Second-Line Targeted Options Considered in ESR1-Mutated Breast Cancer


During a Case-Based Roundtable® event, Ruth M. O'Regan, MD, looks at options for a patients with hormone receptor–positive, HER2-negative breast cancer and an ESR1 mutation in the second article of a 2-part series.

Ruth O'Regan, MD

Ruth O'Regan, MD (Moderator)



Charles Ayrault Dewey Professorship of Medicine

Department of Medicine (SMD)

University of Rochester Medical Center

Rochester, NY


  • A 52-year-old, postmenopausal woman had a history of grade 2, node-negative invasive ductal carcinoma (IDC).
  • Estrogen receptor positive (ER+) and progesterone receptor positive (PR+); HER2 immunohistochemistry (IHC) 0; Ki-67 20%​ of the right breast; 21-gene recurrence score, 27
  • Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole.
  • Three years after completing anastrozole​, metastatic progression was discovered, including symptomatic bone involvement (multiple vertebrae and bilateral iliac crests).
    • Bone marrow aspiration confirmed ER+/PR+, HER2 IHC 0, stage IV IDC.
    • ECOG performance status: 1
    • Mild anemia
  • The patient started letrozole and ribociclib (Kisqali) with denosumab (Xgeva), with good clinical response and marked improvement in her pain​.
    • Required 1 dose reduction to 400 mg ribociclib due to neutropenia.
  • Twenty months after starting therapy, routine staging scans showed new FDG-avid sclerotic and lytic bone lesions​.
    • She noted mild increase in lower back pain​.
    • Laboratory studies were normal.
  • Circulating tumor DNA (ctDNA) analysis confirmed an ESR1 mutation​.
  • No evidence of a PIK3CA/AKT1/PTEN mutations

Which therapeutic option would you choose?

Fulvestrant + a different CDK 4/6 inhibitor
Single-agent chemotherapy

RUTH M. O’REGAN, MD: Using fulvestrant plus a different CDK4/6 inhibitor would not be an unreasonable choice if the patient didn't have an ESR1 mutation. Fulvestrant alone isn’t a [definite] option for a patient like this. I probably wouldn't use exemestane plus everolimus [Afinitor] here because I don't think this patient has definitively endocrine-resistant disease. Likewise, I probably wouldn't give single-agent chemotherapy. So I would agree with the participants and give elacestrant [Orserdu].

TIFFANY A. TRAINA, MD: I absolutely agree. I think elacestrant would be a preferred option.1 But there are some other circumstances where somebody doesn't have access to elacestrant. The ESR1 mutation would drive me towards a selective estrogen receptor degrader over an aromatase inhibitor combination. So thinking about fulvestrant is also a reasonable option, but I think elacestrant [is a recommended] option.

O’REGAN: The patient received ribociclib in the first-line setting—if she got palbociclib [Ibrance], would you consider, if she didn't have any sort of mutation, fulvestrant plus ribociclib based on the MAINTAIN trial [NCT02632045]?

TRAINA: I think [we take into account] the MAINTAIN data.2 They are certainly compelling. I have done that very thing in patients who lack other targetable mutations, had a good run on first-line palbociclib, and just have a small amount of progression. We did see data that ribociclib plus fulvestrant was better than fulvestrant alone in that population. I would consider that, remembering that phase 2 hypothesis-generating study.

KAVITA B. KALRA, MD: If you have an ESR1 mutation as well as a PIK3CA mutation, what comes first? How do you deal with that?

O’REGAN: It's a very good question. It's a data-free zone, but I think given the toxicity profile, I probably would lean towards elacestrant.

TRAINA: I think this depends on the patient in front of you and the volume of their disease. Are they symptomatic, and are we feeling comfortable with single-agent endocrine therapy knowing that we still have the ability to target the PIK3CA pathway at the subsequent progression? I think in the absence of data, it's an art-of-medicine decision. I think there's a place for single-agent endocrine therapy, given the constellation of risk-benefit balance.

O’REGAN: When you look at SOLAR-1 [NCT02437318], the benefit with alpelisib [Piqray] was pretty significant.3 We just don't know the answer right now. And I think you're absolutely right, it depends on the patient.

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 2.2024. Accessed June 6, 2024.
2. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. J Clin Oncol. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392
3. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-217. doi:10.1016/j.annonc.2020.11.011
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