Can an aromatase inhibitor be used in premenopausal women with hormone‑receptor‑positive, HER2‑negative advanced breast cancer, and what ovarian suppression is required?

Can Aromatase Inhibitors Be Used in Premenopausal Women?

Yes, aromatase inhibitors can be used in premenopausal women with hormone receptor-positive, HER2-negative breast cancer, but ONLY when combined with mandatory ovarian suppression or ablation—never as monotherapy. 1, 2

Critical Requirement: Ovarian Suppression is Non-Negotiable

Aromatase inhibitors alone must be avoided in premenopausal women, as no evidence of efficacy exists and they can paradoxically stimulate ovarian function. 1, 3 The FDA label for anastrozole explicitly states that "the effect of anastrozole in premenopausal women with early or advanced breast cancer has not been studied" and that "anastrozole would not be expected to lower estradiol levels in premenopausal women" because aromatization of adrenal androgens is not a significant source of estradiol when ovaries are functioning. 3

Methods of Achieving Ovarian Suppression

• GnRH agonists (goserelin 3.6 mg subcutaneously every 4 weeks or leuprolide 3.75 mg every 28 days) provide reversible suppression 1, 2, 4
• Bilateral oophorectomy provides permanent surgical ablation 1, 2
• Ovarian radiation provides permanent ablation 2

All three methods achieve equivalent clinical outcomes, with the choice guided by patient preference and fertility preservation goals. 2

Mandatory Monitoring: Estradiol Surveillance

High-sensitivity estradiol monitoring is absolutely mandatory when combining aromatase inhibitors with ovarian suppression. 2, 4 This is a critical pitfall that cannot be overlooked:

• Target estradiol level: <26 pmol/L (<7 pg/mL) using high-sensitivity assays 2, 4
• When to monitor: In women <60 years who are amenorrheic ≤12 months, after chemotherapy, after switching from tamoxifen to an AI, or immediately before the next GnRH agonist dose 2, 4
• Why this matters: Aromatase inhibitors can paradoxically stimulate ovarian function through increased gonadotropin secretion, and incomplete ovarian suppression occurs more frequently in younger or obese women 2, 5, 6

Any vaginal bleeding while on an aromatase inhibitor requires urgent physician evaluation. 2, 4

Clinical Scenarios Where AI + Ovarian Suppression is Appropriate

Advanced/Metastatic Disease (First-Line)

For premenopausal women with treatment-naïve HR-positive, HER2-negative metastatic breast cancer, the preferred regimen is a nonsteroidal aromatase inhibitor plus a CDK4/6 inhibitor combined with ovarian suppression. 1 This represents the current standard based on the 2020-2021 NCCN and ASCO guidelines. 1

Alternative first-line options include:

• Ovarian suppression + tamoxifen 1, 2
• Ovarian suppression + fulvestrant ± CDK4/6 inhibitor 1

Advanced/Metastatic Disease (Second-Line and Beyond)

For women progressing on aromatase inhibitors or who develop recurrence within 12 months of adjuvant AI therapy, fulvestrant plus a CDK4/6 inhibitor with continued ovarian suppression should be offered. 1 The key principle is that ovarian suppression must be maintained throughout all lines of endocrine therapy when switching between hormonal agents. 2, 4

Adjuvant (Early-Stage) Disease

The evidence here is more nuanced and risk-stratified:

• High-risk patients (stage II-III requiring chemotherapy): Ovarian suppression combined with either tamoxifen OR an aromatase inhibitor for 5 years is recommended 2
• Select intermediate-risk patients (age <45 years, high-grade tumors, lymph node involvement): May be offered ovarian suppression + AI if they would otherwise be considered for chemotherapy 2
• Low-risk patients (stage I not warranting chemotherapy): Endocrine therapy alone (tamoxifen); ovarian suppression is NOT added 2

The 2008-2009 ESMO and NCCN guidelines explicitly stated that "the adjuvant use of the combination of GnRHA and aromatase inhibitors in premenopausal patients is not currently indicated." 1 However, this has evolved with more recent evidence from the SOFT and TEXT trials, and the 2020-2021 guidelines now support this combination in appropriately selected high-risk adjuvant patients. 2

Duration of Therapy

• Optimal duration: 5 years of ovarian suppression when combined with an aromatase inhibitor 2
• Minimum acceptable duration: 2 years if 5 years is not tolerated, which still provides significant disease-free survival benefit (hazard ratio ≈0.67) 2
• In metastatic disease: Continue ovarian suppression for the entire duration of endocrine treatment, as ovarian function may resume if discontinued 4

Timing of Initiation

• If chemotherapy is planned: Start ovarian suppression concurrently with chemotherapy 1, 2
• If no chemotherapy: Begin ovarian suppression alone for 1-2 cycles until estradiol falls into the postmenopausal range, then add the aromatase inhibitor 2, 4

Common Pitfalls to Avoid

1. Never assume amenorrhea equals adequate suppression. Women who become amenorrheic with chemotherapy may have continued estrogen production from the ovaries in the absence of menses. Serial assessment of LH, FSH, and estradiol is mandatory to ensure true postmenopausal status. 1, 4

2. Do not use 3-month GnRH agonist formulations with aromatase inhibitors. The 3-month formulations of leuprolide have a higher risk of incomplete ovarian suppression and are not recommended when combined with aromatase inhibitors. 4

3. Never prescribe aromatase inhibitors as monotherapy in premenopausal women. This is explicitly contraindicated and can lead to treatment failure. 1, 3

Evidence Supporting This Approach

A 2010 study of 36 premenopausal women with metastatic breast cancer treated with goserelin plus anastrozole as first-line therapy demonstrated 67% clinical benefit rate with a 98% reduction in median estradiol levels (from 574.5 pmol/L to 13.45 pmol/L), with median time to progression of 12 months and excellent tolerability. 7 This provides proof-of-concept that adequate ovarian suppression combined with aromatase inhibitors produces sustained clinical benefit with significant estradiol reduction. 7

However, a 2018 case series reported three instances of ovarian suppression failure during GnRH agonist treatment, highlighting that frequency of GnRH agonist administration, BMI, and young age can affect gonadotropin suppression. 6 This underscores why estradiol monitoring is not optional—it is essential. 6