What is the recommended dose and schedule of Leuprolide (Gonadotropin-releasing hormone agonist) for Ovarian Function Suppression (OFS) in breast cancer treatment?

Leuprolide Dosing for Ovarian Function Suppression in Breast Cancer

For ovarian function suppression in premenopausal women with hormone receptor-positive breast cancer, leuprolide should be administered at 3.75–7.5 mg intramuscularly every 4 weeks OR 11.25–22.5 mg intramuscularly every 12 weeks for a duration of 5 years (or minimum 2 years). 1

Recommended Dosing Schedules

The NCCN guidelines provide two evidence-based dosing options 1:

• Monthly regimen: Leuprolide 3.75–7.5 mg IM every 4 weeks
• Quarterly regimen: Leuprolide 11.25–22.5 mg IM every 12 weeks

Both schedules achieve equivalent ovarian suppression and clinical outcomes. 2 A retrospective study of 201 patients demonstrated that the 22.5 mg every 3 months formulation achieved ovarian ablation in 99% of patients compared to 100% with monthly dosing, with identical 1-year disease-free survival rates (97% vs 95%, P=0.75). 2

Duration of Treatment

Administer leuprolide for 5 years as the optimal duration, based on the TEXT-SOFT trials showing sustained disease-free survival benefit with this timeframe. 1

A minimum of 2 years is acceptable for patients who cannot tolerate the full 5-year course, supported by the ASTRRA trial demonstrating 8-year disease-free survival of 85.4% with 2 years of OFS plus tamoxifen versus 80.2% with tamoxifen alone (HR 0.67,95% CI 0.51–0.87). 1

Timing of Initiation

Start leuprolide according to this algorithm 1:

• With chemotherapy: Begin at the start of neoadjuvant or adjuvant chemotherapy
• Without chemotherapy: Start leuprolide alone for 1-2 cycles OR concurrently with tamoxifen until estradiol reaches postmenopausal range, then consider switching to an aromatase inhibitor
• With radiation: Start concurrent with radiotherapy or upon completion

Critical Monitoring Requirements

Monitor estradiol levels prior to each leuprolide dose, particularly in women under age 45, using high-sensitivity assays to confirm adequate ovarian suppression. 1, 3

Measure estradiol and FSH/LH levels in these specific scenarios 1:

• Women under 60 years who are amenorrheic ≤12 months before starting adjuvant endocrine therapy
• After chemotherapy-induced amenorrhea
• After discontinuing tamoxifen +/- OFS
• Before switching from tamoxifen to an aromatase inhibitor

Target estradiol level: <7 pg/mL (postmenopausal range) when combining leuprolide with aromatase inhibitors. 3

Common Pitfalls to Avoid

The 3-month formulations carry higher risk of incomplete ovarian suppression and require more vigilant estradiol monitoring, especially when combined with aromatase inhibitors. 3 Incomplete suppression occurs more frequently in younger women (under 45 years) and obese patients. 3

If vaginal bleeding occurs while on an aromatase inhibitor plus leuprolide, contact the physician immediately, as aromatase inhibitors can paradoxically stimulate ovarian function if suppression is inadequate. 1

Do not use leuprolide in postmenopausal women—they should receive aromatase inhibitors or tamoxifen alone without ovarian suppression. 4

Patient Selection

Reserve leuprolide for premenopausal women with high-risk features 1, 4:

• Young age (particularly <45 years)
• High-grade tumors
• Lymph node involvement
• Patients who received adjuvant/neoadjuvant chemotherapy and remained premenopausal

Do not use in low-risk premenopausal patients who did not receive chemotherapy—tamoxifen alone achieves 95% disease-free survival in this population. 4

Combination Therapy

Leuprolide should be combined with endocrine therapy 1:

• Leuprolide + exemestane (or another aromatase inhibitor) for highest-risk patients
• Leuprolide + tamoxifen as an alternative, particularly for patients with contraindications to aromatase inhibitors

The TEXT-SOFT trials demonstrated superior disease-free survival with exemestane plus OFS (92.8%) versus tamoxifen plus OFS (88.8%) at 5 years (HR 0.66,95% CI 0.55–0.80, P<0.001). 1

Adverse Effects Management

Expect these common side effects 2, 5:

• Hot flashes (60% increase compared to no OFS, RR 1.60,95% CI 1.41–1.82) 5
• Musculoskeletal pain
• Fatigue and insomnia
• Mood changes and depression (monitor closely) 5
• Osteoporosis risk (RR 1.16,95% CI 1.10–28.82) 5

Consider bone-modifying agents for patients receiving prolonged leuprolide therapy to mitigate osteoporosis risk. 6

After Completing OFS

Premenopausal patients wishing to continue adjuvant endocrine therapy after stopping leuprolide should switch to tamoxifen rather than continuing an aromatase inhibitor, as ovarian function may resume. 1