Dr Tolaney on the Optimal Timing of ESR1 Testing in HR+ Breast Cancer

"[Data from SERENA-6 could lead to a] paradigm shift in the way that we’re thinking [about testing for ESR1 mutations]. I’ve never used ctDNA monitoring [of ESR1 mutation status] to make therapeutic decisions; usually I wait until time of progression. This could be a big step forward."

Sara M. Tolaney, MD, MPH, chief of the Division of Breast Oncology and the associate director of the Susan F. Smith Center for Women’s Cancers and a senior physician at Dana-Farber Cancer Institute; as well as an associate professor of medicine at Harvard Medical School, discussed techniques used to identify ESR1 mutations in hormone receptor (HR)–positive breast cancer, as well as research that could clarify the utility and optimal timing of ESR1 testing. 

ESR1 mutations have emerged as a clinically relevant biomarker for resistance to aromatase inhibitor (AI) therapy in patients with HR-positive breast cancer, Tolaney began. Approximately 30% to 40% of patients receiving AI therapy in the metastatic setting will develop ESR1 mutations, which are predictive of poor response to further AI treatment, she reported. The presence of ESR1 mutations is useful in guiding treatment decisions, including the selection of oral selective estrogen receptor degraders, Tolaney stated. For example, elacestrant (Orsedu) has demonstrated improved efficacy compared with standard endocrine therapies in patients whose tumors harbor ESR1 mutations, she added.

In clinical practice, circulating tumor DNA (ctDNA) assays are often used at the time of patient progression on first-line endocrine therapy plus a CDK4/6 inhibitor to assess the presence of ESR1 mutations and other actionable biomarkers, such as alterations in the PI3K pathway, Tolaney continued. However, the traditional approach has been to perform molecular testing only at progression, she noted. This raises the question of whether earlier detection of resistance mechanisms—such as ESR1 mutations—could inform timely intervention and optimize outcomes, Tolaney said.

The ongoing phase 3 SERENA-6 trial (NCT04964934) was designed to address this concept, Tolaney said. In this study, patients with HR-positive/HER2-negative, ESR1-mutated advanced breast cancer receiving an AI plus CDK4/6 inhibition underwent serial ctDNA assessments, she detailed. Those who had developed an ESR1 mutation prior to radiographic or clinical progression were randomly assigned to either continue receiving an AI plus CDK4/6 inhibition or switch to camizestrant plus CDK4/6 inhibition. A press release published in February 2025 reported that the trial met its primary end point, demonstrating improved progression-free survival with the camizestrant-based strategy, Tolaney reported. These findings may represent a paradigm shift, supporting the incorporation of longitudinal ctDNA monitoring into routine management and enabling earlier therapeutic intervention in patients with emerging endocrine resistance, Tolaney concluded.