The detection of ESR1 mutations is increasingly vital in managing hormone receptor (HR)-positive metastatic breast cancer, influencing treatment decisions and improving patient outcomes. These mutations, which confer resistance to aromatase inhibitors, are more prevalent in advanced stages of the disease, making testing crucial for effective treatment planning.
The recent FDA approval of elacestrant (Orserdu), an oral selective estrogen receptor degrader (SERD), for ER-positive/HER2-negative advanced or metastatic breast cancer, underscores the importance of ESR1 mutation testing. Elacestrant has demonstrated particular efficacy in patients with ESR1 alterations, as shown in the EMERALD study (NCT03778931).
The Role of Mutation Testing
According to Seth Wander, MD, PhD, a medical oncologist at Massachusetts General Hospital and assistant professor at Harvard Medical School, clinicians should prioritize ESR1 testing, especially in patients progressing after standard antiestrogen therapy. Mutation testing can be performed via both solid and liquid biopsies, with liquid biopsy offering a less invasive option for ongoing monitoring.
SERENA-6 Trial: A Potential Game-Changer
The SERENA-6 trial (NCT04964934) is a promising study focusing on patients with ESR1 mutations. This trial has the potential to reshape treatment strategies by tailoring interventions to the specific genetic profiles of patients. The trial's design and endpoints are closely watched by the oncology community, with hopes of providing more targeted and effective treatments.
Understanding Variant Allele Frequency (VAF)
Variant allele frequency (VAF) is a critical factor in interpreting ESR1 mutations. VAF helps assess disease biology and tumor burden, although interpreting these levels can be challenging. Higher VAFs are often associated with endocrine resistance, impacting treatment decisions. Oncologists need to consider VAF when determining the most appropriate course of action for patients with HR-positive metastatic breast cancer.
Challenges and Future Directions
Despite the advancements in ESR1 mutation testing and targeted therapies, challenges remain. Accurately interpreting VAF and understanding the key resistance mechanisms with newer treatments are ongoing areas of research. The integration of ctDNA analysis and the differences between tissue and ctDNA results for ESR1 also require further investigation to optimize treatment strategies and improve patient outcomes.
