What is the role of Letrozole (aromatase inhibitor) in the treatment of a postmenopausal patient with low-grade serous ovarian cancer (LGSOC) that is estrogen receptor-positive?

Letrozole in Low-Grade Serous Ovarian Cancer

Primary Recommendation

Letrozole (or another aromatase inhibitor) should be strongly considered as maintenance therapy or treatment for postmenopausal patients with estrogen receptor-positive low-grade serous ovarian cancer (LGSOC), particularly in the recurrent or platinum-resistant setting, based on the unique biology of this disease and emerging clinical evidence. 1, 2

Rationale: Why LGSOC Differs from High-Grade Disease

Low-grade serous ovarian cancer is fundamentally different from high-grade serous ovarian cancer in its chemosensitivity and hormonal responsiveness:

• LGSOC demonstrates significantly lower response rates to platinum-based chemotherapy compared to high-grade disease, with multiple retrospective studies confirming limited chemosensitivity and less survival benefit from standard cytotoxic regimens 1
• The majority of LGSOC tumors express high levels of estrogen receptor (ER) and progesterone receptor (PR), making them biologically similar to hormone receptor-positive breast cancer where aromatase inhibitors are standard of care 1, 2
• Complete surgical cytoreduction remains the cornerstone of LGSOC management due to the limited chemosensitivity, with even debulking to <1 cm residual disease potentially improving survival when complete cytoreduction is not feasible 1

Clinical Evidence Supporting Letrozole in LGSOC

Strongest Recent Evidence

In a 2020 phase II trial, the combination of ribociclib (CDK4/6 inhibitor) plus letrozole demonstrated 100% progression-free survival at 24 weeks in all three LGSOC patients enrolled, with all three achieving at least partial response lasting over 2 years 2. This represents the highest quality recent evidence specifically addressing LGSOC, though the sample size is small.

Supporting Data

• Small retrospective studies suggest therapeutic value of hormone therapy in both first-line and recurrent LGSOC settings 1
• Letrozole appears to provide prolonged disease control and recurrence-free intervals, particularly when used as maintenance treatment in LGSOC 3
• The favorable toxicity profile of letrozole makes it an attractive option for prolonged maintenance therapy 3

Treatment Algorithm for ER-Positive LGSOC

Primary Setting (After Initial Surgery and Chemotherapy)

1. Complete optimal surgical cytoreduction with no macroscopic residual disease (Level of evidence: IV, Strength: A) 1
2. Administer carboplatin plus paclitaxel as standard chemotherapy, with consideration for adding bevacizumab (Level of evidence: I, Strength: B) 1
3. Consider letrozole as maintenance therapy following completion of chemotherapy in ER-positive disease, particularly if residual disease remains or high-risk features are present 1, 3

Recurrent/Platinum-Resistant Setting

1. Assess ER/PR status if not previously documented 1
2. For ER-positive recurrent LGSOC, prioritize letrozole over additional chemotherapy given the limited chemosensitivity and hormonal responsiveness of this histology 1, 2
3. Consider combination therapy with letrozole plus CDK4/6 inhibitor (ribociclib) if available through clinical trial, as this demonstrated exceptional activity in the phase II trial 2
4. Secondary cytoreductive surgery should be pursued if complete resection is feasible, as this significantly improves progression-free and overall survival in recurrent LGSOC 1

Critical Clinical Caveats

Verification of Menopausal Status

• Letrozole is absolutely contraindicated in premenopausal women and will not adequately suppress ovarian estrogen synthesis in women with functioning ovaries 4
• Serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to confirm true postmenopausal status before initiating aromatase inhibitor therapy 4
• For premenopausal patients with ER-positive LGSOC, ovarian suppression with LHRH agonist plus letrozole may be considered, though this is extrapolated from breast cancer data 1

Monitoring and Duration

• The optimal duration of letrozole maintenance in LGSOC is undefined, but extrapolating from breast cancer guidelines suggests 5 years minimum, with consideration for extended therapy in high-risk cases 4
• Baseline DEXA scan is recommended for patients >65 years or with risk factors for osteoporosis, as aromatase inhibitors increase fracture risk (11.0% vs 7.7% with tamoxifen) 4
• Calcium and vitamin D supplementation should be provided to all patients on letrozole 5

Comparison to High-Grade Serous Ovarian Cancer

Letrozole should NOT be considered standard therapy for high-grade serous ovarian cancer (HGSOC), despite some emerging data:

• While HGSOC may express ER at similar levels to breast cancer, the clinical benefit of aromatase inhibitors in HGSOC remains investigational 6, 7
• One small study suggested letrozole maintenance prolonged recurrence-free survival in ER-positive HGSOC (60% vs 38.5% at 24 months), but this requires validation in randomized trials 6
• The ESMO consensus explicitly states that maintenance anti-estrogen therapy in LGSOC needs further evaluation, and does not endorse it as standard for HGSOC 1

Practical Implementation

Starting Letrozole

• Dose: 2.5 mg orally once daily (standard dose from breast cancer literature) 2
• Timing: Initiate after completion of primary chemotherapy or at time of recurrence in platinum-resistant disease 3
• Monitoring: Clinical assessment every 3 months with CA-125 and imaging every 3-6 months based on disease burden 1

Managing Toxicity

• Arthralgias occur in approximately 35% of patients on aromatase inhibitors and may require switching between non-steroidal (letrozole, anastrozole) and steroidal (exemestane) agents 4
• Vaginal dryness is common; non-hormonal lubricants are first-line, with estriol-based (not estradiol) vaginal preparations as second-line if needed 8
• Bone health monitoring with DEXA every 1-2 years and bisphosphonate therapy if T-score falls below -2.0 or fragility fracture occurs 4, 5

Emerging Combinations

The combination of letrozole with targeted agents shows promise in LGSOC:

• Letrozole plus ribociclib (CDK4/6 inhibitor) demonstrated exceptional activity in the small LGSOC cohort 2
• Letrozole plus MEK inhibitors (avutometinib) and FAK inhibitors are under investigation in preclinical models with acquired resistance to chemotherapy and aromatase inhibitors 9
• These combinations should be pursued through clinical trials when available for patients with recurrent LGSOC 2, 9