FEATURED , Research , Metastatic breast cancer

Alan Stolier, MD/


Presence of mutant ESR1 may stimulate endocrine resistance

Hormonal therapy benefits approximately 30% of patients with metastatic breast cancer. By adding CDK 4/6 inhibitors such as palbociclib and mTOR inhibitors such as everolimus, response rates, and disease-free progression rates are improved over hormonal therapy alone. However, the presence of a mutant form of the somatic ESR1 gene in the metastatic lesions leads to a worse prognosis in hormone receptor positive tumors. ESR1 mutations have been identified only in the metastatic setting and not in primary breast tumors. The most commonly described mutations are located at the Y537 and D538 sites though many other mutations have been described. Whereas most of the mutations have been characterized as estrogen-independent, others have been noted to be associated with estrogen hypersensitivity. 


Several studies suggest that tumors with ESR1 mutations are less sensitive to both tamoxifen and fulvestrant.  Clinical evidence suggests that many ESR1 mutations are acquired during aromatase inhibitor (AI) therapy. A study by Dustin et al suggests that the acquisition of ESR1 mutations are the most common mechanism of hormone therapy resistance in metastatic breast cancer. 


In the PALOMA-3 clinical trial, patients who failed hormonal therapy were randomized to receive either fulvestrant or fulvestrant plus the CDK4/6 inhibitor, palbociclib. ESR1 mutations were detected in 25.3% of these patients. When the ESR1 mutation was present, patients had improved survival when treated with fulvestrant plus palbociclib as opposed to fulvestrant alone. 


Similarly, in the SoFEA trial, women who responded then failed a non-steroidal AI  were randomized to receive fulvestrant plus anastrozole, fulvestrant plus placebo or the steroidal AI, exemestane. No CDK4/6 inhibitors were used. In this cohort, 39.1% of patients had ESR1 mutations. Those with mutations, treated with exemestane alone, had worse progression-free survival compared to those without mutations. Patients with our without ESR1 mutations fared better on fulvestrant. The SoFEA study suggests that patients with metastatic disease should be treated with fulvestrant if an ESR1 mutation is detected. 


The authors suggest “those ESR1 mutations represent a  small subclonal population of primary breast tumors that are most probably enriched during the course of treatment in the metastatic setting.” Furthermore, they note that there has not been a study comparing fulvestrant monotherapy with and AI plus a CDK4/6 inhibitor. Nor has there been a head to head comparison of the various CDK 4/6 inhibitors. Currently, treatment guidelines for metastatic breast cancer do not include testing for ESR1 mutation status. This is likely to change in the near future.

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