The Role of ESR1 Mutations and Approaches to Biomarker Testing in Endocrine-Resistant Breast Cancer


Expert perspective on the role of ESR1 mutations in HR+/HER2- mBC and best practices on biomarker testing for patients experiencing disease progression on endocrine therapy.

Case: A 57-Year-Old Woman with HR+/HER2- Metastatic Breast Cancer


  • A 57-year-old postmenopausal woman with a personal history of breast cancer presented with sternal pain during a followup appointment

Patient history

  • She was diagnosed with stage I ER+/HER2- disease 8 years ago, at 49 years of age
    • At the time, she was prescribed 5 years of adjuvant letrozole treatment, which she completed 3 years ago

Physical exam, clinical workup, and imaging

  • Mid-sternum tenderness to palpation
  • Slight elevation in ALP, all other lab testing unremarkable
  • Bone scan showed uptake in sternum, scapula, lumbar spine, iliac crest
  • Chest/abdomen/pelvis CT revealed sclerotic bone lesions
  • Iliac bone biopsy confirmed ER+/HER2- metastatic breast cancer
    • NGS on biopsy sample was negative for mutations
  • ECOG PS=1


  • The patient received letrozole and ribociclib as first-line treatment for metastatic disease
  • 24 months after treatment initiation, CT showed enlargement of bone lesions and a single new 2-cm liver lesion
    • Liquid biopsy/ctDNA testing revealed an ESR1 mutation
  • The patient then started on elacestrant 345 mg once daily


Hope Rugo, MD, FASCO: Another question that has come up is about the role of ESR1 mutations in therapy-resistant disease. This is an interesting area, and we’ve just started to understand in the recent past. We’re still understanding more about the particular effect of various different mutations in ESR1, which have been correlated with resistance to aromatase inhibitors in particular. There are specific mutations that have been correlated with more resistance to fulvestrant as well. This is very interesting because the mechanism is basically having a mutation that changes the binding site of the estrogen receptor. Under the pressure of treatment, we’ve also seen acquisition of these mutations. For patients who develop metastatic disease and aren’t on therapy, the rate of ESR1 mutations is 3% to 4%. It’s when patients are being treated and going on with aromatase inhibitors or fulvestrant that they develop these mutations in ESR1. Sometimes using ctDNA [circulating tumor DNA], you can see multiple mutations. If I’m doing ctDNA to look at a patient who’s responding to a CDK4/6 inhibitor and an aromatase inhibitor, and I see an ESR1 mutation, I’m not going to change therapy. Sometimes it’s 0.1%, but we don’t know how pervasive it is. When they’re ready to change therapy, I’m taking that into account. As their disease progresses clinically, or they become symptomatic, you end up seeing an increase in the percentage of ESR1 mutation in ctDNA analysis.

There’s always a question about timing of biomarker testing in patients who have hormone receptor–positive, HER2 [human epidermal growth factor receptor 2]–negative disease. Before the approval of elacestrant, we had PIK3CA mutations, which might have motivated a change in treatment. We’re also looking for somatic mutations in BRCA1, BRCA2, and HER2, which may occur in hormone receptor–positive disease. We needed to get the PIK3CA results. We started doing liquid biopsies, essentially doing cell-free DNA—circulating tumor DNA, more accurately. When you think that a patient is starting to progress, it takes about 2 weeks to get the testing back. I start thinking about it when I think a patient is coming close to needing a change in therapy, so I have a better idea of what treatment options are available. Some do all their testing up front at the initial diagnosis of metastatic disease. But unlike PIK3CA mutations, ESR1 mutations are acquired during treatment to a large extent. You’re going to have to test by circulating tumor DNA when you get close a treatment change. That’s an important change in the way we think about our patients. It has occurred gradually, over the course of having new agents directed to specific mutations. That’s helpful to think about.

One other question that comes up is whether you should biopsy a tumor. In a lot of patients, we don’t have areas that are easily accessible. With bone disease, decalcification will impact your ability to look at the immunohistochemical markers. But if you have enough sample, it shouldn’t impact the DNA analysis, looking for mutations. That’s why looking at circulating tumor DNA is helpful in those patients. If you’re questioning ER [estrogen receptor], PR [progesterone receptor], and HER2, then you need to get a tumor biopsy. We’ll often do that when a patient starts to get visceral metastases. If they develop them after the first line of therapy, we’ll biopsy a visceral metastasis. In this patient’s case, she has a liver metastasis. If the liver metastasis is accessible and easy to biopsy, I’d biopsy it because we used bone initially, and the NGS [next-generation sequencing] may be a little less accurate in bone. We’re not certain. You may not get as many tumor cells. In any case, it’s a consideration. I’m always thinking about clinical trials that might be possible for a patient. That’s another consideration that drives the consideration for tissue biopsy.

Transcript edited for clarity.

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