What is the role of Selective Estrogen Receptor Downregulators (SERDs) and Selective Estrogen Receptor Modulators (SERMs) in the treatment of early-stage Estrogen Receptor (ER)-positive breast cancer?

SERDs and SERMs in Early-Stage ER-Positive Breast Cancer

For early-stage ER-positive, HER2-negative breast cancer, standard endocrine therapy remains aromatase inhibitors (AIs) or tamoxifen (a SERM) for 5-10 years, with the addition of CDK4/6 inhibitors (specifically abemaciclib) in high-risk node-positive disease. 1, 2 While oral SERDs represent an exciting advance, they are not yet standard in the early-stage setting and remain investigational in this context. 3, 4

Current Standard: SERMs and AIs Dominate Early-Stage Treatment

Postmenopausal Women

• AIs are preferred over tamoxifen as they demonstrate superior outcomes with modest but meaningful improvements in disease-free survival and overall survival. 1
• Standard duration is 5 years, with extended therapy to 7-10 years further reducing recurrence risk, particularly in higher-stage cancers. 1
• Tamoxifen (a SERM) remains an option for those who decline or have contraindications to AIs. 1

Premenopausal Women

• Tamoxifen for 5 years (with or without ovarian suppression) is standard. 1
• For higher-risk disease, ovarian suppression plus an AI reduces recurrence more than tamoxifen alone and improves overall survival. 1
• Extended tamoxifen up to 10 years should be considered for those remaining premenopausal after initial 5-year treatment. 1

The SERD Story: Fulvestrant's Role

Metastatic Disease Context

• Fulvestrant is the only FDA-approved SERD and is established for metastatic ER-positive breast cancer, not early-stage disease. 5
• In first-line metastatic treatment, fulvestrant (500 mg monthly) showed improved time to progression versus anastrozole (23.4 vs 13.1 months; HR 0.63) and longer overall survival (54.1 vs 48.4 months; HR 0.70). 1
• Fulvestrant demonstrates particular benefit in ESR1-mutated tumors, which commonly develop after AI exposure. 1

Why Not Standard in Early-Stage Disease?

• Fulvestrant requires intramuscular injection, limiting its practicality for long-term adjuvant use. 5, 4
• No established role in curative early-stage treatment based on current guidelines. 1

Emerging Oral SERDs: The Future, Not the Present

Development Rationale

• Oral SERDs were developed to overcome fulvestrant's poor bioavailability and injection requirement. 5, 4
• They show activity against ESR1 mutations, a key resistance mechanism to AIs. 3, 4
• Elacestrant is FDA-approved for ESR1-mutated advanced breast cancer, not early-stage disease. 3

Current Status in Early-Stage Disease

• Oral SERDs are in phase III trials for early breast cancer. 4
• Their impact on survival in the curative setting compared to standard endocrine therapy remains unknown. 3
• Optimal timing, duration, and specific biomarkers for oral SERD use in the adjuvant setting are undefined. 3

High-Risk Early Disease: CDK4/6 Inhibitors Are the Real Advance

For node-positive, high-risk ER-positive breast cancer, adding abemaciclib to endocrine therapy for 2 years is now standard. 1, 2

Abemaciclib Criteria (monarchE Trial)

• ≥4 positive lymph nodes, OR
• 1-3 positive nodes PLUS either:
  • Grade 3 tumor, OR
  • Tumor ≥50 mm, OR
  • Ki-67 ≥20% 1, 2

Efficacy

• 6.4% absolute reduction in recurrence risk at 4 years (HR 0.664). 1
• This represents a more significant advance than any SERD data in early-stage disease. 1

ESR1 Mutation Testing: Not Recommended for Early Disease

• Insufficient data to recommend routine ESR1 testing to guide therapy in early-stage breast cancer. 1
• ESR1 mutations are uncommon in early-stage disease and primarily develop after AI exposure in the metastatic setting. 1
• Testing has established utility only in metastatic disease after AI progression, where it supports switching to fulvestrant. 1

Critical Pitfalls to Avoid

Don't Confuse Metastatic and Early-Stage Evidence

• SERDs (including oral agents) have proven benefit in advanced/metastatic disease, particularly with ESR1 mutations. 1, 5, 3
• This does not translate to standard use in early-stage curative treatment. 3

Don't Overlook Proven Therapies

• AIs remain superior to tamoxifen in postmenopausal women with early-stage disease. 1
• CDK4/6 inhibitors with endocrine therapy are the established advance for high-risk node-positive disease. 1, 2

Don't Assume Oral = Better

• While oral SERDs offer convenience over fulvestrant injections, they lack proven superiority over standard endocrine therapy in early-stage disease. 3, 4
• Bioavailability improvements don't automatically translate to better clinical outcomes. 4

Practical Algorithm for Early-Stage ER+ Breast Cancer

Step 1: Assess menopausal status and risk

• Postmenopausal + standard risk → AI for 5-10 years 1
• Premenopausal + standard risk → Tamoxifen ± ovarian suppression for 5 years 1

Step 2: Identify high-risk node-positive disease

• If ≥4 nodes OR 1-3 nodes with grade 3/size ≥50mm/Ki-67 ≥20% → Add abemaciclib for 2 years 1, 2

Step 3: Extended therapy consideration

• After 5 years, if postmenopausal → Consider AI extension to 7-10 years 1
• After 5 years, if premenopausal → Consider tamoxifen extension to 10 years 1

SERDs and oral SERDs are NOT part of this algorithm for early-stage disease. 3, 4