There is one simple step clinical laboratory teams can and should take today to improve outcomes for patients with a specific type of breast cancer: implement ESR1 mutation testing.
Before treatment, patients with metastatic hormone receptor-positive (HR+) breast cancer rarely have ESR1 mutations. However, first-line endocrine therapies often cause new mutations in this gene, which can signal early treatment resistance. Detecting ESR1 mutations early allows oncologists to adjust treatment, using FDA-approved therapies when needed. For some patients, this adjustment may be crucial in managing their cancer.
Currently, ESR1 mutation testing is mainly used when a patient with metastatic hormone receptor-positive (HR+) breast cancer shows signs of progression while on endocrine therapy. If cancer growth is confirmed through imaging or biopsy, genetic testing is performed, often using whole genome or exome sequencing. However, this approach is inefficient since most breast cancer mutations occur early and are already identified in initial genomic profiling. ESR1 mutations, on the other hand, are acquired later and typically exist at low levels, making plasma-based tests with high sensitivity a better choice.
Since ESR1 mutations are the main drivers of resistance to endocrine therapy, sequencing the entire genome or exome is unnecessary. However, testing only ESR1 mutations with next-generation sequencing is costly. A more efficient option is a qPCR-based method that analyzes exosomal RNA alongside cell-free DNA. This approach enhances detection sensitivity, is cost-effective, and can be performed using a simple blood sample (liquid biopsy). With qPCR technology widely available in clinical labs, ESR1 testing can become routine rather than reserved for advanced disease progression.
Clinical trials support this strategy. The PADA-1 trial, which tracks about 1,000 HR+ metastatic breast cancer patients, uses bimonthly ESR1 monitoring (1,2). If mutations appear, patients switch to the ESR1-targeting drug fulvestrant. Early results show that those who switched had more than double the progression-free survival compared to those who stayed on standard endocrine therapy.
Similarly, the SERENA trials are testing a new therapy for patients with ESR1 mutations after progression on endocrine therapy, with an early-switching phase 3 study underway.
These trials suggest that frequent ESR1 testing could improve outcomes by adjusting treatment before the tumor visibly progresses. Reflecting this, the National Comprehensive Cancer Network has updated its guidelines to recommend ESR1-targeted therapy based on liquid biopsy results, and the American Society of Clinical Oncology now advises routine plasma-based ESR1 testing for metastatic estrogen receptor-positive breast cancer (3).
While some labs may need more data to justify adopting routine ESR1 monitoring, they can take steps now by implementing ESR1 mutation testing at tumor progression. For instance, setting up and validating this process at the point of tumor progression. This groundwork will make scaling up to continuous monitoring easier in the future. Ultimately, routine ESR1 screening could transform metastatic breast cancer care, enabling earlier intervention and optimizing patient care.
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References
- FC Bidard et al., Lancet Oncol, 23, 11 (2022). PMID: 36183733.
- The ASCO Post (2022). Available at: https://ascopost.com/issues/october-10-2022-supplement-breast-cancer-almanac/pada-1-trial-with-early-identification-of-esr1-mutation-switch-to-fulvestrant-in-metastatic-breast-cancer/
- HJ Burstein et al., J Clin Oncol, 41, 18 (2023). PMID: 37196213.
