Potential Mechanisms of Ovarian Protection with Gonadotropin-Releasing Hormone Agonist in Breast Cancer Patients: A Review

How I perform fertility preservation in breast cancer patients

Chemotherapy-induced premature ovarian insufficiency (POI) is one of the potential drawbacks of chemotherapy use of particular concern for newly diagnosed premenopausal breast cancer patients. Temporary ovarian suppression obtained pharmacologically with the administration of a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy has been specifically developed as a method to counteract chemotherapy-induced gonadotoxicity with the main goal of diminishing the risk of POI. In recent years, important clinical evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients, including women who are not interested in conceiving after treatment or that would not be candidates for fertility preservation strategies because of their age. Nevertheless, in women interested in fertility preservation, this is not an alternative to gamete cryopreservation, which remains as the first option to be offered. In this setting, temporary ovarian suppression with GnRHa during chemotherapy should be also proposed following gamete cryopreservation or to women who have no access, refuse, or have contraindications to surgical fertility preservation techniques. In this article, we present an overview about the role of temporary ovarian suppression with GnRHa during chemotherapy in breast cancer patients by addressing the available clinical evidence with the aim of identifying both the best candidates for the use of this strategy and the still existing gray zones requiring further investigation.

The difficult decision-making process for using or not using adjuvant chemotherapy in premenopausal endocrine-responsive breast cancer patients

Although use of gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is an established strategy to protect ovarian function in premenopausal breast cancer patients, no long-term safety data are available, raising some concerns in women with hormone receptor-positive disease. There are controversial data on its fertility preservation potential. The Prevention of Menopause Induced by Chemotherapy: a Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6 (PROMISE-GIM6) trial is a multicenter, randomized, open-label, phase III superiority trial conducted at 16 Italian centers from October 2003 to January 2008. Eligible patients were randomly assigned to (neo)adjuvant chemotherapy alone (control arm) or combined with the GnRHa triptorelin (GnRHa arm). The primary planned endpoint was incidence of chemotherapy-induced premature ovarian insufficiency. Post hoc endpoints were disease-free survival (DFS), overall survival (OS), and post-treatment pregnancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Of 281 randomly assigned patients, 80.4% had hormone receptor-positive breast cancer. Median follow-up was 12.4 years (interquartile range = 11.3-13.2 years). No differences in 12-year DFS (65.7% [95% CI = 57.0% to 73.1%] in the GnRHa arm vs 69.2% [95% CI = 60.3% to 76.5%] in the control arm; HR = 1.16, 95% CI = 0.76 to 1.77) or in 12-year OS (81.2% [95% CI = 73.6% to 86.8%] in the GnRHa arm vs 81.3% [95% CI = 73.1% to 87.2%] in the control arm; HR = 1.17, 95% CI = 0.67 to 2.03) were observed. In patients with hormone receptor-positive disease, the hazard ratio was 1.02 (95% CI = 0.63 to 1.63) for DFS and 1.12 (95% CI = 0.59 to 2.11) for OS. In the GnRHa and control arms, 9 and 4 patients had a posttreatment pregnancy, respectively (HR = 2.14, 95% CI = 0.66 to 6.92). Final analysis of the PROMISE-GIM6 trial provides reassuring results on the safety of GnRHa use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer, including those with hormone receptor-positive disease.

Despite the wide use of a 3-month gonadotropin-releasing hormone (GnRH) agonist for ovarian function suppression in premenopausal breast cancer patients, it remains unclear whether it is as effective and safe as a 1-month GnRH agonist regimen when combined with selective estrogen receptor modulators or aromatase inhibitors, especially in younger patients. This retrospective cohort study included 1109 premenopausal hormone receptor-positive breast cancer patients treated with GnRH agonist plus selective estrogen receptor modulator or aromatase inhibitor. The estradiol (E2) inhibition rate within 1-24 months after treatment with 1-month or 3-month GnRH agonist in cohorts and different subgroups was analyzed. Following 1:1 propensity score matching, 950 patients with a mean age of 39 years and a median follow-up of 46 months were included. Both the 1-month and 3-month groups achieved more than 90% E2 inhibition within 24 months (94.53% vs 92.84%, with a 95% confidence interval for the difference ranging from -4.78% to 1.41%), confirming the noninferiority of 3-month GnRH agonist. Both 1-month and 3-month GnRH agonist rapidly and consistently reduced E2 levels. Of the patients, 60 (6.3%) experienced incomplete ovarian function suppression, with similar rates in the 1-month and 3-month groups (5.5% vs 7.2%). Incomplete ovarian function suppression mainly occurred within the first 12 months, with age younger than 40 years and no prior chemotherapy being the risk factors. Similar disease-free survival and overall survival were found in the 1-month and 3-month groups and in patients with complete and incomplete ovarian function suppression (P > .05). The ovarian function suppression with 3-month GnRH agonist was not inferior to that with 1-month GnRH agonist, regardless of age or combination with a selective estrogen receptor modulator or an aromatase inhibitor.

Background: Recently, chemotherapy with a GnRH agonist was reported to protect against ovarian failure. This study was aimed at determining the oncologic effect of a GnRH agonist concurrent with chemotherapy for breast cancer patients. Patients and Methods: A total of 1189 patients aged 20 to 40 years with stage I to III breast cancer who received (neo or adjuvant) chemotherapy from five hospitals in Korea from 2002 to 2012 were reviewed. A gonadotropin releasing hormone (GnRH) agonist was given to 410 patients for ovarian protection during chemotherapy (GnRH agonist group), and 779 patients received chemotherapy without ovarian protection (Chemotherapy alone group). A matching strategy was used to create matched sets of two groups by age, stage, hormone receptor status, Her2/neu status, neo or adjuvant chemotherapy, and institute. Results: Survival analysis using Cox regression showed that the GnRH agonist group had better distant metastatic-free survival (HR=0.65, 95%CI 0.44-0.97) outcomes but similar disease free survival (HR=0.78, 95% CI 0.57-1.08) compared with the chemotherapy alone group. The survival benefit was significant for hormone receptor positive, Her2/neu negative breast cancer on distant metastasis (HR=0.44, 95% CI 0.20-0.99) and disease free survival (HR0.47 95% CI 0.23-0.93). Conclusion: Ovarian protection using a GnRH agonist can be safely considered for premenopausal breast cancer patients for whom chemotherapy is planned. Citation Format: Kim HJ, Lee MH, Lee JE, Park SH, Lee ES, Kang Y-J, Lee JH, Shin HN, Kim SI, Im SA, Ahn SH, Lee KS, Sohn J, Han W, Nam SJ. The oncologic effect of a gonadotropin releasing hormone (GnRH) agonist for ovarian protection during breast cancer chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-09.

New insights on the role of luteinizing hormone releasing hormone agonists in premenopausal early breast cancer patients.

Combination of gonadotropin-releasing hormone (GnRH) agonists with GnRH antagonists before chemotherapy reduce but does not completely prevent a follicle-stimulating hormone flare-up

Background: Tamoxifen is a standard endocrine therapy for both pre- and postmenopausal ER-positive breast cancer patients. Patients with ER-positive disease have a long-term risk of distant recurrence, thus, long-term follow-up studies are essential to understand true treatment benefit. Clinically used tumor characteristics are prognostic 5-10 years after primary diagnosis, however, whether these characteristics are predictive of long-term tamoxifen benefit is largely unexplored. Therefore, we aimed to determine the long-term tamoxifen therapy benefit by the clinically used tumor characteristics in pre- vs postmenopausal patients in the Stockholm tamoxifen (STO)-trials with 20-years complete follow-up. Methods: Secondary analysis of 1242 ER-positive/HER2-negative patients from the STO-trials, randomized to at least 2 years of 40 mg tamoxifen vs no endocrine therapy (control). Premenopausal lymph node-positive patients were allocated to chemotherapy as standard of care and postmenopausal high-risk patients were further randomized to chemotherapy vs radiotherapy. Tumor immunohistochemical analysis was recently conducted. Complete 20-year follow-up was obtained from Swedish high-quality registries. Long-term distant recurrence-free interval (DRFI) was assessed by multivariable Cox proportional hazard regression and time-varying analysis using flexible parametric modelling. Results: Premenopausal patients showed significantly improved long-term DRFI from tamoxifen vs control if they were lymph node-negative (Hazard Ratio [HR]=0.46; 95% CI, 0.24-0.87), PR-positive (HR=0.61; 95% CI, 0.41-0.91), or of genomic low risk (HR=0.47; 95% CI, 0.26-0.85), see Table. In postmenopausal patients, significantly improved long-term DRFI from tamoxifen vs control was seen for all good prognosis tumor characteristics, i.e. small tumor size (pT≤20mm: HR=0.55; 95% CI, 0.39-0.77), tumor grade 1-2 (HR=0.55; 95% CI, 0.41-0.73), lymph node-negative (HR=0.44; 95% CI, 0.30-0.64), PR-positive (HR=0.60; 95% CI, 0.44-0.80), Ki-67-low (< 15%: HR=0.51; 95% CI, 0.38-0.68), and genomic low risk (HR=0.53; 95% CI, 0.37-0.74), see Table. Also, postmenopausal patients with large tumor size (pT>20mm: HR=0.64; 95% CI, 0.44-0.94) and PR-negative tumors (HR=0.51; 95% CI, 0.32-0.81) showed significant long-term tamoxifen benefit. Time-varying analysis in premenopausal patients indicated that tamoxifen therapy benefit diminished over time. Significant tamoxifen benefit until year 5, 10, and 15 after primary diagnosis was observed for PR-positive, lymph node-negative, and genomic low-risk patients, respectively. Postmenopausal patients had a significant long-term tamoxifen benefit if they had tumors of small or large tumor size, tumor grade 1-2, lymph node-negative status, PR-positive status, low Ki-67 levels, or genomic low risk. Conclusions: This study suggests a differential long-term tamoxifen therapy benefit in pre- vs postmenopausal patients. Clinically defined low-risk postmenopausal patients have long-term tamoxifen benefit, whereas the benefit is absent or diminish over time for premenopausal patients. Improved long-term prognostic and endocrine therapy predictive markers in premenopausal breast cancer patients with poor prognosis and long life-expectancy is needed, which could involve molecular tools. Long-term tamoxifen benefit in premenopausal and postmenopausal breast cancer patients by the clinically used tumor characteristics. Table Multivariable Cox proportional hazard regression analysis of 20-year distant recurrence-free interval (DRFI) for patients with ER-positive/HER2-negative tumors, comparing patients randomized to tamoxifen vs patients randomized to no endocrine therapy (control). Adjusted for age, randomization year, tumor size, tumor grade, lymph node status, PR status, Ki-67 status, chemotherapy, radiotherapy, and type of surgery. Citation Format: Annelie Johansson, Huma Dar, Anna Nordenskjöld, Gizeh Perez-Tenorio, Christina Yau, Christopher C. Benz, Laura J. Esserman, Laura Van’t Veer, Bo Nordenskjöld, Olle Stål, Tommy Fornander, Linda S. Lindström. Differential Long-Term Benefit from Adjuvant Tamoxifen Therapy in Estrogen Receptor (ER)-Positive/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Premenopausal and Postmenopausal Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-11.

Background: Due to their age and life stage, young women with breast cancer (YWBC) encounter distinct challenges related to their diagnosis and treatment. Unmet parity along with potential premature ovarian insufficiency represent a notable concern among this group of patients. Effective strategies to address this issue include fertility preservation techniques, as well as temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) for ovarian protection during cytotoxic treatments. Here we report a comparative analysis of two prospective studies describing the rates and factors associated with fertility and ovarian function preservation choices in YWBC from two countries. Methods: Women with BC at an age ≤40 years were prospectively accrued in the Joven & Fuerte and PREFER multicenter cohorts in Mexico and Italy, respectively. These studies provide early referrals to fertility and/or ovarian function preservation strategies at diagnosis as needed. This analysis comprised YWBC diagnosed from 2014-2019 whose treatment included chemotherapy (CT) with the objective of identifying their uptake of fertility and ovarian function preservation options. Patients’ characteristics within and across cohorts were compared using chi-squared, Fisher’s exact, and Wilcoxon tests. Simple logistic regression was conducted to calculate the likelihood of undergoing fertility preservation. Results:In total, 485 patients were included: 361 (74%) in Mexico and 124 (26%) in Italy. Median age at diagnosis was 35 years (IQR 32-38) in both cohorts. A higher proportion of Mexican patients had a partner compared to Italian patients (65% vs 59%, p=.04). Patients’ median number of children at diagnosis was also higher in Mexico than in Italy (1 [IQR 0-2] vs 2 [IQR 1-3], p<.001). Patients’ distribution by clinical stage (p<.001), timing of CT (p=.01), hormone receptor status (p=.04), and HER2 status (p=.002) also differed between cohorts: Mexican patients were more frequently diagnosed with stage III BC and received neoadjuvant CT, while Italian patients more commonly had positive hormone receptors or HER2 overexpression. Regarding fertility preservation, a technique was used in 8% and 25% of patients in Mexico and Italy, respectively (p<.001). Methods comprised oocyte (50% in Mexico vs 87% in Italy), embryo (53% vs 0%; this strategy is forbidden by law in Italy), and ovarian tissue cryopreservation (0% vs 16%). GnRHa for ovarian protection were used in nearly all Italian patients (98%) but in a minority of Mexican patients (6%). Not undergoing fertility preservation was mainly due to lack of interest (47-50%), urgency to start treatment (4-6%), and personal reasons (3-5%). Fertility preservation uptake was associated with younger age (OR 1.2, 95%CI 1.1-1.2), unpartnered status (OR 3.4, 95%CI 1.9-5.9), childlessness (OR 21.8, 95%CI 10.0-47.6), private healthcare coverage in Mexico (OR 3.0, 95%CI 1.1-8.1), stage I-II BC (OR 3.1, 95%CI 1.5-6.3), positive hormone receptors (OR 2.3, 95%CI 1.2-4.6), and adjuvant CT (OR 2.4, 95%CI 1.4-4.3). Conclusions: This comparative analysis of two prospective studies in Mexico and Italy showed that a significant distinct proportion of YWBC had access to the available fertility and ovarian function preservation techniques in these countries, possibly reflecting the different social and healthcare contexts. Although all women should receive a complete oncofertility counseling, patients who are younger, unpartnered, childless, and have earlier-stage BC appear to be those who particularly benefit from being offered fertility preservation options. This study underscores the need to enhance awareness and access to oncofertility services in order to provide comprehensive, patient-centered care to this young population. Citation Format: Fernanda Mesa-Chavez, Maria Grazia Razeti, Eva Blondeaux, Alejandra Platas, Virginia Delucchi, Alan Fonseca, Valeria Fontana, Marlid Cruz-Ramos, Paola Anserini, Manuel Rolando García Garza, Edoardo Chiappe, Alejandro Mohar, Laura Orlando, Enrique Bargallo-Rocha, Saverio Cinieri, Lucia Del Mastro, Cynthia Villarreal-Garza, Matteo Lambertini. Fertility and ovarian function preservation in young women with breast cancer: A comparative analysis of two prospective cohort studies in Mexico and Italy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-02.

269P - The Relationship Between Serum E2 Level and Recurrence During Endocrine Therapy for Er Positive Pre-Menopausal Early Breast Cancer Patients

1551PD - Role of Temporary Ovarian Suppression Obtained with GNRH Analog in Reducing Premature Ovarian Failure (POF) Induced By Chemotherapy in Premenopausal Cancer Patients: a Meta-Analysis of Randomized Studies

Purpose: In hormone therapy for premenopausal breast cancer (BC), gonadotropin-releasing hormone (GnRH) agonist (GnRHa) formulations, especially long-acting formulations, are often used in combination with tamoxifen (TAM). On the other hand, in recent years, endocrine therapy is increasingly interrupted to achieve pregnancy. Here, we examined ovarian function and the timing of resumption of menstruation after the interruption of GnRHa therapy. Methods: Fertility preservation patients with BC who visited our hospital between January 2010 and August 2023 and who interrupted endocrine therapy with a GnRHa formulation were included. Information on 22 cases (24 cycles), including two interruptions due to the desire for a second child, was collected from medical records and examined retrospectively. Results: Three cases started assisted reproductive technologytreatments before menstruation resumed and were excluded from the analysis. Menstruation resumed at approximately 7, 9, and 12 months from the last dose of the 1-, 3-, and 6-month GnRHa formulations, respectively. The long delay of menstruation resumption was presumably caused by the use of (1) the 3-month formulation in the 6 months before the last GnRHa dose, (2) the 6-month formulation in the 12 months before the last dose, and (3) TAM when menstruation resumed. Conclusions: In BC patients who may seek pregnancy after interrupting endocrine therapy, it may be easier to estimate the timing of resumption of menstruation if the use of long-term GnRHa depot formulations is avoided for >6 months before the interruption. BC endocrine therapy should be optimized to achieve pregnancy and childbirth as soon as possible during its interruption.

Study question How (neo)adjuvant chemotherapy and concurrent administration of luteinizing hormone-releasing hormone agonist (LHRHa) affect Anti-Mullerian hormone (AMH) and estradiol level dynamics in premenopausal breast cancer patients. Summary answer Breast cancer chemotherapy has a major negative impact on patients’ ovarian function and reserve. Women receiving LHRHa showed higher probability of long-term ovarian function recovery. What is known already The risk of developing treatment-induced premature ovarian insufficiency (POI) and infertility following chemotherapy is among the most important concern in premenopausal breast cancer patients. AMH is a promising biomarker for assessing treatment-induced gonadotoxicity in patients receiving anticancer therapies. Concurrent administration of LHRHa with chemotherapy is associated with a lower risk of treatment-induced ovarian failure and higher rates of menstrual function recovery. However, data on the impact of LHRHa during chemotherapy on patients’ ovarian reserve are still insufficient. Study design, size, duration Between 2003 and 2008, the PROMISE-GIM6 trial randomized 281 premenopausal early breast cancer women to receive chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). Primary endpoints were incidence of early menopause and long-term ovarian function. For exploratory purposes in a subset of patients, AMH and estradiol levels were measured at baseline, <3 months after last cycle of chemotherapy, 1 year after last cycle of chemotherapy, and at the end of adjuvant endocrine treatment. Participants/materials, setting, methods The main results of the trial showed that use of concurrent LHRHa significantly reduced the risk of early menopause, increased the chances of long-term ovarian function recovery and did not influence survival outcomes (JAMA 2011, JAMA 2015, JNCI 2022). The present exploratory analysis reports on dynamics of ovarian biomarkers (AMH and estradiol) at baseline and following (neo)adjuvant chemotherapy. Main results and the role of chance Out of 281 enrolled patients, 48 enrolled at the coordinating centers had at least one measurement of AMH and estradiol levels at baseline and after (neo)adjuvant chemotherapy. Baseline patient characteristics were similar between treatment arms, with median age being 41 and 39 years, and median AMH levels being 3.9 and 4.9 mcg/L in the control and LHRHa groups, respectively. In the overall population, estradiol levels showed a significant decrease at the end of chemotherapy, a significant increase after one year, and a return to baseline values at the end of endocrine therapy. By contrast, AMH levels showed a constant decrease over time. As compared to patients in the control group, those in the LHRHa group had a significant reduction in the risk of early menopause (p = 0.02) and significantly higher estradiol levels at the end of chemotherapy and 1 year after chemotherapy (p < 0.001), suggesting a higher probability of ovarian function recovery. By contrast, no significant differences were observed in the AMH level dynamics between patients receiving LHRHa and those who did not. Limitations, reasons for caution Relatively small number of included patients (n = 48) and small number of patients with AMH and estradiol levels determined at each timepoint. Wider implications of the findings This biomarker analysis within a phase III randomized trial confirmed that patients receiving LHRHa had a higher probability of ovarian function recovery also supported by estradiol dynamics. However, both patients in the LHRHa and control group showed a major decline in AMH levels after chemotherapy that persisted over time. Trial registration number NCT00311636

Aromatase inhibitor (AI) combined with Gonadotropin-releasing hormone agonist (GnRH-a) have been recognized as an effective approach to adjuvant endocrinotherapy for breast cancer (BC) in premenopausal patients with adverse predictive factors. However, the risk of non-optimal suppression of the ovaries due to the mechanism of action of aromatase inhibitors has been proven. Recently published SOFT-EST studies showed that the blood estradiol (E2) level in 37% of patients was above the level that was permissible for the purpose of this group of drugs. And although today there is no enough scientific justification to interpret this result, the introduction of aromatase inhibitors in adjuvant therapy in young women requires the search for tactics to reduce the risk of mediated increase in estradiol against the background of such therapy. Alertness occurs when the E2 serum level exceeds the menopause limit by the time the aromatase inhibitors are prescribed. Objective of the study. Determine the tactics for minimizing the risk of increasing estradiol against the background of aromatase inhibitors in combination with GnRH-a in adjuvant therapy for breast cancer in premenopausal patients. Material and methods. 47 patients of ≤ 50 years old with GR + HER2- Stages I-III Breast Cancer and a regular menstrual cycle before the start of neo-/adjuvant chemotherapy were studied. E2 and FSH levels were assessed at the stage prior to chemotherapy and immediately prior to administering adjuvant endocrinotherapy. After the completion of chemotherapy, only 7 out of 47 women had the menstrual cycle - patients without clinical and biochemical suppression of ovarian function (SOF). 86% of cases had cytostatic amenorrhea (n = 40), of which 23 cases (58%) showed that this condition was not combined with the biochemical response of sex hormones, i.e. there was no biochemical SOF. Thus, the study group included 30 patients, who were supposed to be treated with aromatase inhibitors + GnRH analogues, and had no clinical or biochemical menopause by the time adjuvant endocrinotherapy was prescribed. In order to reduce the risk of mediated increase in estradiol, even with pharmaceutical “switching off” ovarian function, the patients were prescribed the GnRH analogue (Buserelin Depot) before starting aromatase inhibitors therapy. Results and conclusion. A progressive decrease in E2 level was determined after each subsequent administration of Buserelin Depot. The median values remained low only after the third injection. Following the chemotherapy, a decrease in estradiol was accompanied by a physiological increase in the FSH levels in 73% of women. The administration of Buserelin Depot led to a significant decrease in FSH median (p <0.01) in 90% of patients. Aromatase inhibitors and continuing GnRH-a were prescribed to 97% of patients. The results indicate that the achievement of ovarian function suppression prior to the administration of IA, can be considered as a reliable tactics for adjuvant endocrinotherapy in patients of reproductive age. The dynamic assessment of reproductive hormones (E2, FSH) is recognized useful when choosing or correcting therapy in such patients.