What FDA‑approved therapy is recommended for a patient with hormone‑receptor‑positive, HER2‑negative breast cancer that harbors an ESR1 mutation?

FDA-Approved Therapy for ESR1-Mutated, HR+/HER2- Breast Cancer

Elacestrant is the FDA-approved oral selective estrogen receptor degrader (SERD) specifically indicated for postmenopausal women and adult men with ER+/HER2-, ESR1-mutated advanced or metastatic breast cancer following disease progression after at least one line of endocrine therapy. 1, 2

Testing Recommendations

• Next-generation sequencing should be performed on tumor tissue or cell-free DNA (ctDNA) in plasma to detect ESR1 mutations when considering treatment options after progression on aromatase inhibitors (AIs). 1
• If no mutation is detected in ctDNA, testing tumor tissue (if available) should be performed, as this will identify additional patients with ESR1 mutations. 1
• ESR1 mutations are uncommon in treatment-naïve metastatic disease but develop in up to 40% of patients after AI exposure, with more than 90% arising as acquired resistance mechanisms. 1, 3

Treatment Algorithm for ESR1-Mutated Disease

After First-Line CDK4/6 Inhibitor + AI Progression:

Primary recommendation:

• Elacestrant monotherapy is the FDA-approved option specifically for ESR1-mutated tumors after progression on ≥1 line of endocrine therapy. 1, 2
• The EMERALD trial demonstrated improved progression-free survival with elacestrant compared to standard-of-care endocrine therapy (fulvestrant or AI) in patients with ESR1 mutations who had failed CDK4/6 inhibitor therapy. 1, 2

Alternative evidence-based options:

• Fulvestrant shows superior efficacy compared to AIs in ESR1-mutated tumors, as retrospective data demonstrate ESR1 mutations serve as a prognostic marker favoring fulvestrant over continued AI therapy. 1
• Fulvestrant + alpelisib if PIK3CA co-mutation is present (38% of patients harbor PIK3CA mutations). 1, 4
• Fulvestrant + capivasertib if AKT1, PIK3CA, or PTEN alterations are present (54% of patients have these alterations). 4, 5

Clinical Context and Nuances

Why ESR1 Testing Matters:

• Trials consistently demonstrate improved response and PFS with fulvestrant versus AIs when ESR1 mutations are detected. 1
• ESR1 mutations confer resistance to AIs but retain sensitivity to SERDs like fulvestrant and elacestrant. 1
• The presence of ESR1 mutations is associated with faster progression and poorer survival, underscoring therapeutic urgency. 3

Important Caveats:

• Routine ESR1 testing is NOT recommended in treatment-naïve metastatic disease because mutations are infrequent without prior AI exposure and unlikely to change initial treatment decisions. 1
• ESR1 mutations can be acquired or lost during treatment, making archival sample interpretation complex. 1
• The PARSIFAL trial showed no PFS difference between letrozole versus fulvestrant (both with palbociclib) in first-line treatment, regardless of ESR1 status. 1

Elacestrant Specifics:

• Approved January 2023 by the FDA for ESR1-mutated, ER+/HER2- advanced breast cancer. 2, 6
• Unlike fulvestrant (intramuscular injection), elacestrant is oral, improving convenience and bioavailability. 3, 6
• Not associated with cardiac or ocular toxicity seen with other SERDs. 3
• Maintains comparable adverse event profile to other endocrine therapies. 2

Emerging Evidence

• Camizestrant, a next-generation oral SERD, showed significantly longer PFS (16.0 vs 9.2 months) when patients switched to camizestrant upon detection of emerging ESR1 mutations during first-line AI + CDK4/6 inhibitor therapy. 7
• Multiple oral SERDs are in development (PROTACs, SERCAs, CERANs) being tested in combination with CDK4/6 inhibitors. 3, 5

Common Pitfalls to Avoid

• Do not continue AI therapy after detecting ESR1 mutations—retrospective data show minimal clinical benefit with ongoing AI in ESR1-mutated tumors. 1
• Do not rely solely on liquid biopsy—if ctDNA is negative but clinical suspicion remains high, test tumor tissue. 1
• Do not test for ESR1 in treatment-naïve patients—insufficient evidence supports routine testing before AI exposure. 1
• Consider co-mutations—38% have PIK3CA mutations and 54% have AKT pathway alterations that may warrant combination therapy. 4, 5