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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: 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.

Hormonal manipulation is probably the second oldest effective therapy utilized for breast cancer treatment after surgical resection. The use of oophorectomy in the setting of breast cancer in the late nineteenth century predates the use of radiation. The first hormonal drug for breast cancer, tamoxifen, has been available for over half a century now. Use of hormonal manipulation has had a profound impact on the treatment and outcome of breast cancers over the decades. Even though they are among the earliest therapeutic modalities, there is still many unanswered questions including those concerning the myriad interactions of estrogen receptors with other receptors, cytokines, and the tumor microenvironment in general. This chapter will cover the basics of hormonal manipulation and its use in the adjuvant setting in breast cancers. There is still considerable debate on how long we need to continue treatment, if there is any role for newer agents including targeted therapy in this setting and if there are any subsets where we can improve outcomes even further using novel biomarkers and combined therapies.

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.

Ovarian suppression (OS) is an effective therapy in hormone-sensitive breast cancer. Oophorectomy and ovarian irradiation have historically been used to achieve the goal of ovarian ablation. Luteinizing hormone releasing hormone (LHRH) analogues have largely supplanted surgical and radiation-based approaches because of less side effects and a lower likelihood of permanent amenorrhea, with the potential for restoration of fertility. LHRH analogues goserelin, buserelin, leuprorelin are equally effective. Buserelin is economically attractive.

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.

In many countries of the developed world, there is an increasing trend toward delay in childbearing from 30 to 40 years of age for various reasons. This is unfortunately concordant with an increasing incidence of breast cancer in women who have not yet completed their family. The current choice for premenopausal women with breast cancer is adjuvant therapy which includes cytotoxic chemotherapy, ovarian ablation (by surgery, irradiation, or chemical ovarian suppression), anti-estrogen therapy, or any combination of these. Although the use of adjuvant therapies with cytotoxic drugs can significantly reduce mortality, it raises issues of the long-term toxicity, such as induction of an early menopause and fertility impairment. The risk of infertility is a potential hardship to be faced by the patients following treatment of breast cancer. The offspring of patients who became pregnant after completion of chemotherapy have shown no adverse effects and congenital anomalies from the treatment, but sometimes high rates of abortion (29%) and premature deliveries with low birth weight (40%) have been demonstrated. Therefore, the issue of recent cytotoxic treatment remains controversial and further research is required to define a "safety period" between cessation of treatment and pregnancy. Preservation of fertility in breast cancer survivors of reproductive age has become an important issue regarding the quality of life. Currently, there are several potential options, including all available assisted technologies, such as in vitro fertilization and embryo transfer, in vitro maturation, oocyte and embryo cryopreservation, and cryopreservation of ovarian tissue. Because increased estrogen levels are thought to be potentially risky in breast cancer patients, recently developed ovarian stimulation protocols with the aromatase inhibitor letrozole and tamoxifen appear to provide safe stimulation with endogenous estrogen. Embryo cryopreservation seems to be the most established fertility preservation strategy, providing a 25-35% chance of pregnancy. In addition, oocyte freezing can be considered as an alternative in patients who are single and in those who do not wish a sperm donor. Although ovarian tissue harvesting appears to be safe, experience regarding ovarian transplantation is still limited due to low utilization, so the true value of this procedure remains to be determined. Nevertheless, in clinical situations in which chemotherapy needs to be started in young patients facing premature ovarian failure, ovarian tissue preservation seems to be a promising option for restoring fertility, especially in conjunction with other options like immature oocyte retrieval, in vitro maturation of oocytes, oocyte vitrification, or embryo cryopreservation. It seems that in vitro maturation is a useful strategy because it improves oocyte or cryopreservation outcome in breast cancer patients undergoing ovarian stimulation for fertility preservation.

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.

Purpose: To investigate person, cancer and treatment determinants of immediate breast reconstruction (IBR) in Australia. Methods: Bi-variable and multi-variable analyses of the Quality Audit database. Results: Of 12,707 invasive cancers treated by mastectomy circa 1998-2010, 8% had IBR. This proportion increased over time and reduced from 29% in women below 30 years to approximately 1% in those aged 70 years or more. Multiple regression indicated that other IBR predictors included: high socio-economic status; private health insurance; being asymptomatic; a metropolitan rather than inner regional treatment centre; higher surgeon case load; small tumour size; negative nodal status, positive progesterone receptor status; more cancer foci; multiple affected breast quadrants; synchronous bilateral cancer; not having neo-adjuvant chemotherapy, adjuvant radiotherapy or adjuvant hormone therapy; and receiving ovarian ablation. Conclusions: Variations in access to specialty services and other possible causes of variations in IBR rates need further investigation. Refereed/Peer-reviewed

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.

The aims of this study are to assess the extent of ovarian movement on consecutive MRI examinations in patients with gynaecological malignancies and to define potential safety volumes around the ovaries that may avoid ovarian ablation during pelvic irradiation.Patients with cervical, vaginal and endometrial cancer who underwent MRI examinations of the pelvis before and during radiotherapy were included in the study. The position of the ovaries was retrospectively determined on two consecutive axial and sagittal T(2) weighted MRI examinations of the pelvis. Ovarian movement was determined in craniocaudal, anteroposterior and mediolateral directions. Safety volumes were calculated by computing elliptical volumes based on the derived 95% and 99% reference intervals.30 patients with a gynaecological malignancy were included. Both ovaries could be identified on the MRI examinations in all cases. The safety volumes around the ovaries encompassing 95% and 99% of ovarian movement were 11 and 25 cm(3) (95%), and 24 and 54 cm(3) (99%), for the left and right ovary, respectively.Adding a safety volume around the ovaries may reduce the high radiation dose to the ovaries. This could potentially avoid ovarian ablation, reducing significant fertility morbidity.

During conditions of ovarian suppression, women with premenstrual dysphoria (PMD) experience abnormal behavioral responses to physiological levels of ovarian steroids. Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation frequently accompanies depression, and ovarian steroids regulate HPA axis responsivity, the role of HPA axis dysregulation in PMD is not known. We hypothesized that women with PMD would show abnormalities of HPA axis function analogous to those reported in depressive illness, and that ovarian steroids would differentially regulate HPA axis function in women with PMD compared with asymptomatic controls (AC).Our objective was to characterize the HPA axis response to physiological levels of estradiol and progesterone in women with PMD and AC.We conducted an open-label trial of the GnRH agonist depot Lupron with ovarian steroid replacement administered in a double-blind crossover design in an outpatient clinic.Forty-three women (18 with prospectively confirmed PMD and 25 AC) participated.Women received Lupron for 6 months. After 3 months of hypogonadism, women received 5 wk each of estradiol (100-μg patch daily) or progesterone (suppositories 200 mg twice daily). During each condition, combined dexamethasone-suppression/CRH-stimulation tests and 24-h urinary free cortisol levels were performed.Plasma cortisol and ACTH levels were evaluated.HPA axis function was similar in PMD compared with AC. In all, progesterone significantly increased the secretion of cortisol compared with estradiol [area under the curve (t(74) = 3.1; P0.01)] and urinary free cortisol (t(74) = 3.2; P0.01) and ACTH compared with hypogonadism [area under the curve (t(74) = 2.4; P0.05)].HPA axis regulation is normal in PMD, suggesting that the pathophysiology of PMD differs from major depression. As observed previously, progesterone but not estradiol up-regulates HPA axis function in women.

BACKGROUND: Although chemotherapy and ovarian ablation independently improve the outcome of breast cancer, there is controversy about the benefit of chemotherapy-induced amenorrhea (CIA) in breast cancer. We investigated impact of CIA on response to neoadjuvant chemotherapy in breast cancer patients. METHODS: We reviewed the records of 198 premenopausal patients with breast cancer treated with neoadjuvant chemotherapy between January 2005 and December 2010. Chemotherapy-induced amenorrhea (CIA) was defined as serum FSH level ≥40 IU/L after completion of all scheduled neoadjuvant chemotherapy and prior to definitive surgery. RESULTS: Among 198 breast cancer patients, 132 pts (66.7%) developed CIA after neoadjuvant chemotherapy. 156 pts (78%) underwent DA chemotherapy. The age of CIA patients was older than non-CIA patients (41.55±5.55 years vs. 38.27 ± 6.86 years, p=0.001). The incidence of CIA after neoadjuvant chemotherapy was significantly higher in responder group (responder vs. nonresponder: 87 pts (74.4%) vs. 45 pts (55.6%); p=0.006). Additionally, FSH level after all scheduled neoadjuvant chemotherapy was significantly higher in responder group (FSH 56.41±32.41 IU/L vs. 45.76±30.31 IU/L; p=0.021). In univariate analysis, CIA (p=0.006) and total number of chemotherapy cycle regardless of chemotherapy regimen (p=0.04) were significantly associated with tumor response. CIA was only independent factor for tumor response after neoadjuvant chemotherapy on multivariate analysis (p=0.012). CONCLUSION: CIA after neoadjuvant chemotherapy was significantly associated with response to neoadjuvant chemotherapy in locally advanced breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-19.

Luteinising hormone releasing hormone agonists (LH-RHa) induce ovarian suppression in premenopausal women that is usually reversible on cessation of therapy. They act by binding to pituitary LH-RH receptors, resulting in down regulation of receptors and subsequent suppression of luteinising hormone and estradiol. LH-RHa are effective in the treatment of advanced breast cancer in premenopausal women but their role as adjuvant treatment of early breast cancer is still controversial. Approximately 60% of tumors in premenopausal women are hormone sensitive and these patients are candidates for hormonal treatment. Tamoxifen for 5 years is considered the standard endocrine therapy for all premenopausal women with hormone sensitive breast cancer. There is no definitive evidence of additional benefit associated with the use of LH-RHa administered as an alternative or in addition to tamoxifen. In this review we discuss available data on the role of LH-RHa alone or in combination with tamoxifen; on the role of LH-RHa in combination with aromatase inhibitors; and on the potential role of LH-RHa as a strategy to preserve ovarian function during adjuvant chemotherapy.

Adjuvant endocrine treatment for premenopausal woman remains a controversial area in the therapeutical approach of early stages of breast cancer. Metaanalysis show that ovarian ablation and suppression produce, in a global way, significant benefits in terms of reduction of the risk of recurrence and death. Nevertheless, in the presence of adjuvant chemotherapy, the benefits of ovarian suppression or ablation are clearly reduced, probably in relation to the impact that amenorrhoea induced by chemotherapy. On the other hand, in premenopausal patients, the same metaanalysis show that the use of adjuvant tamoxifen produces benefits in disease- free survival and overall survival very similar to those observed in postmenopausal women. Additionally, the benefits from tamoxifen persist independently of whether or not adjuvant chemotherapy is being received. Thus, some of the questions to answer are: first, is there, in premenopausal women, an additional benefit when ovarian suppression is associated to tamoxifen? Second, it remains controversial if ovarian suppression must be indicated for all patients who receive chemotherapy or only those that have not reached amenorrhoea when adjuvant chemotherapy is completed. Moreover, although in the last decades more than 15,000 premenopausal patients have been included in specific trials of adjuvant endocrine therapy with ovarian suppression or ablation, the best modality of treatment has not been established, and what is more important, the role of its association with tamoxifen has not been completely defined. Many of these aspects remain controversial and the decision about the best therapeutical approach must be individualised in each patient.

Hormonal therapy for advanced breast cancer has evolved significantly in the more than 100 years since the first publications documenting the effect of ovarian ablation on advanced breast cancer in premenopausal women. Since that time, not only have we developed the methods to measure estrogen and progesterone receptors in cancer cells, but more recently we have understood that expression of these receptors determines response to hormone therapy. The availability of more selective antiestrogen therapies has changed and significantly improved the treatment options for women who have advanced hormone-responsive breast cancer. Current research is focusing on reversing resistance to hormone therapy with the addition of targeted biologic agents to standard hormonal treatment.

Endocrine therapy plays a pivotal role in the early treatment of estrogen receptor (ER)-positive breast cancer. Although evidence suggests that chemotherapy may work partly through ovarian ablation in young women who have ER-positive tumors, combined chemotherapy and endocrine therapy are generally advocated. In postmenopausal women, aromatase inhibition has become the new "gold standard" of treatment. More research is needed to define optimal regimens (aromatase inhibitor monotherapy versus tamoxifen sequential application), optimal duration of therapy and potential advantages of particular compounds. The optimal use of estrogen suppression (ovarian ablation with or without aromatase inhibition) and tamoxifen (administered sequentially or in concert with ovarian ablation) in premenopausal women has yet to be defined.

Adjuvant ovarian function suppression is acknowledged today as effective therapy for premenopausal patients with early breast cancer. Various modalities have been applied to achieve this treatment option: • First, early investigations comparing ovarian ablation with chemotherapy identified similar outcomes in terms of patients’ rates of disease-free survival (DFS). • Second, prospective randomized trials have more recently focused on luteinizing hormone-releasing hormone analogues (LHRHa) that induce medical ovarian suppression and avoid the morbidity and irreversibility associated with surgical ovariectomy or irradiation. These trials analyzed the value of treatment with goserelin or other LHRHa, with or without tamoxifen, as against chemotherapy. Goserelin was subsequently established as a valid alternative, and our own results demonstrated that goserelin + tamoxifen is more effective and better tolerated in hormone-responsive patients. • Third, other multiple-arm studies have compared LHRHa + chemotherapy with chemotherapy alone. Addition of tamoxifen to goserelin + chemotherapy was shown to improve DFS, and significant benefits in goserelin-treated patients were seen irrespective of use of chemotherapy or tamoxifen. • Finally, ongoing trials are addressing the appropriate duration of LHRHa therapy and other unresolved issues. In summary, combined ovarian suppression with adjuvant goserelin and tamoxifen is considered to be at least as effective as chemotherapy in premenopausal breast cancer patients. Published reports have demonstrated that ovarian suppression is a safe means of reducing risk of recurrence in estrogen receptor-positive women and underlined its use as a competitive alternative to chemotherapy in this patient subset.

The Zoladex In Pre-menopausal Patients (ZIPP) study was designed to determine whether addition of goserelin ('Zoladex') and/or tamoxifen to adjuvant therapy (radiotherapy and/or chemotherapy), provided benefit to pre- or peri-menopausal women with operable, early breast cancer. A combined analysis of four randomised trials using a core protocol was performed. Patients (n = 2710) were randomised into a 2 x 2 factorial trial based on goserelin and tamoxifen (n = 1800) or randomised to receive goserelin or not (n = 910; some received elective tamoxifen) for 2 years. The analysis presented here compares women who did (n = 1354) or did not (n = 1356) receive goserelin. After a median follow-up of 5.5 years, goserelin provided a significant benefit for event-free survival (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.69, 0.92; P = 0.002) and overall survival (HR 0.81; 95% CI 0.67, 0.99; P = 0.038). Goserelin was well tolerated. These data show that the addition of goserelin to standard adjuvant therapy is more effective than standard therapy alone in pre-menopausal women with early breast cancer.

Ovarian ablation is an effective adjuvant therapy for primary breast cancer but little is known about its quality of life impact relative to the more widely used adjuvant chemotherapy. This randomized study compared quality of life outcomes of adjuvant ovarian ablation versus cyclophosphamide, methotrexate, fluoracil (CMF) chemotherapy.The Danish Breast Cancer Cooperative Group (DBCG) trial 89-b randomized premenopausal patients with receptor-positive, primary breast cancer between nine cycles of CMF chemotherapy given every 3 weeks and ovarian ablation by oophorectomy. In total, 317 randomized patients were invited to take part in a longitudinal quality of life study with assessments at 1, 3, 5, 9, 15, and 24 months after randomization. The questionnaire included the EORTC QLQ-C30, the Hospital Anxiety and Depression Scale, and additional items assessing potential symptoms not included in the standard instruments.After 2 years, 260 women were alive and recurrence-free, and 196 of these (75%) had completed all six questionnaires. Overall, patients in the chemotherapy group had more symptomatology at the first three assessments (i.e., during the 6 months treatment period), except for hot flushes/sweats. There were few differences between groups at later assessments. In chemotherapy patients, the likelihood of preserving ovarian function decreased steeply with increasing age. CMF chemotherapy and ovarian ablation have similar impact on recurrence and survival.Chemotherapy had more negative impact on health-related quality of life but preserved ovarian function in some younger patients.

For patients with hormone receptor-positive breast cancer, some form of endocrine therapy is central to the management of their disease. For premenopausal patients in whom estrogen synthesis occurs primarily in the ovaries, current treatment options include ovarian ablation or suppression and selective estrogen receptor modulators such as tamoxifen and toremifene. Ovarian ablation and tamoxifen have demonstrated their effectiveness in the adjuvant setting, reducing the risk of recurrence and death. However, although some studies suggest ovarian ablation results in an equivalent outcome to chemotherapy alone, studies examining the combination have not demonstrated a clear benefit with the addition of ovarian suppression to standard chemotherapy. Results from trials combining ovarian suppression with tamoxifen have also been inconclusive. Finally, although aromatase inhibitors cannot be used as monotherapy in premenopausal patients, the reduction in the risk of recurrence observed with the integration of these agents into adjuvant regimens in postmenopausal patients when compared with the standard 5 years of tamoxifen has stimulated interest in evaluating the combination of ovarian suppression with an aromatase inhibitor in premenopausal women. Several ongoing trials will investigate these combinations as well as ovarian suppression plus tamoxifen.

The action of hormone therapy is usually through its effects on steroid hormone regulation and the responsive cancers are those arising in organs under the influence of these hormones, i.e. breast, endometrium and prostate.

Breast cancer is often an estrogen-dependent disease. The primary goals of the treatment of breast carcinomas are multiple, depending on the situation in which the patients are treated. In adjuvant setting, the aims are to delete the time of relapse, to increase the overall survival, and to offer to the patients the best quality of life they may expect. Tamoxifen is the standard hormonal agent for premenopausal women with receptor-positive breast cancer. Recent data show an increasing role for aromatase inhibitors in postmenopausal women. In metastatic setting, the primary goals are improved quality of life and prolonged survival; effective therapies with minimal toxicity, such as endocrine therapy, are highly desirable and should be considered a primary option over chemotherapy for selected estrogen-receptor positive patients. Ovarian ablation has been worldwide used. Methods of irreversible ovarian ablation include surgical oophorectomy and ovarian irradiation. Potentially reversible castration can be medically accomplished using luteinizing hormone releasing hormone analogues (LHRH agonists). In the metastatic setting, ovarian ablation (induced by the use of LHRH agonists or by surgical ovarian ablation) and tamoxifen monotherapies produce comparable outcomes, and may be more effective when used together (combined estrogen blockade). In advanced breast cancer, the combination prolongs the progression-free survival and increases response rates and duration of response rate relative to the use of LHRH agonist alone. In the adjuvant setting, data suggest that ovarian ablation followed by tamoxifen produces similar results to those obtained with adjuvant chemotherapy in hormone-receptor positive breast cancer women. The value of combining these modalities remains unclear, but the addition of the LHRH analogue goserelin to standard treatment results in a significant benefit in terms of relapse-free and overall survival, especially for estrogen-receptor positive patients. Finally, considering the efficacy of the new aromatase inhibitors, the interest of combining these drugs with the LHRH analogues has yet to be defined, both for pre- and post-menopausal patients.

Purpose: The aim of this multicenter trial was to evaluate the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy. Patients and methods: Nine hundred and twenty-six premenopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm). Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years. The analyses were performed with Cox models stratified by center. Results: Median follow-up was 9.5 years. Mean age was 43 years. Ninety per cent of patients had histologically proven positive axillary nodes, 63% positive hormonal receptors and 77% had received an anthracycline-based chemotherapy regimen. Ovarian suppression was by radiationinduced ovarian ablation (45% of patients) or with triptorelin (48%). At the time of randomization, all patients had regular menses or their follicle-stimulating hormone and estradiol levels indicated a premenopausal status. The 10-year disease-free survival rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms (P = 0.51). The 10-year overall survival rates were 66% (95% CI 61% to 70%) for the ovarian suppression arm and 68% (95% CI 63% to 73%) for the control arm (P = 0.19). There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality. However, in patients

Endocrine therapies have played an important role in the management of breast cancer for many years. Tamoxifen had been the unchallenged standard in the adjuvant setting until recently. Data from recent clinical trials have emphasized the emerging roles of aromatase inhibitors and ovarian ablation in patients with early breast cancer. This review highlights previous data that led to the recognition of tamoxifen as the gold standard hormonal therapy in the adjuvant treatment of early breast cancer. We then discuss clinical trials demonstrating the impact of aromatase inhibitors as an alternative to tamoxifen or as a component of sequential treatment with tamoxifen in postmenopausal women with early breast cancer. Finally, we review data related to the incorporation of ovarian ablation into the treatment of early breast cancer in premenopausal women.

Ovarian ablation has been used for a long period of time as an effective method in breast cancer treatment. The effectiveness of this therapy has been proven by multiple trials which by now provide long-time results. Currently available endocrine therapies either lower estrogen production or modulate estrogen receptor (ER) activity or regulate the expression of the ER. The efficacy of chemotherapy is partly related to the induction of secondary amenorrhea in premenopausal women by cytotoxic agents. A comparison of current standard chemotherapies with endocrine therapies shows that ovarian suppression and chemotherapy are equieffective in premenopausal women with hormone-sensitive breast cancer. Ovarian ablation increases long-lasting survival in breast cancer patients younger than 50 years of age, at least in the absence of chemotherapy. In premenopausal women with hormone-sensitive breast cancer ovarian suppression with gosereline with or without tamoxifen seems to be at least as effective as CMF chemotherapy alone. There are data which indicate a superiority of gosereline plus tamoxifen to gosereline monotherapy, at least if chemotherapy has been applied as well. Sequential use of gosereline after CMF chemotherapy seems to be superior to any modality alone in node-negative patients, at least in women younger than 40 years of age with hormone-sensitive tumors. Monochemotherapy alone is not sufficient in patients younger than 35 years of age with hormone-sensitive tumors. On the basis of the available data a final answer to the use of combined chemoendocrine therapy cannot be given as yet.

BACKGROUND In 1994, the Eastern Cooperative Oncology Group (ECOG) initiated for the Breast Intergroup a randomized clinical trial (E3193) in premenopausal patients with early-stage breast carcinoma (lymph node-negative and receptor-positive, with tumors measuring ≤ 3 cm) comparing tamoxifen as adjuvant systemic therapy with tamoxifen and ovarian ablation by one of three different methods. Ovarian ablation could be accomplished either via radiotherapy (RT) (20 Gray [Gy]/10 fractions to a modified pelvic volume), surgical oophorectomy, or goserelin/leuprolide injections as per patient/physician choice. In the current study, we report the efficacy of pelvic RT with this dose-fractionation scheme in the induction of ovarian ablation. METHODS Twenty-two of 174 patients (13%) who were randomized to treatment with tamoxifen and ovarian ablation received RT for ovarian ablation. RT quality assurance was performed. Of the 22 patients, 19 were treated per protocol, 1 patient had a minor violation (20 elapsed days for 10 RT fractions), and 2 patients had major violations (1 patient who was treated with RT as per protocol but who was treated at a non-Intergroup center, and 1 patient who was treated at a dose of 15 Gy/5 fractions). RESULTS No acute Grade 3 or 4 (according to the Common Toxicity Criteria of the National Cancer Institute) toxicities were reported during RT. Of the 22 patients receiving RT, evaluable follow-up data were available for 20 patients. Based on postmenopausal levels of estradiol or follicle-stimulating hormone at varying intervals after the completion of RT, 15 of 20 patients (75%) achieved successful ovarian ablation with RT. At a median follow-up of 54 months (range, 21–66 months), no Grade 3 or 4 complications from RT were observed. CONCLUSIONS Ovarian ablation by RT as performed in the current trial (given at a dose of 20 Gy in 10 fractions to a modified pelvic treatment volume) was found to be effective for ovarian ablation in the majority of patients, but may take some months to be complete. Consequently, patients should be evaluated to ascertain that ablation has been accomplished. Cancer 2004. © 2004 American Cancer Society.

This study was initiated to evaluate the efficacy of luteinizing hormone-releasing hormone (LH-RH) agonists in protecting premenopausal patients against the adverse gynaecological effects induced by tamoxifen. Between January 1998 and January 2000, 85 premenopausal breast cancer patients were included in this prospective study. All were to receive LH-RH agonists and tamoxifen for a minimum of two years. All patients underwent a pretreatment gynaecological evaluation and annual follow-up. Bone density was also measured at the start of treatment and then after 2, 3 and 4 years. Pretreatment evaluation revealed 2 polyps. At one and two years of follow-up, no abnormal symptoms were noted and echographic findings were normal. At three years of follow-up, a polyp associated with adnexal masses was discovered. Histology revealed ovarian and endometrial metastases of infiltrating lobular breast carcinoma. Bone density evaluation after 2, 3 and 4 years of treatment showed no significant bone loss. LH-RH agonists offer safe protection against the gynaecological side-effects of tamoxifen in premenopausal breast cancer patients.

Endocrine therapy remains a cornerstone of systemic therapy for breast cancer even though it was first introduced more than a century ago. In the past three decades a large number of randomized trials involving several tens of thousands of patients have been performed to determine the role of endocrine therapy in the adjuvant setting. The results of these studies indicate that hormonal therapy should be considered the standard adjuvant systemic treatment for the majority of patients with invasive breast cancer irrespective of age, menopausal status or tumour stage. This chapter aims to describe the ‘state of the art’ relative to the use of adjuvant endocrine therapy with special focus on a number of salient issues, including: (i) the role of ovarian ablation and luteinising hormone releasing hormone (LHRH) analogues among pre-menopausal patients; (ii) optimal duration of tamoxifen; (iii) adjuvant therapy with third-generation, selective aromatase inhibitors; (iv) predictive biomarkers; (v) side-effects; (vi) combination endocrine therapy; (vii) future development of endocrine therapy.

Data from patient self-report questionnaires provide valuable information about side effects that patients may view as having a significantly detrimental impact on their quality of life and yet are not always recognised as important by healthcare professionals. Such information is very important in enabling patients to make informed choices regarding treatment options. Despite this, formal data collection from patient self-report assessments still fails to influence management decisions as much as traditional outcome measures such as disease-free survival, or clinician-recorded symptoms. There are now a number of different options for the treatment of patients with breast cancer. These include antioestrogens, aromatase inhibitors and oestrogen receptor antagonists for postmenopausal women, and chemotherapy and ovarian ablation (via oophorectomy, irradiation or with luteinising hormone-releasing hormone agonists) for premenopausal women. However, there are still surprisingly few published reports from comprehensive quality-of-life studies comparing such treatments and thus little is known about the relative impacts of each of these on quality of life. Here, the evolution of hormonal therapies for breast cancer is reviewed and the differences between the tolerability profiles of currently available treatment options are highlighted.

Breast cancer is rare before age 40. Sixty to seventy percent of breast cancers in this age group express estrogen or progesterone receptors. All following considerations refer to endocrine responsive disease. Ovarian ablation reduces the relative risk of recurrence and death by at least one quarter in the absence of chemotherapy. Chemotherapy induced amenorrhea reduces the risk of recurrence and death when compared to patients with continuing menses. Chemotherapy is insufficient therapy for very young patients with hormone responsive disease, particularly if chemotherapy fails to induce amenorrhea. Tamoxifen is effective in young patients even in combination with chemotherapy. The ablation or suppression of ovarian function was equivalent to chemotherapy in at least eight randomized trials. Preliminary evidence is compatible with an additional adjuvant effect of LHRH agonists after chemotherapy, particularly in women < 40 years of age. Young patients with endocrine responsive tumors should be treated on a clinical trial. If this is impossible, they should receive tamoxifen and either an LHRH agonist or chemotherapy or both.

Ovarian ablation is an effective treatment for premenopausal women with hormone receptor positive breast cancer. It can be achieved permanently by surgery or radiotherapy and reversibly by LhRH agonists. This paper discusses the evidence that it is an effective adjuvant therapy and defines the place of oophorectomy in the management of such patients. The achievement of an amenhorreic state is important and chemotherapy may well exert some of its effects by causing ovarian suppression. The use of LhRH agonists in managing such patients is discussed.

Purpose. HER-2/neu oncogene expression is modulated by an estrogen-sensitive binding site in the HER-2/neu promoter. Utilizing the circulating antigen of HER-2/neu in serum (sHER-2/neu) as a surrogate marker we investigated whether ovarian ablation by adjuvant therapy leads to an upregulation of HER-2/neu in breast cancer patients. Patients and methods. The analysis was done on sera from premenopausal, node-positive, hormone-receptor positive patients randomized in a multi-center trial. The study was designed with patients receiving either 11.25 mg of leuprorelin s.c. every 3 months over 2 years or CMF chemotherapy for 6 cycles. Sera, available from 80 patients in the leuprorelin arm and from 53 patients in the CMF arm, were collected at 0, 3, 6, 12, 18, 24 and 30 months. sHER-2/neu was measured using a standardized ELISA assay that has an upper limit of normal of 15 ng/ml. sHER-2/neu results were correlated to the levels of LH, FSH and estradiol as indicators of ovarian ablation and to the tumor marker, CA 27.29. Results. During estradiol deprivation, sHER-2/neu levels increased significantly by more than one third from 8.1 ng/ml to 11.0 ng/ml (p < 0.0001) in both treatment arms. The most pronounced relative increase occurred within the first 3 months (p < 0.001). In only 2.7% (16/587) of sHER-2/neu measurements, the sHER-2/neu results were elevated above 15 ng/ml, confirming the upper limit of normal for breast cancer patients irrespective of their menopausal status. At month 30, the sHER-2/neu level started to decrease in the leuprorelin arm, reflecting reversible castration and estradiol reconstitution. Conversely, CA 27.29 levels did not show a trend over time, indicating that sHER-2/neu changes were of a regulatory nature and were not merely a reflection of increasing residual disease. Conclusion. Our study demonstrates the upregulation of HER-2/neu during ovarian ablation. These results are consistent with data showing that the percentage of HER-2/neu positive tumors, evaluated by standardized immunohistochemistry on the primary tumor, is significantly increased during the follicular phase of the menstrual cycle (Balsari et al., Am J Pathol 155: 1543–1547, 1999). Regulatory processes at the HER-2/neu gene should be considered when prescribing specific therapy for breast cancer.

Background Ovarian ablation has been employed in the treatment of breast cancer for many decades and, more recently, its value as an adjuvant treatment for premenopausal women with early-stage disease has been clearly demonstrated. This review examines the different methods of achieving ovarian ablation and assesses the relevance of ovarian suppression as a treatment aim. Methods Medline searches were used to identify recent key articles relating to the adenoma–carcinoma sequence. Further relevant articles were obtained by manual scanning of the reference lists of selected papers. Results and conclusion Ovarian ablation has historically been achieved by surgical or radiological intervention. Although beneficial in premenopausal disease, these methods produce permanent ablation that results in a premature menopause, which may be associated with long-term adverse events. A series of trials have recently demonstrated the benefits of luteinizing hormone releasing hormone (LHRH) agonists, such as goserelin and leuprorelin, as adjuvant treatment for premenopausal hormone-sensitive disease. LHRH agonists produce a reliable suppression of ovarian oestrogen production of equivalent efficacy to adjuvant chemotherapy in hormone-sensitive disease. Effective ovarian suppression is marked by amenorrhoea, but studies have suggested that permanent amenorrhoea is not necessary to confer benefit in the treatment of early breast cancer. LHRH agonists therefore represent a beneficial therapeutic option for premenopausal patients with hormone-sensitive early disease.

During the recently held 8th International Conference on Primary Therapy of Early Breast Cancer, (March 12-15, 2003 St. Gallen/Switzerland) established recommendations for adjuvant endocrine treatment were confirmed, while new options were introduced. Ovarian ablation, limited for 2 years (e. g. Goserelin, combined with 5 years of Tamoxifen), was suggested as an effective treatment option in premenopausal patients with a hormonsensitive breast cancer. The efficacy of this endocrine regimen is equivalent to CMF-chemotherapy in these patients. In "very" young patients with hormonsensitive tumors, chemotherapy alone is not sufficient. These patients will particularly benefit from endocrine treatment. The reversibility of endocrine treatment is its main advantage, avoiding long lasting symptoms of hormone deficiency. In postmenopausal hormonsensitive patients the aromatase inhibitor Anastrozol (Arimidex trade mark ) has been approved as an alternative for patients with contraindications against Tamoxifen (e. g. increased risk of thromboembolism, varicosis, smokers, endometrium changes). The initiation of endocrine should be postponed until the completion of chemotherapy, because combined application reduces the efficacy of adjuvant treatment. "Older" patients will get only limited advantage of chemoendocrine treatment compared to endocrine treatment alone. Preliminary treatment recommendations comprise a wide range of possible treatment options.