Breast Cancer
Conditions
Keywords
Breast Cancer, ovarian suppression
Brief summary
This is a multicenter, prospective, randomized controlled, phase II study. The primary objective is to evaluate the effect of endocrine therapy modification (switching from a 3-month to a 1-month GnRHa) versus continuation of the 3-month GnRHa on E2 control at 3 months in young patients with hormone receptor-positive breast cancer and iOFS.
Detailed description
In China, breast cancer occurs at a young age, with a peak incidence at 40-49 years; patients aged ≤45 years account for 20%-24% of cases, and this proportion is increasing. Ovarian function suppression (OFS) combined with aromatase inhibitor (AI) or tamoxifen (TAM), with or without CDK4/6 inhibitors, has become a preferred adjuvant endocrine therapy for intermediate to high-risk premenopausal hormone receptor-positive (HR+) patients with HR+ breast cancer. AI is effective in premenopausal women only when ovarian estrogen production is suppressed, which can be achieved with GnRH agonists (GnRHa). The 3-month GnRHa formulation is commonly preferred in the real world due to its convenience and reduced injection frequency; however, its effectiveness compared with the 1-month formulation remains a concern. Among premenopausal patients receiving GnRHa combined with AI or TAM, approximately 8% experience incomplete ovarian function suppression (iOFS, E2 ≥30 pg/mL). Persistent iOFS may reduce the efficacy of endocrine therapy and potentially increase the risk of disease recurrence. Current clinical guidelines recommend monitoring serum estradiol (E2) levels during GnRHa treatment and suggest potential management strategies, including switching GnRHa formulations from 3-month to 1-month or modifying endocrine therapy (e.g., AI to TAM). However, evidence supporting these strategies is largely derived from retrospective studies or small case series, and prospective data remain limited. This multicenter, prospective, randomized, phase II study is designed to evaluate whether switching from a 3-month to a 1-month GnRHa can reduce E2 levels to \<30 pg/mL within 3 months in premenopausal HR+ young breast cancer patients with iOFS. This study will also assess the long-term efficacy and safety of this strategy.
Interventions
DRUG1-month GnRH
1-month GnRH (goserelin 3.6 mg depot or goserelin 3.6 mg implant or leuprolide 3.75 mg depot) +endocrine therapy (aromatase inhibitor/tamoxifen±CDK4/6 inhibition)
DRUG3-month GnRH
3-month GnRH (goserelin 10.8 mg implant or leuprolide 11.25 mg depot) + endocrine therapy (aromatase inhibitor/tamoxifen±CDK4/6 inhibition)
Sponsors
Fudan University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Participants will be randomized into one of two groups: an intervention group that receives the 1-month GnRHa and a control group that receives the 3-month GnRHa.
Intervention model description
Participants will be randomized into one of two groups: an intervention group that receives the 1-month GnRHa and a control group that receives the 3-month GnRHa.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
Step 1：iOFS detection phase 1. Female, aged ≥18 and ≤45 years; 2. Histologically confirmed hormone receptor-positive (HR+) (estrogen receptor \[ER\] and/or progesterone receptor \[PR\] ≥1%) and human epidermal growth factor receptor 2-negative (HER2-) early invasive breast cancer (stage I-III according to the American Joint Committee on Cancer \[AJCC\], version 8)； 3. Completed curative surgery, with prior (neo)adjuvant chemotherapy and radiotherapy completed if applicable; 4. Currently receiving adjuvant therapy with a 3-month GnRH agonist (GnRHa) plus aromatase inhibitor (AI) or tamoxifen (TAM), with or without CDK4/6 inhibitors (excluding abemaciclib due to its potential interference with estradiol monitoring), for ≥1 dose, and presenting with estradiol (E2) ≥30 pg/mL within 28 days prior to enrollment (measured by CLIA). 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1; adequate bone marrow, hepatic, renal, and cardiac function. 6. Voluntarily sign a written informed consent form before the trial screening. Step 2：Randomized treatment phase 1. iOFS confirmed using the SEMS assay (E2 ≥30 pg/mL); 2. Ongoing adjuvant therapy with a 3-month GnRHa plus AI or TAM, with or without CDK4/6 inhibitors. 3. No evidence of disease progression.
Exclusion criteria
Step 1：iOFS detection phase 1. Bilateral breast cancer, inflammatory breast cancer, or distant metastasis; 2. Use of GnRHa for ovarian function preservation; 3. History of ovarian resection or ablation; planned pregnancy or breastfeeding; 4. Concomitant use of hormonal agents other than estrogen, progesterone, selective estrogen receptor modulators (SERM), or selective estrogen receptor degraders (SERD); 5. Severe uncontrolled comorbidities; 6. Other malignancies within the past 5 years (except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma); 7. Failure to comply with follow-up or psychiatric disorders. Step 2：Randomized treatment phase a)Prior conversion from a 3-month GnRHa to a 1-month GnRHa.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants with E2 <30 pg/mL at 3 Months | 3 months post randomization | The primary endpoint is defined as the proportion of patients with E2 \<30 pg/mL at 3 months, comparing patients who switch to GnRHa 1M versus those who continue GnRHa 3M therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with E2 <30 pg/mL at 6 months after randomization | 6 months post randomization | This endpoint is defined as the proportion of patients with E2 \<30 pg/mL at 6 months, comparing patients who switch to GnRHa 1M versus those who continue GnRHa 3M therapy. |
| Time to adequate ovarian function suppression | Assessed over a period of up to 12 months following randomization | This endpoint is defined as the time from the first occurrence of iOFS to the first measurement of E2 \<30 pg/mL. |
| Patient Age | At randomization | Age of participants at the time of randomization, categorized by iOFS status (Persistent vs. Transient). |
| 3-year invasive disease-free survival in patients who switch to GnRHa 1M versus those who continue GnRHa 3M therapy | From the date of randomization until the date of locoregional recurrence, distant metastasis, second primary breast cancer, or death from any cause, up to 3 months | Invasive disease-free survival is defined as the time from randomization to the first occurrence of locoregional recurrence, distant metastasis, second primary breast cancer, or death from any cause. |
| 3-year invasive disease-free survival in patients with persistent iOFS and those with transient iOFS | From the date of randomization until the date of locoregional recurrence, distant metastasis, second primary breast cancer, or death from any cause, up to 3 months | — |
| Intraclass Correlation Coefficient (ICC) for the Consistency of the SEMS Method | post SEMS assay | The consistency of the SEMS method will be assessed by calculating the Intraclass Correlation Coefficient (ICC) between GnRHa 1M and GnRHa 1M at the post-assay time point. |
| Adverse events | From the date of treatment initiation until the date of disease progression, intolerable toxicities, death, withdrawal of consent, or completion of planned 3-year postoperative follow-up, whichever occurred first | Adverse events will be graded according to the NCI-CTCAE Version 5.0. |
Contacts
CONTACTJian Zhang
CONTACTYanchun Meng
Outcome results
None listed