatment for patients with ER+/PR+ breast cancer. Drugs that block estrogen receptors or that lower estrogen levels are the mainstay of treatment. High-risk patients benefit from the addition of ovarian function suppression (OFS)/ablation to either an aromatase inhibitor (AI) or tamoxifen. This case report discusses a 36-year-old premenopausal female who presented with an abnormal right breast lump in the upper outer quadrant of the right breast. Due to high suspicion of malignancy, a biopsy was performed which showed features of both lobular and ductal carcinoma with ER and PR positivity, HER 2 was negative. The patient underwent mastectomy with axillary lymph node removal due to concern for multifocal disease. No clinically relevant genetic mutations were present. Oncotype DX breast recurrence score was 16 and no chemotherapy was offered. Due to large tumor size, young age OFS with goserelin 3.6mg/28 days and letrozole 2.5 mg once daily was recommended. After 16 months of treatment, the patient developed a failure of goserelin-induced ovarian suppression. This case report highlights the possibility of the development of hormonal resistance after long-term use of goserelin.

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.

The aim of the study was to determine the clinical relevance of cyclin D1 (cD1) and its association with clinicopathological parameters in breast cancer patients treated with hormonal therapy. Material and methods The study included 96 primary breast cancer patients with known clinicopathological parameters. In adjuvant setting, 44 patients were tamoxifen-treated and 52 were treated with ovarian irradiation/ablation. The cD1 status (gene amplified/nonamplified) was determined on formalin-fixed paraffin-embedded tumor tissue sections by chromogenic in situ hybridization. Associations between parameters were analyzed by Chi-square and Spearman’s rank order correlation tests. Cox proportional hazards regression test was performed. Survival curves for relapse-free survival were constructed according to the Kaplan-Meier method. Results There were no significant associations between cyclin D1 and clinicopathological parameters in either patient group. Amplified cyclin D1 associated significantly with the actual relapse incidence in the ovarian ablation patient group (p = 0.01, HR = 3.1), but not in the tamoxifen-treated patient group. Estrogen receptor and cyclin D1 have proven to be independent parameters of poor outcome in the ovarian ablation patient group (p = 0.03, HR = 2.9; and p = 0.009, HR = 2.5; respectively). Conclusions Cyclin D1 might be a candidate biomarker of poor outcome in breast cancer patients treated with ovarian ablation, suggesting its possible involvement in acquirement of hormonal resistance. The role of cyclin D1 as potential parameter of response to tamoxifen was not as pronounced.

Purpose: We examined whether there were differences in major depression outcomes and independent risk factors associated with gonadotropin-releasing hormone agonists (GnRHa) and ovarian ablation (OA) in premenopausal breast cancer patients. Methods: Premenopausal breast cancer patients from seven hospitals who received OFS participated in the study between June 2019 and June 2020. The independent variable was the type of ovarian suppression, categorized as either OA (n = 174) or GnRHa (n = 389). Major depression was evaluated using the Patient Health Questionnaire (PHQ-9), and the Female Sexual Function Index questionnaire was used to assess sexual function.Results: A total of 563 patients completed the surveys. The mean PHQ-9 sum score was slightly lower in the GnRHa cohort than in the OA cohort (11.4 ± 5.7 vs. 12.8 ± 5.8, P = 0.079). There were significantly fewer patients with major depression (PHQ-9 ≥ 15) in the GnRHa cohort (31.1% vs. 40.2%, P = 0.025). Further, the duration of OFS was closely correlated with major depression, indicating a time-dependent trend [duration of OFS > 2 years vs. duration of OFS ≤ 2 years: Exp (B) = 1.651, P = 0.031]. Sexual dysfunction was negatively correlated with major depression [sexual dysfunction vs. normal: Exp (B) = 0.769, P = 0.046].Conclusions: This is the first study to demonstrate that GnRHa results in more favorable depression outcomes than OA. Moreover, most patients preferred alternatives to their OFS treatment. These findings can contribute to improving and alleviating the adverse effects of OFS.

Most breast cancers are hormone receptor-positive, and tamoxifen is the mainstay of endocrine therapy for such patients. However, with the introduction of aromatase inhibitors and then fulvestrant, tamoxifen became a less preferred drug, even in a premenopausal setting. Many new approaches to tackle the recently identified resistance pathways for endocrine therapy are widely used. Cyclin-dependent kinase 4/6 inhibitors such as ribociclib, palbociclib, and abemaciclib, and inhibitors of the mechanistic target of rapamycin such as everolimus, are effective but have been associated with considerably higher costs and distinctive toxicities. We describe the clinical course of a young patient with advanced-stage breast cancer living in an under-resourced region who failed to respond to chemotherapy, including both anthracyclines and taxanes, but achieved complete and durable response to tamoxifen and ovarian ablation therapy. This case demonstrates the value of well-established, low-cost endocrine therapy for breast cancer. It also highlights the need to address the sequencing of endocrine therapy for patients in low-income countries.

BACKGROUND AND OBJECTIVE: There is no available evidence to recommend gonadotropin-releasing hormone (GnRH) analogue-based ovarian suppression versus bilateral salpingo-oophorectomy (BSO) in the adjuvant treatment of early breast cancer, since the two approaches are considered equivalent in terms of oncologic outcome. The role of surgical ovarian ablation has been revitalized based on the advances of minimally invasive surgery, and a better understanding of clinical and molecular basis of hereditary breast/ovarian cancer syndromes. The aim of this study is to analyze the cost-effectiveness of laparoscopic BSO and GnRH analogue administration in patients aged 40-49 years with hormone-sensitive breast cancer.\ud \ud METHODS:\ud A probabilistic decision tree model was developed to evaluate costs and outcomes of ovarian ablation through laparoscopic BSO, or ovarian suppression through monthly injections of GnRH analogue. Results were expressed as incremental costs per quality-adjusted life years (QALYs) gained.\ud \ud RESULTS:\ud Laparoscopic BSO strategy was associated with a lower mean total cost per patient than GnRH treatment, and considering the difference in terms of QALYs, the incremental effectiveness did not demonstrate a notable difference between the two approaches. From the National Health Service perspective, and for a time horizon of 5 years, laparoscopic BSO was the dominant option compared to GnRH treatment; laparoscopic BSO was less expensive than GnRH, €2385 [95% confidence interval (CI) = 2044, 2753] vs €7093 (95% CI = 3409, 12,105), respectively, and more effective.\ud \ud CONCLUSION:\ud Surgical ovarian ablation is more cost-effective than GnRH administration in the adjuvant treatment of hormone-sensitive breast cancer patients aged 40-49 years, and the advantage of preventing ovarian cancer through laparoscopic BSO should be considered.

Historically, ovarian ablation (OA) was used as therapy for women with recurrent hormone-receptor-positive (HRP) premenopausal breast cancer. With the publication of the SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) randomized trials, there is considerable interest in OA as an adjuvant treatment, either in combination with tamoxifen or an aromatase inhibitor (AI). Thus, we have reviewed current guidelines and key studies on this important topic and have highlighted the relevant biological and pharmacological aspects of the various endocrine therapies. The results of two key randomized trials addressing the use and controversies of OA in premenopausal breast cancer are discussed and recent research emphasizing the detrimental consequences of premature menopause and the cost-effectiveness of OA is presented. In low-risk patients with HRP premenopausal breast cancer, OA is not beneficial and tamoxifen remains the anti-hormone treatment of choice. In high-risk women (previous chemotherapy or women younger than 35), OA in combination with AI is more effective but is arguably not cost-effective, particularly when OA is achieved medically using a GnRH agonist/antagonist. Compared to tamoxifen alone, the SOFT trial showed a 4.5-7.7% reduction in breast cancer relapse using OA (in combination with either tamoxifen or AI) in high-risk women, though the 5-year overall survival benefit was limited (1.4-3.6%). Premature menopause is associated with long-term mortality risks and women often experience significant menopausal symptoms that impact on quality of life. These considerations should play a role in the treatment selection of those patients who may benefit from adjuvant OA.

Management of Carcinoma breast has evolved over decades from Radical mastectomy to present day breast conservation surgeries and reconstructive surgeries, from 2D radiation therapy technique to present day IMRT/IGRT and Brachytherapy techniques, from toxic chemotherapy regimen to addition of taxanes and targeted therapy. Carcinoma breast is extensively studied to better the treatment options available and also to address the increasing incidence in young women. Ovarian Suppression did not take prime role in the management of cancer breast since it was mainly seen in perimenopausal who mostly attain amenorrhea after adjuvant chemotherapy and in postmenopausal women. Over the decades the incidence of carcinoma breast in young, premenopausal women has been on the rise owing to lifestyle changes, early detection by awareness programmes. Considering the changing population, the concept of ovarian suppression needs to be revisited and explored.

Background Ovarian hormones play crucial roles in mammary carcinogenesis. However, whether ovarian ablation by ovariohysterectomy (OHE) improves the prognosis in dogs with mammary carcinomas is unclear. Objectives Determine if OHE at the time of mastectomy improves the prognosis in dogs with mammary carcinomas and evaluate if hormonal factors influence the effect of OHE. Animals Sixty intact dogs with mammary carcinomas. Methods Dogs were randomly assigned in a 1 : 1 ratio to undergo OHE (n = 31) or not (n = 29) at the time of tumor removal. Peri-surgical serum estradiol (E2) and progesterone concentrations were measured, tumor diagnosis was confirmed histologically, and tumor estrogen and progesterone receptor status was immunohistochemically determined. The dogs were monitored for recurrence and metastases every 3-4 months for at least 2 years. Uni- and multivariable survival analyses were performed with relapse and all-cause death as endpoints in addition to univariable subgroup analyses. Results Overall, OHE did not significantly decrease hazard of relapse (hazard ratio [HR], 0.64; P = .18) or all-cause death (HR, 0.87; P = .64) in univariable analyses. In multivariable analysis OHE did not significantly influence the hazard of relapse (HR, 0.54; P = .12), but an interaction effect was identified between ER status and E2 (P = .037). Subgroup analysis identified decreased hazard of relapse in the OHE group compared to the non-OHE group in the subsets of dogs with increased E2 (HR, 0.22; P = .012) or grade 2 tumors (HR, 0.26; P = .02). Conclusion Dogs with grade 2, ER-positive tumors, or with increased peri-surgical serum E2 concentration represent a subset of dogs with mammary carcinomas likely to benefit from OHE.

Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5-10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta-analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS + tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS + AI compared with OFS + tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone.

Breast cancer and osteoporosis are common conditions affecting women, particularly following menopause. With increasing breast cancer incidence, effects of therapies and decreasing mortality, issues relating to the preservation of bone health with breast cancer therapy have become a priority. Contributing factors to bone loss and fractures in women with breast cancer include tumor effects, estrogen deprivation secondary to breast cancer therapies (chemotherapy, ovarian ablation or aromatase inhibitors), natural menopause and secondary causes of bone loss, typically from concurrently prescribed medications. Management of osteoporosis and other survivorship care is complex, and a multi-disciplinary approach is recommended with assessment of risk factors for bone loss, optimization of bone health through lifestyle approaches and pharmacological interventions based on evidence-based algorithms. This review examines the pathophysiology of bone loss and gives guidelines for the management of bone disease in women with breast cancer.

Purpose: To assess the efficacy and safety of ovarian ablation followed by letrozole as a first or second-line treatment for premenopausal women with metastatic breast cancer (MBC).Patients and method: Premenopausal women with estrogen receptors and/or progesterone receptor positive MBC, received ovarian ablation by radiotherapy (16Gy in 4 consecutive fractions) followed by letrozole tablets 2.5mg by mouth daily.Results: Between May 2010 and March 2013 thirty-five patients were eligible and included in the study. Twenty-four patients (68.6%) had bone metastases and half of patients (n=18; 51.4%) had only one metastatic site. Twelve (34.3%) patients achieved partial response (PR) and 11 had (31.4%) stable disease (SD). The clinical benefit rate (PR+ SD) was 65.7%. With a median duration of follow-up 24 months the median progression-free survival (PFS) was 7 months and the median overall survival was 18 months. Longer PFS was significantly observed in patients with one metastatic site, HER2/neu negative and longer disease-free interval when used as a first-line therapy. No serious toxicities secondary to letrozole or radiotherapy were reported.Conclusion: The results suggest that ovarian ablation by radiotherapy followed by letrozole is an effective first-line treatment for premenopausal women with hormonal receptor positive MBC.

Endocrine therapy has significantly improved outcomes for patients with early- and advanced-stage hormone-receptor (HR)-positive breast cancer. Despite the success of adjuvant endocrine therapy, some patients with early-stage disease will experience relapse. Additionally, all patients with advanced disease will eventually experience disease progression on endocrine therapy due to resistance. Improved understanding of the mechanisms associated with resistance to endocrine agents has recently led to the approval of new therapeutics. Multiple questions remain unanswered, including the optimal duration of adjuvant therapy, the role of ovarian ablation in early-stage breast cancer in premenopausal women, and how to best incorporate targeted agents with endocrine therapy in the metastatic setting. This article reviews the optimization of endocrine therapy in patients with HR-positive breast cancer, focusing on these controversial areas.

In this case presentation, we describe the challenges of performing magnetic resonance-guided radiation therapy (MRgRT) with plan adaptation in a patient with advanced endometriosis, in whom several prior therapeutic attempts were unsuccessful and extensive pelvic irradiation was regarded as being too toxic. Treatment was delivered in two sessions, first for the seemingly only active right ovary, and at a later stage for the left ovary. Some logistical problems were encountered during the preparation of the first treatment, which were subsequently optimized for the second treatment by using transvaginal ultrasound to determine the optimum time point for simulation and delivery. Using breath-hold gated delivery and plan adaptation, radiation dose to the bowel could be minimized, resulting in good tolerance of treatment. Because of the need to simulate and deliver in a brief optimal time span for visibility of the follicles in the ovaries, a single fraction dose of 8 Gy was used in our patient. Hormonal outcome after her second treatment is still pending. In conclusion, MRgRT with plan adaptation is feasible for the occasional patient with refractory endometriosis. Simulation and delivery needs to be synchronized with the menstrual cycle, ensuring that the Graafian follicles allow the ovaries to be visible on magnetic resonance imaging (MRI). Because the ovaries are only visible on T2-weighted MRI for a very brief period of time, we suggest that it is preferable to use single fraction radiotherapy with a brief interval between simulation imaging and delivery.

The use of tamoxifen is conventional adjuvant hormone therapy in premenopausal patients with receptor-positive breast cancer. Clinical trials demonstrating the benefits of ovarian function suppression as adjuvant treatment had an ambiguous interpretation. There is no scientific evidence favoring the empiric use of ovarian suppression for these patients. The members of the American Society of Clinical Oncology consider that ovarian ablation or suppression should be used during adjuvant hormone therapy only in certain cases. Irreversible ovarian function ablation may improve time to relapse, by simultaneously deteriorating the quality of life in patients. Irreversible fertility loss in the patients who have experienced breast cancer may become a leading stressful factor for these patients. Many investigators believe that chemotherapy-induced amenorrhea reduces the risk of recurrence. The paper discusses the usage of gonadotropin-releasing hormone agonists in combination with tamoxifen and aromatase inhibitors during adjuvant hormone therapy for early breast cancer. Whether ovarian suppression is needed during hormone therapy is considered, it is the reversible ovarian function suppression that must be standard treatment in premenopausal patients.

Leuprolide is a safe and effective treatment of estrogen receptor-positive premenopausal breast cancer. Data from the SOFT/TEXT trials solidified leuprolide in combination with an aromatase inhibitor as an effective hormonal treatment for premenopausal breast cancer. However, the efficacy of monthly leuprolide depot compared to leuprolide depot every 3 months in combination with an aromatase inhibitor in this patient population is unclear.In this single center retrospective study, 201 patients were enrolled between January 1, 2015, and October 1, 2016; 100 were included in the 7.5 mg leuprolide monthly injection plus aromatase inhibitor group and 101 in the 22.5 mg leuprolide injection every 3 months plus aromatase inhibitor group. The primary end point was the proportion of patients who experienced ovarian ablation, defined as an estradiol concentration less than 40 pg/mL and a follicle-stimulating hormone concentration of 23 to 116 mU/mL after 3 months of treatment. Significance threshold was P .05 (2 sided). Secondary end points included disease-free survival and overall survival at 1-year follow-up, as well as adverse events reported during treatment.All patients in the monthly leuprolide arm experienced ovarian ablation compared to 100 (99%) of 101 patients in the arm treated every 3 months (P = 1). The disease-free survival rate at 1 year was 95% in the monthly leuprolide arm and 97% in the arm treated every 3 months (P = .75). The overall survival rate at 1 year was 100% in the monthly leuprolide arm and 99% in the arm treated every 3 months (P = 1). The most common treatment-related adverse events between the 2 groups were musculoskeletal pain, hot flashes, fatigue, and insomnia.Leuprolide acetate depot administered every 3 months is as efficacious and tolerable as a monthly injection in combination with an aromatase inhibitor for premenopausal patients with hormone receptor-positive breast cancer.

Background To assess the effects of a gonadotropin-releasing hormone agonists (GnRHa) administration in young patients with malignant ovarian germ cell tumour (MOGCT) during chemotherapy on the prevention of chemotherapy-induced ovarian insufficiency. Methods This multicenter, retrospective study was conducted at fifteen sites in Korea and enrolled 354 patients between January 1995 and January 2018. Among them 227 patients were included in this study according the inclusion criteria: 1) patients diagnosed as pathologically malignant germ cell tumours of the ovaries, 2) who have preserved the uterus and at least one ovary, 3) who received postoperative chemotherapy at least 3 cycles, 4) age at diagnosis, after menarche ∼ Results There was no difference in age, parity, menarche, stage, and type of operation (unilateral or bi-lateral adnexal surgery) among the two groups. The distribution of histology and types of chemotherapy drugs were different. After the end of chemotherapy, the resumption of menstruation was 100% in GnRHa group and 91% in non-GnRHa group (p = 0.0132). The univariate analysis of the factors affecting menstrual resumption showed that the use of GnRHa during chemotherapy was statistically significant difference (OR, 0.00 (0∼0.69;95% CI, p = 0.013). Conclusions The present findings provide evidence for the efficacy of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced ovarian insufficiency and potentially improve fertility in young patients with MOGCT. Legal entity responsible for the study The author. Funding CHA Bundang Medical Centre. Disclosure The author has declared no conflicts of interest.

Background Breast cancer is the second most frequent cancer among women. Disease free survival (DFS) and overall survival (OS) have been improved by different adjuvant chemotherapy regimens; as a consequence, premenopausal patients developed chemotherapy-induced amenorrhea (CIA). Although chemotherapy and ovarian ablation independently improve the outcome of breast cancer, there is controversy about the effect of CIA in these patients. The aim of this study was to analyze the prognostic impact of chemotherapy- induced amenorrhea (CIA) on disease-free survival and overall survival in premenopausal patients with breast cancer following adjuvant chemotherapy. Methods Retrospectively, we reviewed the data of 200 premenopausal breast cancer patients, who underwent adjuvant chemotherapy at the Clinical Oncology Department of Ain Shams University, Cairo, Egypt during 2014. The data of one hundred ninety-two patients were analyzed in the study. CIA was defined as the absence of menstruation for a year after the end of chemotherapy. The survival analyses were done using the Kaplan-Meier method and the log Rank Test. Results The median follow-up was 4 years. Mean age was 40.8 ± 6 years. CIA occurred in 66.1% of patients. Age and tumor grade were CIA predictors in logistic regression analysis. The 4-year disease-free survival (DFS) was higher in the CIA group than that in the non-CIA group (47.39 months vs 31.80 months, respectively; P = Conclusions Chemotherapy-induced amenorrhea positively affects disease-free survival and overall survival in the Egyptian premenopausal breast cancer patients treated with adjuvant chemotherapy. It was a better prognostic marker and might be used as a surrogate marker for effective chemotherapy in those patients. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Historically, endocrine therapy for breast cancer began with ovarian ablation (OA) for the treatment of premenopausal patients. After the identification of estrogen receptors and the development of many antiestrogens, tamoxifen has been approved and used as the standard endocrine therapy for hormonal receptor (HR)-positive premenopausal patients to date. With the development of luteinizing hormone-releasing hormone agonists, the paradigm of endocrine therapy for premenopausal women with HR-positive breast cancer began to change from OA to ovarian function suppression (OFS). To date, the indication for OFS was limited to those premenopausal patients with HR-positive breast cancer who were unable to use tamoxifen as the primary adjuvant endocrine therapy. However, following the definitive demonstration of the therapeutic role of OFS added to tamoxifen or aromatase inhibitor after chemotherapy in large randomized trials, such as Tamoxifen and Exemestane Trial or Suppression of Ovarian Function Trial, the American Society of Clinical Oncology guidelines for the use of endocrine therapy in premenopausal HR-positive breast cancer were recently updated to recommend OFS in high-risk patients who required adjuvant chemotherapy. In contrast, the role of OFS to protect ovarian function during chemotherapy in premenopausal women has remained controversial, and some evidence showing the protective effect of OFS on the ovaries during chemotherapy as well as its therapeutic effect for breast cancer in premenopausal women with HR-negative breast cancer was recently published. Further evaluation is necessary to determine its exact role. In conclusion, the role of OA or OFS has been evolving, not only to improve the efficacy of breast cancer treatment, but also to preserve ovary function. OFS remains a main strategy for premenopausal women with HR-positive early breast cancer, though its exact role should be determined in further studies.

Mushabbab Al Asiri,1,* Mutahir A Tunio,1,* Reham Abdulmoniem,2,*1Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia; 2Radiation Oncology, National Cancer Institute, Cairo, Egypt *These authors contributed equally to this work Background: A meta-analysis was conducted to assess the impact of radiation-induced ovarian ablation (RT-OA) on amenorrhea cessation rates, progression-free survival, and overall survival in pre/perimenopausal women with breast cancer. Materials and methods: The Medline, CANCERLIT, and Cochrane Library databases and search engines were searched to identify randomized controlled studies comparing RT-OA with control for early or metastatic breast cancer. Further, radiotherapy doses, techniques, and associated side effects were evaluated. Results: Six controlled trials with a total patient population of 3,317 were identified. Pooled results from these trials showed significant amenorrhea rates (P

Luteinising hormone releasing hormone agonists (LH-RHa) are effective in the treatment of advanced endocrine-sensitive breast cancer in premenopausal patients, but their role in the adjuvant setting has remained controversial for a long time. Tamoxifen for 5 years has been traditionally considered the standard endocrine therapy for premenopausal patients and this is still valid for many patients. However, the recently reported SOFT trial has suggested that adding ovarian function suppression (OFS) to tamoxifen could improve DFS in women at sufficient risk to warrant adjuvant chemotherapy and who remained premenopausal after this therapy. The administration of an aromatase inhibitor plus OFS represents an additional therapeutic option for hormone-receptor positive premenopausal breast cancer patients, according to the combined analysis of the SOFT and TEXT trials. Temporary ovarian suppression induced by LH-RHa has been recognized as an effective strategy to preserve ovarian function from the toxic effects of chemotherapy and is now recommended in young breast cancer patients with endocrine-insensitive tumors. In this review, we discuss recent data on the role of LH-RHa in combination with tamoxifen or with an aromatase inhibitor, and we comment on its role as a strategy to preserve ovarian function in young patients candidates for adjuvant or neo-adjuvant chemotherapy.

Cancer Care Ontario&rsquo, s Program in Evidence-Based Care (pebc) recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question &ldquo, What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?&rdquo, The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and her2 (human epidermal growth factor receptor 2)&ndash, targeted therapy. For the systematic review, the literature in the medline and embase databases was searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were &ldquo, breast cancer&rdquo, and &ldquo, systemic therapy&rdquo, (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. Several hundred documents that met the inclusion criteria were retrieved. Meta-analyses from the Early Breast Cancer Trialists&rsquo, Collaborative Group encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. The results of the systematic review constitute a comprehensive compilation of high-level evidence, which was the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. The review of the evidence for systemic endocrine therapy (adjuvant tamoxifen, aromatase inhibitors, and ovarian ablation and suppression) is presented here, the evidence for chemotherapy and her2-targeted treatment&mdash, and the final clinical practice recommendations&mdash, are presented separately in this supplement.

e12536 Background: Ovarian ablation is increasingly used to complement endocrine therapy in select premenopausal women with hormone-receptor positive (HR+) breast cancer (BC). It can be achieved by either medical ovarian suppression (OS) or therapeutic bilateral salpingo-oophorectomy (BSO). We sought to investigate trends of therapeutic BSO in premenopausal patients at our institution. Methods: Premenopausal women with HR+ primary BC diagnosed from 2010-2014 were identified in our prospectively maintained BC database. Patients with confirmed BRCA1/2 mutations were excluded. Distribution of patient and disease characteristics between treatment groups were assessed using univariate logistic regression analyses. Surgical details and complications were extracted from our surgical database. Results: We identified 2,854 eligible patients; 2,113 (74%) received endocrine therapy without ovarian ablation, 246 (9%) received endocrine therapy plus medical OS, 180 (6%) underwent additional BSO, and 315 (11%) did not receive endocrine therapy at the time of analysis. Independent predictors for undergoing ovarian ablation were younger age (OR 0.98; 95%CI, 0.96-0.99; p < 0.001), higher grade (grade 3 vs 1: OR 3.17; 95%CI, 1.70-5.90; grade 2 vs 1: OR 3.13; 95%CI, 1.64-5.95; p < 0.001), lymph node involvement (OR 1.46; 95%CI, 1.19-1.80; p < 0.001), and higher AJCC stage as well as de novo metastatic BC (II vs I: OR = 1.35; 95%CI, 1.03-1.76; III vs I: OR 2.57; 95%CI, 1.86-3.55; IV vs I: OR 19.69; 95%CI, 12.76-30.39; p < 0.001). Among patients who underwent ovarian ablation, patients of younger age (1.04; 95%CI, 1.01-1.07; p = 0.009) and with metastatic BC (stage IV vs I: OR 0.36; 95%CI, 0.20-0.68; p = 0.007) were less likely to undergo BSO than OS. In 180 patients undergoing BSO, five adverse events were noted: two grade 1, two grade 2, and one grade 3 complication. Conclusions: Premenopausal women with HR+ BC with high-risk features or metastatic disease were more likely to undergo ovarian ablation at our institution. Surgical ovarian ablation is a safe alternative, with low complication rates. Understanding patient preferences, side effects, and quality of life implications will help guide personalized treatment decisions.

Hormone receptor (HR) positive breast cancers represent the vast majority of breast cancers. Adjuvant and/or neoadjuvant endocrine therapy is highly effective and appropriate for nearly all women with HR positive tumors. Adjuvant tamoxifen (TAM) is a major endocrine treatment option, which has been found to be effective in both premenopausal and postmenopausal patients. Considerable evidence has been accrued of a benefit for ovarian ablation or suppression (OA/S) in premenopausal patients, for aromatase inhibitors (AIS) in postmenopausal patients, for the longer duration of adjuvant endocrine therapy and for the clinical utility of neoadjuvant endocrine therapy. Clinical practice guidelines should keep changing with developing evidence-based practice guidelines pertaining to breast cancer care. The present publication conducted a comprehensive systematic review of the literature addressing the use of endocrine therapy as adjuvant or neoadjuvant therapy for HR positive breast cancer, focusing on selecting the best agents for both premenopausal and postmenopausal patients, as well as the optimal duration of such treatment.

The TEXT and SOFT trials concluded that an aromatase inhibitor (AI) with ovarian ablation (OA) yields a higher 5-year disease-free survival than tamoxifen alone in premenopausal ER+ high-risk early breast cancer. However, the long-term health consequences and costs of OA, either by GnRH agonist or oophorectomy, have not been evaluated. The objective was to conduct a cost-effectiveness analysis comparing tamoxifen to OA with AI. Markov Monte Carlo simulation model estimated the costs and benefits of 3 endocrine strategies: (1) tamoxifen; (2) GnRH agonist with AI (GnRHa-AI); (3) bilateral salpingo-oophorectomy with AI (BSO-AI). Effectiveness was measured in life expectancy gain (years), and costs were averaged over a lifetime (USD 2015). Adverse events and deaths from each strategy were modeled in the United States population over a time horizon of 40 years. For women without prior chemotherapy (low-risk), tamoxifen alone was more effective (18.03 years) and less costly ($1566) than GnRHa-AI (17.66 years, $93,692) or BSO-AI (17.63 years, $25,892). For those with prior chemotherapy (high-risk), BSO-AI was more costly but more effective (16.78 years, $25,368) than tamoxifen alone (16.55 years, $1523) with an ICER of $102,290, while GnRHa-AI yielded an ICER of $443,376. The simulation estimated 787 and 577 deaths attributable to OA among 9320 high-risk women after BSO-AI and GnRHa-AI, respectively. There may be a role for ovarian ablation in premenopausal women with ER+ high-risk early breast cancer; however, this analysis raises concerns about the long-term health consequences of ovarian ablation and the potential effects on overall survival.