Understanding the Significance of ESR1 Mutations in Breast Cancer
Seth Wander, MD, PhD, discusses the significance of ESR1 mutations in patients with hormone receptor–positive, HER2-negative metastatic breast cancer.
Seth Wander, MD, PhD, a medical oncologist at the Massachusetts General Hospital and instructor in medicine at Harvard Medical School, discusses the significance of ESR1 mutations in patients with hormone receptor–positive, HER2-negative metastatic breast cancer.
Initially, ESR1 mutations are rare in newly diagnosed patients, occurring in less than 5% of cases. However, in patients who have undergone extensive prior therapy, particularly with aromatase inhibitors, these mutations become more common, according to Wander.
These mutations, often found in the ligand binding domain of the estrogen receptor, enable the receptor to remain active even without estrogen, allowing tumors to resist aromatase inhibitor therapy. Wander says this underscores the importance of using next-generation sequencing after a patient’s cancer progresses on anti-estrogen therapy, since ESR1 mutations may be missed if oncologists are relying solely on initial samples.
0:10 | This is a very important area of active research, and it’s dramatically reshaped our understanding of how patients respond and progress to anti-estrogen therapy for patients who have hormone receptor–positive, HER2-negative metastatic breast cancer. The ESR1 gene encodes the estrogen receptor protein and in patients who have newly diagnosed breast cancer, whether that’s primary breast cancer that’s never been treated, or metastatic breast cancer that hasn’t had a lot of prior therapy, mutations in the ESR1 gene are exceedingly rare—typically low single digits, well under 5%.
0:48 | For patients who have had a fair amount of prior therapy, typically with an aromatase inhibitor over a number of years, you start to see accumulation of mutations in ESR1. These mutations tend to occur in the ligand binding domain of the protein, and they allow the estrogen receptor to be constitutively active even in the absence of ligand, in the absence of estrogen. So that's how the tumors can find their way around aromatase inhibitor therapy, which is just lowering the amount of estrogen in the body. I think this really highlights the importance of pursuing next-generation sequencing after a patient progresses on anti-estrogen therapy. If we’re only relying on the baseline sample, we'll often miss the ESR1 mutations, which tend to pop up later.
