Ovarian Suppression Research Articles

Denosumab Prevents Bone Loss and Microarchitectural Deterioration in Premenopausal Women With Breast Cancer Receiving Estradiol Suppression Therapy: A Randomized Controlled Trial.

Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women. In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437). Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm2 [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted. Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.

The role of elagolix in ovulation suppression during controlled ovarian stimulation: a retrospective cohort study

The role of elagolix in ovulation suppression during controlled ovarian stimulation: a retrospective cohort study

Ovarian function recovery in breast cancer patients receiving adjuvant anastrozole treatment: updated results from the phase 3 DATA trial

PurposePatients with chemotherapy-induced ovarian function failure (CIOFF) may experience ovarian function recovery (OFR). Earlier, we showed that OFR during treatment with anastrozole impacted the prognosis of hormone receptor-positive (HR+) breast cancer (BC) patients with CIOFF. Here, we present the long-term follow-up results.MethodsPostmenopausal women with HR+ BC who were 45–57 years of age and received chemotherapy were identified from the phase 3 DATA study (NCT00301457) on the extended use of anastrozole. Eligible patients were categorised into two groups: patients with CIOFF and definitely postmenopausal patients. Patients with CIOFF were monitored for OFR. Disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS) were compared between patients with OFR and patients without OFR using multivariable Cox regression analyses, including OFR as a time-dependent covariate. BC-specific mortality (BCSM) was compared between groups using the Fine and Gray method.ResultsThis study included 656 patients: 395 patients with CIOFF and 261 definitely postmenopausal patients. OFR occurred in 39 (12%) of 329 patients with CIOFF who were monitored for OFR. The median follow-up time was 13.3 years. Patients with OFR experienced a deterioration in DFS (hazard ratio (HR) = 1.54; 95% confidence interval (CI) 0.85–2.81), DRFS (HR = 1.51; 95% CI 0.73–3.11), OS (HR = 1.64; 95% CI 0.75–3.55), and BCSM (subdistribution HR = 1.98; 95% CI 0.84–4.63) when compared with patients without OFR.ConclusionIn patients with CIOFF, OFR during treatment with anastrozole was associated with a deterioration in BC outcomes. These findings underscore the importance of adequate ovarian function suppression in this subgroup of patients.

A randomized single-blind non-inferiority trial of delayed start with drospirenone-only and ethinyl estradiol-gestodene pills for ovulation inhibition

We compared the efficacy of 4 mg drospirenone (DRSP) progestin-only pills (POPs) versus combined oral contraceptive pills (COCs) containing 0.02 mg of ethinyl estradiol (EE) and 0.075 mg of gestodene (GS) in ovulation inhibition and inducing unfavorable cervical mucus changes using a delayed-starting approach. This randomized controlled trial involved 36 participants aged 18–45 years. The major outcomes included ovulation inhibition assessed using the Hoogland and Skouby score, and cervical mucus permeability, assessed using the modified World Health Organization score. The results demonstrated ovulation inhibition rates of 77.8% for the EE/GS group and 88.9% for the DRSP group. The risk ratio and absolute risk reduction were 0.50 (95% confidence interval [CI]: 0.10, 2.40) and − 0.11 (95% CI: − 0.35, 0.13), respectively, satisfying the 20% non-inferiority margin threshold. The median time to achieve unfavorable cervical mucus changes was comparable between the DRSP (3 days, interquartile range [IQR]: 6 days) and EE/GS (3.5 days, IQR: 4 days) groups. However, the DRSP group had a higher incidence of unscheduled vaginal bleeding (55.56% vs. 11.11%; p = 0.005). DRSP-only pills, initiated on days 7–9 of the menstrual cycle, were non-inferior to EE/GS pills in ovulation inhibition. However, they exhibited delayed unfavorable cervical mucus changes compared to the standard two-day backup recommendation.Clinical trial registration: Thai Clinical Trials Registry (TCTR20220819001) https://www.thaiclinicaltrials.org/show/TCTR20220819001.

Palbociclib plus exemestane with GnRH agonist vs capecitabine in premenopausal patients with HR+/HER2- metastatic breast cancer: Updated survival results of the randomized phase 2 study Young-PEARL.

LBA1002 Background: The Young-PEARL study demonstrated improved progression free survival (PFS) (mPFS: 20.1 vs. 14.4 mo.) of exemestane plus palbociclib with ovarian function suppression (OFS) compared to capecitabine in premenopausal patients with HR+/HER2- metastatic breast cancer (mBC). Here we report updated survival outcomes with median follow-up of 54.8 months (data cutoff, November 30, 2023). Methods: Premenopausal women aged 19 years or older with HR+/HER2- BC who had relapsed or progressed during previous tamoxifen therapy were enrolled. One line of previous chemotherapy for mBC was allowed. The primary endpoint was PFS, which was defined as the time from C1D1 to disease progression or death. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate (ORR) and toxicities. Results: 184 patients were randomly assigned to exemestane plus palbociclib with OFS (n=92) or capecitabine (n=92). Median age was 44.0 years (range, 28-58). Key efficacy and safety are shown in Table. Final analysis was conducted for 174 patients. The updated mPFS was 19.5 mo. (90% CI, 14.3-22.3) for exemestane + palbociclib + OFS compared with 14.0 mo. (90% CI, 11.7-18.7) for capecitabine (HR 0.75, P=0.04). mOS was 54.8 mo. (95% CI, 48.9-77.1) for palbociclib arm and 57.8 mo. (95% CI, 46.3-N/A) for capecitabine arm (HR 1.06, P=0.77). mPFS2 (from the date of 1st PD to 2nd PD) was significantly shorter in palbociclib arm than those of capecitabine arm (7.5 vs. 11.7 mo. P=0.02). Confirmed ORR based on the investigator assessments was 33.3% (95% CI, 23.6-43.1) for palbociclib and 33.7% (95% CI, 23.6-43.9) for capecitabine. Median treatment duration was 18.9 mo. (range 1.6-88.4) in palbociclib and 13.5 mo. (range 0.1-70.8) in capecitabine. In palbociclib arm, 86 (93.5%) experienced grade 3 or more TEAEs, mainly asymptomatic neutropenia (64.1%), compared to 41 (48.2%) patients with grade ≥3 TEAEs in the capecitabine arm, mainly Hand-Foot syndrome and neutropenia (18.8% for each). Conclusions: Young-PEARL study showed exemestane + palbociclib with OFS improves efficacy compared with capecitabine in terms of PFS, which did not lead to an OS benefit for patients with premenopausal HR+/HER2- mBC (median follow-up duration: 54.8 months). The overall safety profile of palbociclib and capecitabine continues to be manageable with longer follow-up. Clinical trial information: NCT02592746 . [Table: see text]

Different dosage forms of gonadotropin-releasing hormone agonist with endocrine therapy in premenopausal hormone receptor-positive breast cancer.

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.

Real-world treatment patterns of adjuvant endocrine therapy and ovarian suppression in premenopausal HR+/HER2+ breast cancer.

The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real-world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC. This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti-HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use. Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients <35 years were more likely to receive OS compared with those ≥35 years (odds ratio 2.33, p < 0.001). This is the first real-world study evaluating ET treatment patterns in HR+/HER2+ premenopausal BC. OS use was uncommon and the majority received tamoxifen as the preferred ET regardless of most clinicopathologic risk factors. Additional research is needed to optimize ET decisions in young women with this distinct BC subtype.

A phase III trial evaluating addition of adjuvant chemotherapy to ovarian function suppression + endocrine therapy in premenopausal women with pN0-1, HR+/HER2- breast cancer (BC) and oncotype recurrence score (RS) ≤25 (OFSET): NRG-BR009.

TPS612 Background: The TAILORx and RxPONDER trials demonstrated that RS identifies many postmenopausal pts with node-neg and node-pos BC and RS ≤25, who do not benefit from addition of ACT to endocrine therapy (ET). Both trials also showed that certain subsets of premenopausal pts (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25) benefited from adding ACT to ET. Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, we developed OFSET, a phase III, multicenter clinical trial comparing OFS+ET v ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI). Choice is per investigator discretion; tamoxifen is allowed if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per investigator discretion per protocol guidelines. The HRQOL substudy will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score between arms, as well as increased pain severity (PROMIS). Blood and tumor specimens will be collected for future research. Accrual of 3,960 pts is anticipated to be completed in 7 yrs, 7 mos. Per NSABP B-28 and RxPONDER data, 5yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with one-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur~11 yrs after study initiation. OFSET was activated Aug 2023. Clinical trial information: NCT05879926 .

Short-term risk of recurrence in patients (pts) with HR+/HER2− early breast cancer (EBC) treated with endocrine therapy (ET) in randomized clinical trials (RCTs): A meta-analysis.

541 Background: ET ± chemotherapy (CT) has been standard of care for HR+/HER2− EBC for ≈20 yrs, yet pts continue to experience disease recurrences up to decades after completing adjuvant (adj) treatment (tx). There is little information on early recurrences (≤5 yrs) in the more recent tx landscape, which includes optimized local tx and improved systemic tx. This meta-analysis of ET arms in RCTs in pts with HR+/HER2− EBC seeks to fill this gap by evaluating 3- and 5-yr risk of recurrence (RoR). Methods: A systematic literature review identified RCTs that met study criteria: phase 3 trials that included pts with HR+/HER2− EBC who received 5 yrs of adj ET (aromatase inhibitors ± ovarian suppression or tamoxifen) ± CT with invasive disease-free survival (iDFS) or disease-free survival (DFS) reported at 3 and/or 5 yrs post tx randomization. Neoadj or extended ET trials were excluded. Survival curves were digitized for iDFS estimates. Meta-analysis of proportions, using a random-effects model with double arcsine transformation, was used to evaluate pooled 3-yr RoR (100 − iDFS/DFS rate) for all pts, by lymph node (LN) status (N0: 0, N1: 1-3, N+ any positive LN), and 5-yr RoR where available. The 3-yr RoR across ET arms in a subset of only adj cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) trials was evaluated given the recency of these RCTs. Results: RoR estimates were obtained from 14 trials (across 23 distinct ET-only arms), including 4 adj CDK4/6i trials that met study criteria; studies included pts with stage I-III disease ± nodal involvement. Pooled 3- and 5-yr RoR for the overall HR+/HER2− EBC pt population regardless of LN/stage were 7% and 12%, respectively. In trials with nodal status subgroups, pooled 3-yr RoR was 5% for N0, 6% for N1, and 13% for N+ pts. In a sensitivity analysis excluding cohorts with low to medium risk scores based on genomic testing, pooled 3-yr RoR estimates for N0 and N1 subgroups were 7% and 10%, respectively. Meta-analysis across ET arms of CDK4/6i trials revealed 3-yr RoR of 15% (all stage I-III) and 10% (N0). Conclusions: Despite the potential for late recurrence of HR+/HER2− EBC, short-term RoR is considerable and accumulates over time for these pts treated with ET ± CT in the adj setting. These findings highlight the unmet need for tolerable tx escalation among at-risk pts, including node-positive and select N0 pts with high-risk features.

The immunomodulatory impacts of endocrine therapy on host immunity in early-stage hormone receptor positive, HER2 negative breast cancer.

572 Background: Endocrine therapy (ET) reduces mortality in hormonally driven breast cancer (BC). The impacts of ET on the estrogen receptor are well known; however, there is limited data on the impact of ET on the host's immune system. This project aims to elucidate the potential immunomodulatory effects of ET-induced estrogen deprivation in HR+/HER2 negative early-stage breast cancer patients (pts) as well as baseline differences between BC pts and healthy controls (HC). Methods: Pts with Stage I-III HR+/HER2- BC initiating ET after completion of local regional therapy and/or chemotherapy were enrolled (NCT03719495). Whole blood, E1 (estrone) and E2 (estradiol) levels were collected at baseline (T1), 4 weeks (T2), 12 weeks (T3) and 24 weeks (T4) after ET initiation. 5 cohorts were enrolled: premenopausal and postmenopausal HCs, premenopausal pts on tamoxifen (TAM) or aromatase inhibitors (AIs) plus ovarian suppression, postmenopausal pts on AIs. Bulk RNA sequencing of whole blood was performed using NuGEN mRNA-seq on the Illumina Nova-seq platform. Differential expression analysis was performed using DESeq2 between HC and ET groups at T1, and between T1 and T4 within BC pts. The Benjamini-Hochberg method was used to adjust the P values for multiple comparisons. A curated set of 192 immune related gene signatures was used in the gene signature analysis. For each signature/module, a score was computed by taking the median of the expression values from all genes in each gene signature. CIBERSORT analysis was performed using the LM22 signature gene file and 100 permutations. Paired t-test was performed to compare T1 and T4. Results: Between 2019 and 2023, 64 pts were enrolled. Pts with missing samples or prior chemotherapy were excluded in this analysis. T1 samples of 25 pts with BC versus 14 HCs revealed marked changes in circulating immune cell (IC) composition with 537 DEGs (p value &lt; 0.05). Circulating ICs in BC pts had marked upregulation of genes associated with oxidative phosphorylation, adipogenesis, interferon alpha, reactive oxygen species compared to HCs. Immune cell composition was inferred by CIBERSORT analysis which suggests that BC pts had fewer circulating naïve B cells (p=0.048) whereas regulatory T cells (p=0.025) and activated NK cells (p=0.0039) were higher in BC pts than HCs at T1. BC pts with reductions in E1/E2 levels 6 months after ET had 77 DEGs in PBMCs between T1 and T4. Gene signature analysis shows that B cells and NK cells (p=0.0077) signatures are elevated post ET whereas a reduction of neutrophil signature (p=0.0034) was noted. Conclusions: There are significant differences in the baseline IC repertoire/activity in BC pts compared to HCs. The reduction in B cell activity/number and an increase in regulatory T cell number suggests a possible compromised immune system in BC pts. After surgery and 6 months of ET, these suppressed immune phenotypes reversed. Clinical trial information: NCT03719495 .

Real-world duration of interruptions in imaging and endocrine therapy (ET) after pregnancy in early-stage estrogen receptor (ER) positive breast cancer (BC).

11157 Background: Pre-menopausal women with early-stage ER-positive BC often desire the option for future fertility. The POSITIVE trial demonstrated that a pause in ET to conceive is safe. However, the real-world durations of these pauses, as well as how many patients resume ET, are unclear. Additionally, there are limited data about when and if women reestablish imaging surveillance after childbirth. Methods: We generated a cohort of BC patients with a pregnancy-related ICD diagnosis from the Oncoshare registry. This registry merges EMR and California Cancer Registry data for patients treated in the Stanford Health Care Alliance which includes an academic hospital, a community hospital, and a community practice network. Included patients had ≥1 pregnancy after a diagnosis of stage 0-3 ER-positive BC. Chart review confirmed pregnancy and was used to abstract treatment information. Data are presented as unadjusted percentages or medians with interquartile ranges (IQR). Among patients without bilateral mastectomies, we compared time from delivery to first imaging (MRI or mammogram) for those who breastfed vs not and those who restarted ET vs not using the Wilcoxon rank sum test. Results: Of the 317 charts reviewed, 71 were included. Most exclusions were due to no pregnancy (46%) or ER-negative disease (25%). Year of diagnosis ranged from 1994 to 2020, with the majority (79%) from 2010 to 2020. Median age at diagnosis was 33 years (IQR 30-35). The distribution of stages was 18% in situ disease, 51% stage 1, 17% stage 2, 14% stage 3. 23% (16/71) of women never started ET, with 14 attributing this decision to desiring pregnancy. Among the 55 women who started ET, 75% received tamoxifen without ovarian suppression (OS). After 2015, use of OS became more prevalent (45% of ET), coinciding with the emergence of the SOFT/TEXT data. The median time from ET onset to a pause for pregnancy was 32 months (IQR 22-53), and the median ET pause to delivery was 23 months (IQR 14-48). We recorded 90 pregnancies resulting in 85 live births. After delivery of their first child, the median follow-up was 3.8 years (IQR 2.0-6.8). 40% of patients never restarted ET. Those who did restart did so at a median of 5 months (IQR 3-11) post-delivery. Imaging surveillance resumed for 42% (27/64) at a median of 6 months post-delivery [IQR 3-11]. Time from delivery to imaging was similar between those who restarted ET and those who did not (p=0.91), and between those who breastfeed and those who did not (p=0.42). Conclusions: These data support prior work showing that fertility concerns strongly influence adjuvant therapy choice in ER-positive BC. The ET resumption rate after pregnancy was lower in our analysis compared to the POSITIVE trial (73% vs. 40%). Only 42% of women resumed surveillance imaging. This points to clear gaps between the clinical trial population and the real-world clinical setting.

Guideline concordance of recurrence risk assessment for early breast cancer in a county-level setting in China.

e23263 Background: Guideline-centric risk-based decision-making is crucial for the treatment of HR+HER2- and HER2+ early breast cancer (eBC). However, the consistency of recurrence risk assessment (RA) between real-life clinical practice and guidelines in China has not been thoroughly investigated. As part of the interim analysis of CHASE001 (NCT05544123), we explored the guideline concordance of RA for HR+HER2- and HER2+ eBC in a county-level setting in China. Methods: Cohorts of HR+HER2- and HER2+ eBC patients (pts) from a county-level observational study (CHASE001) were included in this analysis. Clinical recurrence risk were collected for each patient. Descriptive statistics reported the proportion of pts classified into each risk level under real-life assessment by healthcare professionals (HCPs) (H-low/intermediate/high) and guideline-consistent assessment (G-low/intermediate/high). To investigate the factors associated with lower consistency, univariate (UVA) and multivariate logistic regression analysis (MVA) were performed. Results: 1254 HR+HER2- and 841 HER2+ eBC pts from 26 county-level hospitals were included in this analysis. A comparison between recurrence risk under HCPs assessment (HA) and guideline-consistent assessment (GA) revealed divergence. In HR+HER2- cohort, the proportions of pts classified as low, intermediate (int), and high clinical risk for recurrence under HA/GA were 27.2%/2.0%, 48.0%/57.4%, 24.8%/40.6%, respectively. Notably, 36.8% of pts classified as G-int were categorized as H-low, while 47.5% G-high pts were classified as H-int/low. On UVA and MVA, pT1 stage, histological grade 1 and Ki67 &lt; 20% were associated with G-int/H-low; whereas lymphovascular invasion and pN1 were associated with G-high/H-lower. Among 562 G-int/high premenopausal pts, 280 (49.8%) achieved ovarian function suppression (OFS) and the OFS rates were 46.1% in G-int and 55.3% in G-high pts. In HER2+ cohort, the proportions of pts classified as low, int and high risk under HA/GA were 17.2%/0%, 48.2%/51.2% and 34.6%/48.8%. In pts with pN0, 17.2% were classified as H-low and 12% as H-high. In pts with positive lymph nodes (LN+), 11% were classified as H-low and 31% as H-int. Dual anti-HER2 target therapy was administered in 72% of pts with LN+. In both cohorts, HCPs who were medical oncologists had higher consistency with guideline for high-risk evaluation compared to surgical oncologists, whereas surgical oncologists showed higher consistency for int-risk evaluation compared to medical oncologists. Conclusions: This analysis highlights differences in clinical practice between county-level HCPs and guideline recommendations, revealing a significant underestimation of breast cancer recurrence risk. Further efforts should be made to enhance guideline adherence and promote guideline-centric clinical risk-based decision-making at county-level hospitals. Clinical trial information: NCT05544123 .

A window-of-opportunity (WOO) trial of giredestrant +/- LHRHa vs anastrozole+LHRHa in premenopausal women with ER+/HER2- early breast cancer (EBC; IBCSG 67-22; PREcoopERA).

TPS628 Background: Adjuvant endocrine therapy (ET) for premenopausal women with ER+/HER2- EBC often includes ovarian function suppression (OFS) via a GnRH or LHRH agonist (LHRHa) plus an aromatase inhibitor (AI) or tamoxifen. Younger age is associated with lower rates of ET adherence indicating side effects are less acceptable to these women. The development of drug regimens without OFS are clearly an unmet medical need in this setting. New oral selective ER degraders (SERDs) are emerging as potentially useful ETs in the (neo)adjuvant settings. Giredestrant is an efficient and potent SERD and a full antagonist, which translates into better anti-proliferation activity than known SERDs. PREcoopERA is a WOO trial aiming to determine, among premenopausal women with ER+/HER2- EBC: if giredestrant+LHRHa provides greater anti-proliferative activity than anastrozole+LHRHa; and if giredestrant without LHRHa provides similar (non-inferior) anti-proliferative activity to giredestrant+LHRHa. Results would provide rationale for subsequent (neo)adjuvant clinical trials. Methods: PREcoopERA (NCT05896566) is a randomized, open-label, 3-arm, WOO trial evaluating the anti-proliferative activity and safety of the oral SERD giredestrant +/- LHRHa triptorelin, as compared to the AI anastrozole + triptorelin. Eligible are premenopausal women with untreated ER+/HER2- operable stage I-III (excl. T4) EBC, with Ki-67 ≥10%. 220 women will be randomized in 2:2:1 ratio to giredestrant (30 mg/d po for 4 weeks until rebiopsy) + triptorelin (3.75 mg IM on D1); giredestrant alone; or anastrozole (1 mg/d po) + triptorelin. Rebiopsy is planned for D29, either during primary surgery or standalone procedures. The primary endpoint is change in Ki-67 labeling index between pre-treatment diagnostic tumor biopsy and post-treatment rebiopsy, as assessed by the IBCSG Pathology Office. Sample size of 80:80:40 randomized women are planned to test superiority of 4 weeks giredestrant+triptorelin vs anastrozole+triptorelin to reduce Ki-67 (hypothesized percentage changes -80% vs -65%) and to test non-inferiority of 4 weeks giredestrant vs giredesrant+triptorelin (within 10% as non-inferiority margin). The trial was activated on 9 October 2023. The first woman was enrolled on 25 January 2024. Clinical trial information: NCT05896566 .

Exploring sexual health in premenopausal patients with hormone positive early breast cancer: Comparison between LHRH and oophorectomy.

e23172 Background: Ovarian function suppression (OFS) is recommended for premenopausal patients with hormone (HR) positive early breast cancer at higher risk of recurrence. This is achieved with the use of the luteinizing hormone–releasing hormone agonist (LHRH) or oophorectomy. Sexual health is an important aspect for women with breast cancer, although unfortunately this issue is often not addressed. The aim of this study was to explore sexual health issues in premenopausal HR-positive patients with LHRH vs. Oophorectomy. Methods: A prospective observational study was conducted during the period of June 2023 and December 2023, enrolling premenopausal patients with Early stage HR positive (HER2 positive or negative) breast cancer diagnosed between 2017 and 2023, who were treated with OFS and remained free of disease. Involved patients were divided in two groups: Group A – received LHRH and Groups B - underwent oophorectomy. All patients were surveyed with EORTC QLQ-BR-45 questionnaire during their follow-up or scheduled LHRH injection visits at clinic. The questionnaire included Functional (F) and Symptom (S) scales evaluating sexual functioning, sexual enjoyment, endocrine therapy symptoms, endocrine sexual symptoms. Results: It was planned to enroll 100 patients in the study, but only 34 patients (24 in Group A, 10 in Group B) consented to participate, the majority of patients did not want to share their sexual life issues, even anonymously. Of those enrolled, median age was similar (42 in group A, 43 in group B), all had stage I-II breast cancer, and all were in continued remission at the time of enrollment. A similar proportion had HER2 positive disease (25% and 20%, respectively). Far more people in Group A were treated with breast conserving surgery (67% vs 30%, respectively) with 20% of participants in in Group B undergoing bilateral mastectomy. More volunteers received chemotherapy in Group A (88% vs 60% in group B). Among those in Group B, 6 of 10 were previously treated with LHRH before oophorectomy and the procedure was done due to endometrial hyperplasia (n = 3), known BRCA mutation (n = 1), persistent estrogen levels despite LHRH (n = 1), and patient preference (n = 5). More patients had a partner at enrollment in group B (90% vs 67% in Group A); only one person identified as a lesbian (enrolled in group B). F score S &gt; 60 was noted in more Group A vs Group B participants (50% vs 30%). More people in Group A had S score S &lt; 40, indicating higher quality of life (79% vs 50%, respectively). Conclusions: The study suggests that sexuality after cancer is a difficult area to study in Georgia, likely due to cultural issues. While we could not account for the contribution of known variables that impact sexuality in this population (e.g. surgery type, chemotherapy) due to small numbers, our data suggest that LHRH antagonist use may have a lesser risk to sexual function compared to oophorectomy.

The CROWN study: Cardiac outcomes with near-complete estrogen deprivation.

TPS12146 Background: Treatment for premenopausal women with high/intermediate risk hormone receptor (HR)-positive breast cancer (BC) includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near-complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV morbidity. Given the overall CV injury associated with BC treatment and the future life-years of these women, the CV impact of NCED warrants further study. The CROWN study uses sophisticated imaging assessments of cardiac dysfunction and biomarker and demographic correlates to understand the evolution of CV injury with the goal of developing tools to assess and mitigate CV risk. Methods: This is an NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Duke University, Wake Forest University and Virginia Commonwealth University) that includes premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-2. HR-positive BC patients are receiving an AI and OFS. Women with HR-negative BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table). These assessments include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. Correlation of CMR imaging with CCTA detail of coronary plaque changes is planned. The relevance of pre-existing risk factors on study outcomes, including an emphasis on race and dynamic change in modifiable and treatment related risk factors will also be assessed. We plan to enroll 90 women,65 in the NCED group and 25 in the HR-negative group, allowing for a 10% drop out rate. The first primary statistical analyses will include testing hypotheses between group (NCED vs HR-negative) and within group (longitudinal changes within the NCED group). Secondary analyses involve developing predictive equations to determine if patient demographics, clinical parameters and serum biomarkers are associated with CV changes over time. We have currently enrolled 34 women (31 NCED and 3 HR-negative). 2 out of 3 patients entering the 2nd year of the study have returned for their year 1 imaging. Retention will be a key component of this study as analysis of the primary and secondary endpoints are dependent on completion of imaging. Clinical trial information: NCT05309655 . [Table: see text]

A phase II trial of anlotinib and fulvestrant in patients with HR-positive and HER2-negative, secondary aromatase inhibitor–resistant, metastatic breast cancer.

e13065 Background: Fulvestrant is used after aromatase inhibitor (AI) failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using anlotinib, a novel multi-target tyrosine kinase inhibitor, may delay fulvestrant resistance in patients (pts) and thus improve its efficacy. This single-arm, phase II trial aims to evaluate the efficacy and safety of the combined regimen in pts with HR-positive and HER2-negative, previously AI treated, locally advanced or metastatic breast cancer. Methods: The key enrolled criteria were women aged 18 years or older of any menopausal status (premenopausal or perimenopausal women received ovarian function suppression), ECOG PS 0-1, histologically confirmed HR-positive and HER2-negative breast cancer, and disease relapse within 12 months after a more than 24 months AI adjuvant setting or disease progress after a more than 6 months AI metastatic setting. Eligible pts received 500 mg fulvestrant by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days). Pts were also given 12 mg oral anlotinib once daily for 2 weeks, followed by a week off in a 21-day cycle. The primary endpoints is progression-free survival (PFS) and the secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Results: 30 pts have been enrolled from Aug 2021 to Dec 2023. After a median follow-up time of 12.9 months (95% CI, 9.0-16.8), the overall median PFS was 6.4 months (95% CI 3.4-9.5) and the mOS has not reached. In the 29 pts whose efficacy could be evaluated, the ORR was 20.7% (95% CI, 8.0-39.7) and the DCR was 79.3% (95% CI, 60.3-92.0), with partial response and stable disease recorded in 6 and 17 pts. The CBR was 41.4% (95% CI, 23.5-61.1), with 6 pts reach SD for more than 6 months. Pts who have not received CDK 4/6 inhibitors previously had longer PFS (14.8 months, 95% CI 3.7-25.9) than those who have received CDK 4/6 inhibitors (4.6 months, 95% CI 3.0-6.3) in the subgroup analysis (HR=0.33, P=0.038). At the same time, we find pts who have not received systemic chemotherapy previously also had longer PFS (9.7 months, 95% CI 6.0-13.2) than those who have received systemic chemotherapy (5.5 months, 95% CI 3.6-7.4) (HR=0.47, P=0.12). TEAEs of any grade were observed in 90.0% of pts, and the frequent AEs included hypertension (43.3%), wight loss (20.0%), proteinuria (20.0%), increased TSH (20.0%), and hand-foot syndrome (20.0%). Grade 3 TEAEs occurred in 11 (36.7%) pts, the most common of which was hypertension (26.7%). Dose reductions or discontinuation of anlotinib occurred in 12 (40.0%) pts. Conclusions: Anlotinib combined with fulvestrant showed a promising efficacy with an acceptable safety profile for patients with metastatic breast cancer previously treated with AI. Further results are expected. Clinical trial information: NCT05075512 .

Effect and acceptability of jasmine compound essential oil for premenopausal breast cancer survivors suffering from genitourinary syndrome of menopause: A prospective interventional study.

1063 Background: Genitourinary syndrome of menopause (GSM) includes dyspareunia, vaginal dryness, vaginal burning, urinary urgency, and recurrent urinary tract infections. Breast cancer survivors (BCSs) exhibit more severe symptoms of GSM than healthy aging women, especially premenopausal BCSs in sexually active lifetime. GSM detrimentally impacts their quality of life and contributes to the premature cessation of endocrine therapy for breast disease. This study aims to explore the efficacy and safety of Jasmine compound essential oil in the treatment of GSM in premenopausal breast cancer women. Methods: Premenopausal sextually-active women with hormone receptor (HR) positive stage I to III BC taking ovarian function suppression (OFS) treatment and endocrine therapy with self-reported vaginal dryness, dyspareunia, or decreased libido were enrolled to the 12 weeks topically applied Jasmine compound essential oil trial. E2 and FSH was measured at baseline and weeks 12. A series of validated sexual quality-of-life questionnaires were completed at baseline, and subsequently at weeks 4, 8, and 12. The primary endpoint is the improvement in sexual pain evaluated based on the Female Sexual Function Index scale (FSFI). Acceptability was measured by patient preference and reported intention to continue using the products. Gynecologic examinations and metagenomic profiling of the vaginal microbiota were conducted at baseline and post-treatment for patients in an exploratory cohort. Results: Overall, 96 BCSs signed consent (mean [range] age, 45 [32-55] years) and 89 completed 12 weeks of treatment. E2 and FSH were maintained within the postmenopausal range without significant fluctuations during the treatment. Topically applied Jasmine compound essential oil resulted in significant improvements in dyspareunia, vaginal dryness, irritation and quality of life over time (all P&lt; 0.001). Both BCSs and their sexual partners reported being satisfied with the essential oil treatment and the adherence rate reached 95% (SD 10). In the 20-patient exploratory cohort, there were improvements in vaginal pH (baseline mean 6.07 compared with 12-week mean 4.68[ P&lt;.001]), and vaginal maturation index (45.3 compared with 52.1[ P&lt;.001]). We also observed a positive influence on the vaginal microbiota after intervention. In patients with elevated baseline abundance of Lactobacillus in the vaginal microbiome, there was a more pronounced improvement in scale scores following essential oil access. Conversely, a high baseline abundance of Escherichia coli may be considered a detrimental factor associated with less benefit from essential oil. Conclusions: Jasmine compound essential oil could relieve vaginal symptoms and improve vaginal health in breast cancer survivors who have experienced menopause after cancer treatment.

Assessment of endocrine therapy adherence in a nurse-led cancer survivorship clinic: Results from the Linking You to Support and Advice (LYSA) trial.

1627 Background: The care of those living with and beyond a cancer diagnosis requires dedicated cancer survivorship services to ensure optimal symptom control and quality of life. Supporting adherence to adjuvant endocrine therapy is also an essential component of care. We examined endocrine therapy adherence rates, and factors associated with non-adherence, in patients with early-stage breast cancer enrolling in a survivorship trial (LYSA). Methods: Women with early-stage hormone positive breast (n=168) cancers within 12 months of completing primary therapy, were enrolled in a randomized control trial with parallel arms (PMID 36357934). Experimental arm had access to nurse-led symptom management, dietetic consultation, and undertook bimonthly electronic patient reported outcome (ePRO). Active comparator group had access to conventional care and ePRO was completed at beginning and end of study. Endocrine therapy adherence was reported as the ability to take medication as prescribed over prior 4 weeks (Michigan Oncology Quality Consortium Adherence Tool), with response quantified as Excellent (adherence close to 100%), Very Good (80%), Good (60%), Fair (40%) and Poor (20%). Adherence Objective (Secondary) was adherence rate at 12 months after study entry in both arms, and factors associated with non-adherence. Results: A total of 148/168 women with breast cancer who completed the LYSA study reported adjuvant endocrine therapy use (74 experimental arm, 74 active comparator) during study conduct. Therapies included aromatase inhibitors (53%), tamoxifen (39%) and ovarian suppression combinations (8%). At study entry ≥ 80% adherence was reported in 74% of overall cohort (75% experimental, 72% comparator, p=0.7), with 1.6% reporting not taking any medication. By end of study (12 months), ≥ 80% adherence was reported in 74% overall (77% experimental, 71% comparator, p=0.4), while non-adherence rates were 2.9%. Among the pre-specified reasons for non-adherence at study end, “simply missing it” ranked highest (10%), and 5% “experienced side effects”. Post-menopausal patients were more likely than pre-menopausal to report excellent (versus sub-excellent) adherence at study end (OR 4.60, 95%CI 1.45 – 16.13, p = 0.012, adjusted for arm, age, and ECOG). Additional exploration of reasons for non-adherence will be presented. Conclusions: Adjuvant endocrine therapy adherence rates in both arms at 12 months after study entry collected via ePRO were good (≥ 90% reporting excellent or very good adherence). Additional factors potentially associated with non-adherence are being analyzed including self-care agency, symptom burden and quality of life. Clinical trial information: NCT05035173 .

Adherence to fertility preservation guidelines in young patients with breast cancer: A retrospective analysis.

e23255 Background: Breast cancer affects a considerable proportion of women of childbearing age making it important to provide options for fertility preservation. At Chihuahua's State Cancer Center, a state-federal-funded institution providing free oncological care, and ensuring access to fertility preservation measures is integral to the multidisciplinary approach for young cancer survivors. Recognizing chemotherapy's impact on fertility, implementing fertility preservation measures is key. Assessing adherence to these guidelines is essential for comprehensive care and holistic well-being in young breast cancer patients at our center. Methods: In this retrospective study at the Chihuahua´s State Cancer Center, we examined adherence to fertility preservation guidelines among breast cancer patients aged 18 to 40 years. The primary method used for fertility preservation was the administration of GnRH analogs, such as triptorelin and goserelin. Data on GnRH analog use, chemotherapy regimens, and patient demographics were collected from medical records. The study aimed to assess the integration of fertility preservation measures, particularly GnRH analogs, into treatment plans for young breast cancer patients. Additionally, we aimed to identify barriers to accessing fertility preservation services in this population. Results: The study findings revealed that out of the 749 registered breast cancer patients, 95 (12.6%) were 40 years old or younger. Among these, 75 (79%) received adjuvant and/or neoadjuvant chemotherapy, with 58 (77.3%) being in locally advanced clinical stages. Of the 75 patients who underwent chemotherapy, 20 (26.7%) also received GnRH analogs, while 55 (73.3%) did not. Among the 75 chemotherapy recipients, 16 (p = 0.046) were estrogen receptor-positive and received analogs. Furthermore, out of the 20 patients with triple-negative breast cancer, only 1 (1.3%) received an analog. Conclusions: The study indicates that GnRH analogs usage in breast cancer patients is significantly associated with estrogen receptor positivity. While estrogen receptor status is crucial for determining treatment suitability, GnRH analog utilization was notably low among triple-negative breast cancer patients. This suggests that triple-negative status alone should not preclude GnRH analog use. The findings underscore the need to raise awareness and improve adherence to ovarian suppression recommendations to enhance clinical outcomes and quality of life for breast cancer patients.

Adjuvant treatment strategy evolution and risk stratification for hormone receptor-positive, human epidermal growth factor receptor-2 negative early breast cancer in China.

Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) early breast cancer (EBC) with high-risk clinicopathological features face an increased risk of recurrence. This study explored the evolving treatment landscape and clinical outcomes in patients with EBC using a nationwide database. The study cohort comprised HR+/HER2-, stages 1-3, patients with EBC who underwent surgery and received adjuvant endocrine therapy (AET) from January 2013 to March 2021. High-risk patients were defined by ≥4 positive axillary lymph nodes, or 1-3 positive lymph node(s) with at least one high-risk feature (histologic grade 3, tumor size ≥5 cm, or Ki-67 ≥20%). A low-risk cohort included patients not meeting the criteria. Survival analysis was conducted with a cutoff of September 2021. The study included 4088 eligible patients (1310 high-risk patients and 2778 low-risk patients). High-risk patients were more likely to receive adjuvant chemotherapy and radiotherapy compared to low-risk patients. From 2013 to 2021, an increasing proportion of patients received aromatase inhibitors and ovarian function suppression as part of their AET. The 2-, 5-, and 7-year invasive disease-free survival for high-risk cohort were 90.67%, 75.26%, and 57.10%, respectively, these rates were notably higher for low-risk cohort at 97.14%, 89.85%, and 84.83%. High-risk patients demonstrated a higher risk of recurrence or death compared with low-risk patients (hazard ratio, 2.38; 95% CI, 1.82-3.12). In the setting of standard or even intensive AET, patients with EBC with high-risk features still present high recurrence risk, highlighting the urgent need for innovative adjuvant treatment strategies.