Ovarian Suppression Research Articles

Clinical Management of Ovarian Function Suppression in Premenopausal Women With Breast Cancer: A Survey of Members of ASCO.

Ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHas) is a standard of care for premenopausal patients with high-risk stage II/III hormone receptor-positive breast cancer (BC). Practical guidance on the optimal choice of GnRHa, timing, schedule, and monitoring is limited. Our aim was to determine how oncologists use OFS in routine care. We designed a questionnaire to determine the choice of GnRHa, schedule, duration, initiation, use of bone modifiers, and monitoring of estradiol (E2). The questionnaire was sent to oncologists treating BC, in practice for >1 year and participating in the ASCO Research Survey Pool (RSP). It was also forwarded by investigators to oncologists meeting these criteria. The survey was open between November 14, 2023, and January 5, 2024. Of 996 oncologists participating in the ASCO RSP, 178 (18%) completed the survey. An additional 56 oncologists contacted by investigators responded. Respondents were from the United States (57%), Asia (15%), and Europe (14%). Goserelin (54%) and leuprolide (39%) were the most frequently used GnRHas and were administered once every month by 46%. Approaches to starting GnRHas were varied. Most continued them for the duration of aromatase inhibitor therapy (57%). Estradiol monitoring was performed regularly, sometimes, or never by 43%, 27%, and 27%, respectively. The E2 assays used were standard (65%), ultrasensitive (16%), and unknown (14%). Interpreting E2 assay results were considered difficult by 55%; however, 62% of oncologists changed treatment on the basis of them. A total of 92% of respondents would like ASCO guidance on the practical use of OFS. Considerable practice variation exists for similar clinical scenarios in OFS administration. Respondents would welcome ASCO guidance on all aspects of OFS.

Radiation-induced Ovarian Ablation and Survival in Breast Cancer: A Single-Institutional Evaluation

ABSTRACT Background: Radiation-induced ovarian ablation (ROA) was one of the main modalities in the early years in inducing suppression of hormone levels of estradiol (E2) and follicle-stimulating hormones (FSHs) in estrogen receptor/progesterone receptor-positive breast cancer patients. However, as newer techniques such as medical ovarian suppression (MOS) and laparoscopic oophorectomies (LOs) emerged, ROA began to take a back seat. Nonetheless, ROA remains a valuable option for certain patients with specific indications. It is worth noting that ROA is still as effective as MOS and LO in achieving desired hormonal suppression levels. Materials and Methods: After receiving approval from the institutional ethics committee, we enrolled 41 female breast cancer patients who were scheduled for ROA at our institute between 2016 and 2018. Two patients declined to participate and were, therefore, excluded from the final analysis. Patients were evaluated for pre- and postradiation hormone levels, specifically E2 and FSH, cessation of menstrual periods, radiation-induced toxicity, disease-free survival (DFS), overall survival (OS), and the clinical profile as well. Results: Among 39 patients, 89.74% (n = 35) achieved postmenopausal hormone levels after ROA. Only 17.94% (n = 7) patients were menstruating before radiation exposure to the pelvis (postchemotherapy) and among these, 3 patients (42.85%) attained amenorrhea after ROA. The mean age of patients was 42 years, and the most common stage at presentation was Stage III (n = 15) 38.5%. Her2 positivity was seen in (n = 11) 28.2%. Breast conservation surgery was done in 64.1% (n = 25) and mastectomy was done in 23.1% (n = 9). About 71.7% (n = 28) have received tamoxifen, 43.5% (n = 17) were on letrozole, and 17.9% (n = 7) have received trastuzumab. None had shown any Grade 3 or 4 acute skin toxicity during treatment and late radiation-induced complications during their follow-up. The mean 5-year DFS was 62.2% and the mean 5-year OS was 59%. Conclusion: ROA is not widely used anymore due to its irreversible nature, and there are now reversible and noninvasive methods for ovarian suppression. Observing the effectiveness of ROA, it may still be an option for a selective group of breast cancer patients especially those who have contraindications for MOS or are willing for a short course of treatment.

Hormonal suppression in premenopausal patients with estrogen receptor-positive breast cancer: a randomized trial comparing monthly versus trimonthly GnRH analogs

Background: Currently the standard of care for premenopausal women with estrogen receptor-positive breast cancer is the combined use of a gonadotropin-releasing hormone (GnRH) analog with either tamoxifen or an aromatase inhibitor in patients at high risk for relapse or when it is deemed necessary to optimize ovarian function suppression. Monthly GnRH analogs have been used for years but, recently, longer-acting formulations have been gaining approval. Yet, there is still a gap of evidence regarding the use of longer-acting formulations; only a few studies exist that examine their efficacy in breast cancer and compare them to the monthly formulations. It is the investigators’ hypothesis that trimonthly injections, which are more convenient for the patient and ensure better compliance, are better suited for use in breast cancer patients and may induce equally effective estrogen suppression as the monthly injections. Aim: A comparison of trimonthly versus monthly GnRH analogs in eliciting ovarian function suppression in premenopausal patients with estrogen receptor-positive breast cancer. Methodology: This is a prospective randomized open-label trial involving 25 premenopausal patients that were randomized to receive either a monthly or a trimonthly GnRH analog. Estrogen (E2) levels, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured on day 0 and on week 12. Patients, also, completed a questionnaire regarding exhibiting amenorrhea and other side-effects of the analogs. Results: All patients (N=25; 100%) from both groups achieved ovarian function suppression according to the criteria set by the researchers, which are E2 levels <30 pg/mL and amenorrhea. Both groups exhibited a statistically significant decrease (almost by 50%) in E2 levels by week 12 (monthly group: E2 levels’ decrease equal to -18.5 pg/mL, p=0.00293; trimonthly group: E2 levels’ decrease equal to -13.9 pg/mL, p=0.0002441). On the contrary, FSH and LH levels did not show a statistically significant difference in either group. Moreover, when the two groups were compared, there was no statistically significant difference in the variation of all hormone levels between day 0 and week 12. All patients developed amenorrhea. There were no statistically significant differences in the number of side-effects between the two groups, even though the trimonthly group had fewer (in absolute number) side-effects than the monthly. Conclusion: This study demonstrates that the trimonthly formulations of GnRH analogs are equally effective in eliciting ovarian function suppression and present a similar percentage of side-effects as the monthly formulations, with the added benefit that patients need not undergo monthly injections.

Active symptom monitoring for premenopausal women with breast cancer initiating adjuvant endocrine therapy: Protocol for the SWOG S2010 randomized controlled efficacy trial

BackgroundPremenopausal women with early stage, high risk hormone receptor positive breast cancer are at risk of early discontinuation of adjuvant endocrine therapy (ET), primarily because of toxicity, which can increase the risk of disease recurrence and death. We hypothesize that identification of bothersome symptoms between clinic visits, and automated notification of clinicians about symptoms, will result in improved persistence with ET. MethodsPre- and perimenopausal women planning to receive adjuvant treatment with tamoxifen or an aromatase inhibitor plus ovarian function suppression or ablation for treatment of breast cancer are eligible. A total of 540 participants will be enrolled and randomized 1:1 to patient education with or without Active Symptom Monitoring (ASM). The ASM intervention includes 6 symptom questions (hot flashes, sadness, anxiety, insomnia, vaginal dryness, joint pain) that will be completed via text, email, or telephone weekly for 24 weeks, then every 4 weeks for 48 weeks. All participants will complete a battery of questionnaires every 12 weeks to examine symptoms, beliefs about medicine, self-efficacy, and ET adherence. Optional blood draws will be collected at baseline and after 12, 48, and 72 weeks of therapy to examine estradiol and ET concentrations. The primary endpoint is time to nonpersistence with initially prescribed ET within the first 72 weeks, evaluated using Kaplan-Meier plots and multivariable Cox regression. ConclusionWe expect early identification and management of ET-related toxicities to improve persistence with breast cancer therapy, breast cancer outcomes, and quality of life for premenopausal women at high risk of breast cancer recurrence.Clinicaltrials.govNCT05568472

7701 Comparative Analysis of Dried Blood Spot and Serum ELISAs for AMH, FSH, and LH in Patients Seeking IVF Treatment

Abstract Disclosure: T. Kumar: None. R. Chauhan: None. B. Kalra: None. A.S. Patel: None. S. Chauhan: None. A. Kumar: None. Relevance: Dried Blood Spot (DBS) technology has not been widely implemented in the diagnostic industry due to its limitations in obtaining reliable, quantitative data from small blood samples. However, recent advancements in methods, i.e., sensitive antibodies, homogeneous and reproducible paper quality, and painless needles have renewed the interest in the DBS collection technique. Objective: The aim of the study is to validate the hormone measurements using DBS technology and compare the correlation matrix between AMH, LH, FSH, inhibin B, Antral Follicle Counts (AFC), age, and BMI in patients seeking infertility workup. Materials and Methods: Matched serum and DBS samples from thirty-nine patients between the ages of 18 and 45 years were collected on day 3 of the cycle. The subjects were visiting the clinic for initial fertility workup and subjects on medications for ovarian suppression were excluded. The samples were tested on Ansh Labs DBS AMH (AL-129), FSH (AL-187), and LH (AL-190), PCOCheck AMH (N-N terminus, AL-196), picoAMH (C-N terminus, AL-124-r), US Inhibin B (AL-195) ELISAs. Baseline AFC obtained via transvaginal ultrasound, BMI, and age were collected. Spearman’s correlations, and regression analysis using Passing and Bablok were calculated to examine the relationship between AFC, AMH, inhibin B, FSH LH, age, and BMI. Results: DBS samples were highly correlated to their matched serum specimens. The slope and Spearman’s rank correlation (rs) between matched serum and DBS specimens for AMH, FSH, and LH were 1.17x, 1.07x, 1.07x, and 0.98, 0.93, and 0.97, respectively. DBS AMH strongly correlated with AFC. The Spearman’s rank correlation (rs) between AFC and DBS AMH, DBS LH, and DBS FSH were 0.80, -0.11, and -0.31, respectively. A strong correlation was observed between age and AMH, LH and FSH. A weak correlation was observed between BMI and AMH, LH and FSH. The Spearman’s rank correlation (rs) between age and DBS AMH, LH, and FSH were -0.34, 0.28, and 0.25, respectively. DBS AMH, LH, and FSH correlation with BMI were -0.06, 0.05, and 0.09, respectively. Inhibin B had a strong correlation to age (rs -0.33), BMI (rs -0.67), AFC (rs 0.44), DBS AMH (rs 0.40), DBS FSH (rs -0.19), DBS LH (rs-0.11), respectively. AMH method comparison between N-N and N-C terminal ELISA using 39 serum samples yielded slopes of 0.85x and Spearman’s rank correlation of 0.97. Conclusions: DBS and serum measurements for AMH, LH, and FSH are very accurate and precise. They can be used interchangeably. The strong relationship between BMI and Inhibin B will require further investigation and may open new avenues in obesity and reproductive endocrinology. Presentation: 6/1/2024

Updates in Systemic Treatment of Hormone Receptor-Positive Early-Stage Breast Cancer.

Hormone-receptor positive (HR +) and human epidermal growth factor receptor 2 (HER2) negative early breast cancer (eBC) is a heterogeneous disease with several contributing factors for increased risk of recurrence, including tumor features, individual biomarkers, and genomic risk. The current standard approach in the management of HR + /HER2neg eBC includes chemotherapy and endocrine therapy (ET), and additional therapies based on risk profile, menopausal status, and genetics are sometimes appropriate. The risk of recurrence is more pronounced in patients with high-risk eBC including large tumor size, nodal involvement, high proliferative index, and genetic predisposition. In premenopausal patients with high-risk eBC, ovarian function suppression in combination with adjuvant ET improves survival. In postmenopausal patients, extended aromatase inhibitor (AI) therapy can be considered. Recent trials have identified novel treatment approaches to reduce the risk of recurrence in high-risk HR + /HER2neg eBC including the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to adjuvant ET. For patients with germline BRCA1/BRCA2 mutations, adjuvant poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have been shown to improve overall survival (OS). However, despite these recent advances, the risk of recurrence remains substantial, highlighting an area of unmet need. There are several ongoing clinical trials further investigating the role of CDK 4/6 inhibitors and immunotherapy in high-risk HR + /HER2neg eBC.

Cardiovascular Disease With Hormone Therapy and Ovarian Suppression in Premenopausal Breast Cancer Survivors

Cardiovascular Disease With Hormone Therapy and Ovarian Suppression in Premenopausal Breast Cancer Survivors

A pioneer of hormonal contraception: Joseph W. Goldzieher.

On 19 July, 2024, at the age of almost 105 years, Joseph W. Goldzieher, the last survivor of the group of pioneers who created oral contraception, peacefully passed away. Here we briefly reconstruct the salient points in his long, productive life, and highlight his achievements in the development of hormonal contraception. His work is indissolubly enshrined in the complex history of hormonal contraception, from the first, fundamental observations, to the first clinical trials, both in the form of combined oestrogen-progestin oral pills and long-acting injectable contraceptives. After Pincus and his Group created an oral contraceptive containing an oestrogen and a progestin, Goldzieher was the second international scientist to conduct clinical trials of the new modality. He teamed-up with investigators in Mexico creating a fruitful, long-lasting collaboration. They produced evidence that ovulation inhibition could be achieved with all the progestins used at the time. Of importance, he was among the first to explore the possibility of using oestrogens to block ovulation, and developed the concept of sequential contraception. For all this lifetime of work, we believe he deserves to be named a 'giant in reproductive endocrinology'.

Correction to: Empowerment-Led Guided Self-Help Intervention for Symptom Burden in Breast Cancer Women Treated With Ovarian Function Suppression: A Randomized Trial Protocol

Correction to: Empowerment-Led Guided Self-Help Intervention for Symptom Burden in Breast Cancer Women Treated With Ovarian Function Suppression: A Randomized Trial Protocol

Treatment patterns of goserelin 3.6 mg once monthly and 10.8 mg every three months in women with breast cancer: A real-world analysis.

391 Background: Goserelin is a gonadotropin-releasing hormone agonist used for ovarian function suppression in the treatment of pre- and peri-menopausal patients with breast cancer. Goserelin, administered as a subcutaneous implant, is available in doses of 3.6 mg once monthly or 10.8 mg every three months; goserelin 3.6 mg is approved in the US, and both the 3.6 mg and 10.8 mg doses are approved by Health Canada and the European Medicines Agency. A study utilizing US real-world evidence was conducted to characterize treatment patterns of patients treated with goserelin 3.6 mg and/or 10.8 mg. Methods: Electronic health record data of adult patients with a history of breast cancer and with ≥2 prescriptions of goserelin between 1 January 2017 – 31 December 2022 were identified through TriNetX. Index date was the initiation of goserelin administration. Patients were followed until 15 March 2024. Patient demographics, treatment adherence, and healthcare resource utilization (HCRU) were examined and summarized using descriptive analytics. Results: Overall, 3,620 patients were identified: 2,870 treated with goserelin 3.6 mg, 410 with goserelin 10.8 mg, and 340 who switched from goserelin 3.6 mg to 10.8 mg. Peak utilization of goserelin 10.8 mg (36.6%) and peak dosage switching (26.5%) occurred in 2020. Across groups, mean age at index date was 42.2–44.4 years, and patients were white (64.1–67.6%), black (11.8%–13.9%), Asian (8.0%–11.8%), and American Indian and/or Alaskan native (0.3%–2.9%). Of patients with known BMI, BMI mostly ranged between 18.5–24.9 kg/m 2 in all groups. Patients who switched from goserelin 3.6 mg to 10.8 mg had the longest median treatment duration (776 days) (Table). Patients treated with goserelin 10.8 mg remained on treatment for a median of 426 days; 74.4% of these patients were treatment-adherent (Table). In comparison, patients treated with goserelin 3.6 mg had a shorter median treatment duration (226 days) and were less adherent (56.4%) (Table). HCRU during the 12 months after index date was broadly similar across groups. Conclusions: Treatment with goserelin 10.8 mg every three months is associated with greater adherence and longer treatment duration, compared with 3.6 mg once monthly, in patients with a history of breast cancer. Patients who switched from goserelin 3.6 mg to 10.8 mg were treatment-adherent for nearly two years, consistent with clinical recommendations. Goserelin 3.6 mg (n = 2,870) Goserelin 10.8 mg (n = 410) Switched from goserelin 3.6 mg to 10.8 mg (n = 340) Median duration of treatment (days) 264 429 776 Median time to switch (days) — — 218 Patients adherent* to dosing schedule 1,608 (56.4%) 306 (74.4%) — Status as of March 15, 2024 Discontinued goserelin 2,018 (70.8%) 261 (64.3%) 173 (50.9%) Death 88 (3.1%) 10 (2.5%) 3 (0.9%) *Defined as: ≤36 days between prescriptions (3.6 mg) or ≤108 days between prescriptions (10.8 mg).

Patient-reported outcome and survival in premenopausal hormone receptor-positive breast cancer patients at moderate to high risk: comparing toremifene with aromatase inhibitor in a real-world study.

Toremifene, a selective estrogen receptor modulator, is commonly used in China for premenopausal breast cancer patients. This real-world study aimed to compare patient-reported outcome (PRO) and survival between toremifene and aromatase inhibitor (AI) plus ovarian function suppression (OFS) in patients with moderate-/high-risk premenopausal hormone receptor (HR)-positive breast cancer. The primary endpoint was PROs, assessed using SF-36 and EQ-5D-5L questionnaires between January and March 2023. A total of 392 patients were included, with 171 receiving toremifene and 221 receiving AI. The toremifene group showed significantly higher scores in the role physical (p=0.034) and mental health (p=0.009) dimensions of SF-36 and lower anxiety/depression (AD) scores (p=0.038) in EQ-5D-5L compared to AI group. The estimated 5- and 8-year disease-free survival (DFS) rates were similar in toremifene and AI groups: 96.5% versus 91.9%, and 87.4% versus 87.8% (p=0.39), respectively. Adverse event rates were similar in two groups, except for a greater risk of endometrial thickening (p<0.001) and a lower occurrence of morning stiffness (p<0.001) in the toremifene compared to the AI group. Premenopausal HR-positive breast cancer patients receiving toremifene plus OFS had better role physical and mental health outcomes and lower AD dimensions than those receiving AI plus OFS. Both treatments had comparable DFS and favorable tolerability profiles.

233MO Ovarian function suppression in HR-positive, HER2-positive breast cancer: An exploratory analysis from the HERA trial

233MO Ovarian function suppression in HR-positive, HER2-positive breast cancer: An exploratory analysis from the HERA trial

The Impact of Adenomyosis on Pregnancy.

Adenomyosis is characterized by ectopic proliferation of endometrial tissue within the myometrium. Histologically, this condition is marked by the presence of islands of benign endometrial glands surrounded by stromal cells. The myometrium appears thinner, and cross-sectional analysis often reveals signs of recent or chronic hemorrhage. The ectopic endometrial tissue may respond to ovarian hormonal stimulation, exhibiting proliferative or secretory changes during the menstrual cycle, potentially leading to bleeding, uterine swelling, and pain. Adenomyosis can appear as either a diffuse or focal condition. It is crucial to understand that adenomyosis involves the infiltration of the endometrium into the myometrium, rather than its displacement. The surgical management of adenomyosis is contingent upon its anatomical extent. The high incidence of the disease and the myths that develop around it increase the need to study its characteristics and its association with pregnancy and potential obstetric complications. These complications often require quick decisions, appropriate diagnosis, and proper counseling. Therefore, knowing the possible risks associated with adenomyosis is key to decision making. Pregnancy has a positive effect on adenomyosis and its painful symptoms. This improvement is not only due to the inhibition of ovulation, which inhibits the bleeding of adenomyotic tissue, but also to the metabolic, hormonal, immunological, and angiogenic changes associated with pregnancy. Adenomyosis affects pregnancy through disturbances of the endocrine system and the body's immune response at both local and systemic levels. It leads to bleeding from the adenomyotic tissue, molecular and functional abnormalities of the ectopic endometrium, abnormal placentation, and destruction of the adenomyotic tissue due to changes in the hormonal environment that characterizes pregnancy. Some of the obstetric complications that occur in women with adenomyosis in pregnancy include miscarriage, preterm delivery, placenta previa, low birth weight for gestational age, obstetric hemorrhage, and the need for cesarean section. These complications are an understudied field and remain unknown to the majority of obstetricians. These pathological conditions pose challenges to both the typical progression of pregnancy and the smooth conduct of labor in affected women. Further multicenter studies are imperative to validate the most suitable method for concluding labor following surgical intervention for adenomyosis.

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Monitoring of estradiol levels in premenopausal women receiving adjuvant abemaciclib and ovarian function suppression.

Approximately 15% of women who receive ovarian function suppression (OFS) as adjuvant treatment for high-risk, localized hormone receptor-positive (HR+) breast cancer may have inadequate estradiol suppression which can require therapeutic modification when used in combination with an aromatase inhibitor (AI). We previously reported that abemaciclib may interfere with the estradiol Abbott Alinity chemiluminescent microparticle immunoassay (CMIA) commonly used to monitor estradiol levels and suggested liquid chromatography-mass spectrometry (LC-MS/MS) is preferred in this setting. The aim of this study was to determine discrepancies in estradiol levels using CMIA compared to LC-MS/MS and subsequent treatment changes in a larger patient population. We conducted a retrospective review of premenopausal women with early-stage HR+ breast cancer at our institution who received adjuvant OFS and abemaciclib with at least 1 CMIA estradiol level drawn during abemaciclib therapy from October 2021 to April 2023. Of the 22 women who met criteria for review, 20 (90.9%) had CMIA estradiol levels in the premenopausal range, of whom 9 also had estradiol measured by LC-MS/MS. All 9 women receiving OFS and abemaciclib with estradiol measurements by both methods had premenopausal range CMIA estradiol levels and postmenopausal range LC-MS/MS estradiol levels. Of the 20 patients with premenopausal estradiol levels by CMIA estradiol, treatment changes included increased OFS dosage or preparation (n = 7), change from AI to tamoxifen (n = 3), and surgical oophorectomy (n = 7). Our findings suggest the likely interference of abemaciclib with the Abbott Alinity immunoassay which may lead to unnecessary treatment changes. It is recommended that the LC-MS/MS assay be used when monitoring estradiol levels in patients receiving abemaciclib concurrently with OFS.

Estrogen levels in young women with hormone receptor-positive breast cancer on ovarian function suppression therapy

Ovarian function suppression (OFS) benefits young women with hormone receptor (HR)-positive breast cancer but they are at risk for ovarian function breakthrough. We assessed endocrine effects of gonadotropin-releasing hormone agonist (GnRHa) treatment in a prospective cohort of patients aged ≤ 40 years with HR-positive breast cancer. Plasma estradiol (E2), estrone, and follicule-stimulating hormone (FSH) levels were measured from blood samples drawn 1 and 4 years after diagnosis. Patient characteristics, invasive breast cancer-free survival (iBCFS), and overall survival (OS) were compared between those with and without E2 > 2.72 pg/mL during GnRHa treatment. Among eligible patients, 54.7% (46/84) and 60% (15/25) had E2 > 2.72 pg/mL at 1 and 4 years, respectively. Factors associated with E2 > 2.72 pg/mL at 1 year were no prior chemotherapy (P = 0.045) and tamoxifen use (P = 0.009). After a median follow-up of 7 years, among patients with stage I-III breast cancer (N = 74), iBCFS events were seen in 6 (8.1%) with E2 > 2.72 pg/mL and 5 (6.8%) with E2 ≤ 2.72 pg/mL (P = 0.893). Among patients with de novo metastatic breast cancer (N = 12), 6 (50%) with E2 > 2.72 pg/mL and 3 (25%) with E2 ≤ 2.72 pg/mL died during follow-up (P = 0.052). Larger studies exploring the clinical implications of incomplete E2 suppression by GnRHa are needed to ensure optimal OFS treatment strategies are being employed for this population.

An Overview of Long-Acting GnRH Agonists in Premenopausal Breast Cancer Patients: Survivorship Challenges and Management.

Managing breast cancer in premenopausal women poses unique challenges due to its considerable effect on both morbidity and mortality. Goserelin, a gonadotropin-releasing hormone agonist, has emerged among the various modalities as a preferred option for ovarian function suppression, owing to its efficacy in reducing ovarian estrogen production in premenopausal women with hormone receptor-positive breast cancer. Recent studies have affirmed the efficacy and safety of long-acting (LA) goserelin 10.8 mg every 12 weeks, offering comparable outcomes to monthly injections. This flexibility enables personalized treatment approaches, potentially enhancing patient satisfaction. Off-label utilization of goserelin LA surged during the coronavirus disease pandemic, prompting initiatives to broaden its use for breast cancer treatment. Switching to goserelin LA can streamline treatment, boost adherence, and optimize resource utilization. With the recent approval of goserelin 10.8 mg LA by Health Canada on 6 May 2024, for use in breast cancer, Canada is the latest to join over 60 countries worldwide to expand the accepted indications for goserelin LA and ensure its availability to potentially enhance healthcare delivery, patient care, and breast cancer outcomes. Goserelin LA offers premenopausal patients a means to more effectively manage the constraints imposed by breast cancer treatment and its impact on survivorship.

Adjuvant endocrine therapy choices in premenopausal patients with hormone receptor-positive early breast cancer: Insights from the prospective GIM23-POSTER study

BackgroundMost premenopausal patients with early breast cancer (eBC) are diagnosed with hormone receptor-positive disease and therefore candidate for adjuvant endocrine therapy (ET). Patients and methodsThe Gruppo Italiano Mammella (GIM) 23-POSTER (GIM23) is a multicenter, prospective, observational study conducted in 26 Italian institutions, aiming to evaluate ET choices for premenopausal patients affected by hormone receptor-positive eBC in a real-world setting. Here we report also the results in terms of type of ET prescribed according to the definition of high-risk patients by monarchE and NATALEE trials. ResultsBetween October 2019 and June 2022, 600 premenopausal patients were included, with a median age of 46 years. Almost half (271, 45.2 %) of the patients had stage I disease, while 254 (42.3 %) and 60 (10.0 %) patients had stage II and III, respectively. Overall, 149 (25.1 %) patients received tamoxifen alone, 83 (14.0 %) tamoxifen with ovarian function suppression (OFS), while 361 (60.9 %) received aromatase inhibitor (AI) with OFS. Patients treated with AI and OFS had higher number of metastatic axillary nodes, higher grade and more often received chemotherapy (all p < 0.001). According to the inclusion criteria of the monarchE and NATALEE trials, 81 patients (15.6 %) were considered high-risk for the monarchE and received AI with OFS in 88.9 % of the cases, while 231 patients (44.4 %) were considered high-risk for the NATALEE trial and received AI with OFS in 74.5 % of cases. ConclusionsAI with OFS is the most prescribed adjuvant ET among premenopausal patients, especially in the presence of high-risk features.

The cardiovascular and metabolic effects of ovarian suppression in combination with tamoxifen or an aromatase inhibitor as adjuvant therapy for early estrogen receptor-positive breast cancer: a systematic review

Adjuvant endocrine therapy is a key treatment in oestrogen receptor positive early breast cancer (BC). For premenopausal women ovarian function suppression (OFS) in combination either tamoxifen or aromatase inhibitor (AI) is utilised in high-risk cases. The resultant suppression of circulating oestradiol from OFS could have adverse cardiovascular and metabolic effects, subsequently increasing the risk of cardiovascular disease. Our study highlights the potential cardio-metabolic impact endocrine therapy and OFS have on premenopausal women with BC. It also highlights the pressing need for standardisation of routine collection and recording of cardiometabolic history and risk factors as part of baseline assessment and adverse event reporting to better understand the cardiometabolic impact these treatment has on our patients. Further studies, with particular focus on baseline and subsequent development of cardiovascular risk factors are needed to explore the impact of these drugs on the cardiovascular health of these young women with BC

P-642 The effect of oral dydrogesterone (DYD) on the hypothalamic-pituitary-ovarian (HPO) axis (gonadotropin and sex-steroid levels) and ovulation inhibition: a double-blind, phase I, randomized-controlled, parallel-group trial

Abstract Study question What is the effect of oral dydrogesterone (three cycles daily 20mg/30mg) on pituitary, ovarian and adrenal hormones, ovulation inhibition and endometrium in healthy ovulatory women? Summary answer Daily oral dydrogesterone, 20mg or 30mg, suppresses LH and inhibits ovulation in 33% and 73% of subjects, respectively, while not reducing E2 and other hormones. What is known already Dydrogesterone, a stereoisomer of progesterone, has high oral bioavailability and has demonstrated clinical utility in several indications, including endometriosis and assisted reproduction technologies. Progestin primed ovarian stimulation (PPOS) provides a cost effective and convenient alternative to the GnRH antagonist protocol to suppress a premature LH surge during ovarian stimulation in preparation for frozen embryo transfer IVF. In PPOS, studies have shown that dydrogesterone provides a comparable number of mature oocytes as a standard GnRH antagonist. The effects of various formulations and routes of administration of different progestins on sex hormones and the HPO has not been determined across the indications. Study design, size, duration A single-centre, double-blind, randomised, multiple-dose, parallel-group study of two doses of oral dydrogesterone over three 28-day treatment cycles: dydrogesterone 30mg, 10mg in the morning, afternoon and evening; dydrogesterone 20mg, afternoon dose replaced with placebo. The primary efficacy outcome was the number of subjects with “no ovulation at all” (Hoogland and Skouby score [HSS] 1-4) or “ovulation without pregnancy risk” (HSS 5-6 with negative Landgren criterion) recorded in all treatment cycles. Participants/materials, setting, methods The study population was 44 healthy, pre-menopausal women aged 18–35 years, with proven pre-treatment ovulation. The inclusion/exclusion criteria were defined to reflect the intended target population and the general contraindications for hormonal preparations. The primary objective was to compare the effect of the two self-administered doses of dydrogesterone on ovarian follicular growth leading to ovulation and E2 suppression. Secondary objectives included effect on other HPO hormones, the endometrium, PK characteristics and safety. Main results and the role of chance The number of responders to ovulation inhibition was dose-dependent: DYD 30mg, 72.7%, 95% CI: 49.78–89.27%; DYD 20mg, 33.3%, 95% CI: 14.59–56.97%. Based on HSS and Landgren criteria, there was 42.4% and 15.15% ovulation with pregnancy risk with the 20mg and 30mg doses, respectively. Neither dose had any clinically relevant influence on the average E2 concentration or FSH, androstenedione, dehydroepiandrosterone sulphate, testosterone and sex hormone binding globulin levels, while both doses suppressed the pre-ovulatory LH surge. Endometrial proliferation was mildly suppressed to a comparable extent with both daily doses. Hyperechogenic endometrium pattern was observed in 50% and 72% of treatment cycles in ovulating women in the 20mg and 30mg groups, respectively. Treatment with DYD did not significantly delay follicular growth or postpone ovulation in ovulating women. The more pronounced progesterone suppression with the higher 30mg dose may be due to the higher number of subjects without ovulation and thus without a post-ovulatory progesterone rise in that group. Return of ovulation after treatment cessation occurred in 91% women in the 42-day post-treatment period. The most frequently reported TEAE was ‘ovarian cyst’; all cases were of mild intensity and resolved at the end of the trial. No severe TEAE was reported. Limitations, reasons for caution Only two doses were studied in healthy, ovulatory women. DYD is used in various clinical contexts with concomitant other medications, such as gonadotropins for ovarian stimulation, or under luteotropic circumstances with human chorionic gonadotropin activity from exogenous or endogenous sources. Only limited morning PK sampling was performed. Wider implications of the findings Oral dydrogesterone used for endometriosis symptom reduction may be associated with a low risk of long-term adverse events from hypoestrogenism and suppression of androgens. Oral dydrogesterone displays relevant and short-term effects on LH levels, supporting its use in PPOS protocols. At therapeutic doses, dydrogesterone does not completely inhibit ovulation. Trial registration number EudraCT-No.: 2021-004747-24