Testing for the emergence of ESR1 mutations should be routine at disease recurrence or progression for patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer whose disease is being managed with endocrine therapy, according to an ASCO guideline rapid recommendation update.1 The preferred testing method is blood-based circulating tumor DNA (ctDNA), owing to greater sensitivity compared with tissue testing.
“The tumor should be tested in real time, and possibly multiple times, to determine if it has acquired an ESR1 mutation, and the easiest way to do this is through a liquid biopsy,” said Expert Panel Co-Chair Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute. “Our panel agreed that ctDNA is an important molecular diagnostic test to identify the presence of an acquired ESR1 mutation. We endorsed liquid biopsy [ctDNA testing] and, if necessary, serial liquid biopsy testing, which I think is an important step forward.”
Harold J. Burstein, MD, PhD
Angela DeMichele, MD
According to the update, patients whose tumor or ctDNA tests remain ESR1 wild-type may warrant retesting at subsequent disease progression to determine whether an ESR1 mutation has emerged.
In addition to the testing recommendation, the updated guideline adds the oral selective estrogen receptor degrader elacestrant as a treatment option for patients with metastatic breast cancer and a detectable ESR1 mutation when experiencing disease progression on endocrine therapy, with or without prior CDK4/6 inhibitor treatment.
“We needed to update the treatment guideline and the testing guideline simultaneously,” said Expert Panel Co-Chair Angela DeMichele, MD, of the University of Pennsylvania. “This is the first time we’ve utilized ESR1 mutations to choose a specific therapy. It’s an example of what’s to come as we are better able to identify the particular biologically sensitive groups of tumors that will respond to targeted therapies, and that’s what we’re after in terms of precision medicine.”
New Data Spur Updated Guidance
On January 27, 2023, the U.S. Food and Drug Administration (FDA) approved elacestrant for the treatment of disease in postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, who experience disease progression following at least one line of endocrine therapy, based on the findings from EMERALD.2 A companion diagnostic to identify the mutation in blood was also approved by the FDA.
The new recommendations update a 2021 clinical practice guideline and reflect data from the phase III randomized EMERALD trial.3 The panel that issued the 2021 guidance reconvened to review EMERALD, which randomly assigned postmenopausal women or men with advanced breast cancer to either elacestrant or physician’s choice standard-of-care endocrine therapy following cancer progression after first-line or second-line endocrine therapy and a CDK4/6 inhibitor in combination with endocrine therapy as part of their prior treatment. In EMERALD, the overall study population and participants with detectable ESR1 mutations in ctDNA who were randomly assigned to elacestrant experienced an improvement in progression-free survival compared with the standard of care; whereas among participants without detectable ESR1 mutations, no significant improvement in progression-free survival with elacestrant compared with the standard of care was observed.
According to the updated guideline, other choices at disease progression with an ESR1 mutation are combination regimens that incorporate fulvestrant; treatment options at disease progression with prior CDK4/6 inhibitor treatment and a detectable ESR1 mutation include elacestrant or other endocrine therapy, either alone or in combination with targeted agents, such as alpelisib (for those with PIK3CA-mutated tumors) or everolimus. Elacestrant should not be used as part of a combination regimen at this point, as safety data to this approach are currently lacking, Dr. Burstein added.
REFERENCES
1. Burstein HJ, DeMichele A, Somerfield MR, et al: Testing for ESR1 mutations to guide therapy for HR-positive, human epidermal growht factor receptor 2-negative metastatic breast cancer: ASCO guideline rapid recommendation update. J Clin Oncol. May 17, 2023 (early release online).
2. Bidard FC, Kaklamani VG, Neven P, et al: Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol 40:3246-3256, 2022.
3. Burstein HJ, Somerfield MR, Barton DL, et al: Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol 39:3959-3977, 2021.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, May 18, 2023. All rights reserved.
