Can aromatase inhibitors (AIs) plus ovarian function suppression (OFS) be used in premenopausal women with hormone receptor-positive breast cancer?

Yes, Aromatase Inhibitors Plus Ovarian Function Suppression Can Be Used in Premenopausal Women

Premenopausal women with hormone receptor-positive breast cancer should be offered aromatase inhibitors (AIs) combined with ovarian function suppression (OFS) as a treatment option, particularly for those at higher risk of recurrence. 1, 2

Mandatory Requirement: Ovarian Suppression

• AIs cannot be used alone in premenopausal women - they are ineffective without concurrent ovarian suppression because residual ovarian estrogen production renders them useless. 3
• Ovarian suppression must be achieved through GnRH agonists (goserelin 3.6 mg SC every 4 weeks or 10.8 mg SC every 12 weeks; leuprolide 3.75-7.5 mg IM every 4 weeks or 11.25-22.5 mg IM every 12 weeks), bilateral oophorectomy, or radiation therapy. 1
• This is a strong recommendation from ASCO - premenopausal women must receive ovarian suppression or ablation when starting any endocrine therapy, not just AIs. 2

Evidence Supporting AI + OFS Over Tamoxifen + OFS

• The most recent high-quality evidence shows AIs are superior to tamoxifen when combined with OFS. A 2022 patient-level meta-analysis of 7,030 premenopausal women demonstrated that AI + OFS reduced breast cancer recurrence by 21% compared to tamoxifen + OFS (RR 0.79,95% CI 0.69-0.90, p=0.0005). 3
• The absolute benefit was a 3.2% reduction in 5-year recurrence risk (6.9% vs 10.1%), with the main benefit occurring in years 0-4 when treatments differed. 3
• Distant recurrence was also reduced with AI + OFS (RR 0.83,95% CI 0.71-0.97). 3

Which Premenopausal Women Benefit Most

• NCCN specifically recommends AI + OFS for premenopausal patients at higher risk of recurrence, including those with young age, high-grade tumors, or lymph node involvement. 1
• Both first-line and relapsed settings are appropriate: for early relapse (≤12 months after adjuvant therapy), use OFS + AI (nonsteroidal preferred); for late relapse (>12 months), options include OFS + fulvestrant ± palbociclib or OFS + AI + fulvestrant. 2

Critical Monitoring Requirements - This Is Non-Negotiable

• Estradiol monitoring with high-sensitivity assays is mandatory when using AIs with OFS. 2, 4
• Target estradiol levels must be in the postmenopausal range (<26 pmol/L or <7 pg/mL). 2
• Monitor estradiol and FSH/LH levels if under 60 years old and amenorrheic for ≤12 months, after chemotherapy, after switching from tamoxifen to AI, or prior to the next dose of GnRH agonist (particularly in women under 45). 1
• AIs can paradoxically stimulate ovarian function - if vaginal bleeding occurs while on AI, contact physician immediately. 1

Duration and Initiation

• 5 years is optimal duration according to SOFT and TEXT trials, with a minimum of 2 years of OFS encouraged. 1
• If no chemotherapy is planned, start OFS alone for at least 1-2 cycles or concurrently with tamoxifen until estradiol reaches postmenopausal range, then switch to AI. 1

Important Toxicity Considerations

• Bone fractures are significantly increased with AI + OFS compared to tamoxifen + OFS (6.4% vs 5.1%; RR 1.27,95% CI 1.04-1.54). 3
• Hot flushes are more common with OFS (RR 1.60,95% CI 1.41 to 1.82). 5
• Premature menopause side effects include vasomotor symptoms, bone loss, cardiovascular effects, and sexual dysfunction - these must be discussed with patients. 2

Critical Counseling Point

• Fertility preservation must be discussed before initiating OFS, including options for cryopreservation of embryos or oocytes, as this decision is irreversible with surgical oophorectomy and potentially permanent with GnRH agonists. 2