The American Society of Clinical Oncology (ASCO) has updated its guidelines to recommend routine testing for ESR1 mutations in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer. This recommendation applies at the time of disease recurrence or upon progression on endocrine therapy, marking a significant shift in the standard of care for this patient population.
The updated guideline is based on the results of the EMERALD trial, an international, open-label, randomized phase III study. The trial evaluated the efficacy and safety of elacestrant, an oral selective estrogen receptor degrader (SERD), versus standard-of-care endocrine monotherapy (including fulvestrant, anastrozole, letrozole, or exemestane). Patients included in the study had HR-positive, HER2-negative advanced breast cancer that had progressed after one or two lines of endocrine therapy and prior CDK 4/6 inhibitor treatment.
EMERALD Trial Results Drive Guideline Change
The EMERALD trial demonstrated that elacestrant improved progression-free survival (PFS) in both the overall study population and, more significantly, in patients with detectable ESR1 mutations in circulating tumor (ct)DNA. In the subgroup of 228 patients with ESR1 mutations, median PFS was 3.8 months for elacestrant compared to 1.9 months for standard-of-care endocrine therapy (HR=0.55, 95% CI 0.39-0.77). The 6-month PFS rate was 41% for elacestrant versus 19% for the standard of care.
Eleonora Teplinsky, MD, Head of Breast Medical Oncology at Valley Health System, noted the importance of these findings, stating that the EMERALD trial results and subsequent FDA approval of elacestrant in January 2023 prompted the guideline update. Prior ASCO guidelines did not recommend routine ESR1 mutation testing.
Testing Recommendations and Methodology
The updated ASCO guideline recommends that testing for ESR1 mutations be performed on either blood or tissue samples. However, it emphasizes that testing should be conducted at the time of disease progression, as ESR1 mutations often develop during treatment. Re-testing for ESR1 mutations at subsequent progressions can help determine if a mutation has emerged. Blood-based ctDNA testing is recommended due to its greater sensitivity and reduced risk to the patient compared to repeated biopsies.
Alternative Treatment Options
For patients without ESR1 mutations, alternative treatment options remain available. These include endocrine therapy alone or in combination with targeted agents such as alpelisib (for patients with PIK3CA mutations) or everolimus. The potential FDA approval of capivasertib in combination with fulvestrant is also anticipated as another treatment option for this patient population.
