Identifying ESR1 Mutation Drives Treatment in Advanced Breast Cancer

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In this first part of a 2-article series, Joyce O’Shaughnessy, MD, recent updates to treatment and testing guidelines for patients with advanced breast cancer whose disease harbors an ESR1 mutation.

CASE

  • A 56-year-old, postmenopausal woman presented with a palpable right breast mass with no clinically abnormal axillary lymph nodes​.
  • Core biopsy: grade II invasive ductal carcinoma (IDC), estrogen receptor positive (ER+)/progesterone receptor positive (PR+), HER2 immunohistochemistry (IHC) score of 0, Ki-67 33%​
  • Lumpectomy and sentinel lymph node biopsy: 3.0 cm, grade 2 IDC, 2 sentinel lymph node (SLN) negative for malignant cells​
  • 21-gene recurrence score: 27​
  • She received 4 cycles of docetaxel and cyclophosphamide, followed by radiation therapy and completed 5 years of adjuvant aromatase inhibitor (AI).
    • Three years later she reported right-sided abdominal pain and mild nausea​.
    • CT scan CAP shows 3 suspicious liver lesions (right lobe, largest 2 cm)​.
    • Liver biopsy shows adenocarcinoma consistent with breast primary.
      • ER+/PR+, HER2 IHC 0​
  • The patient's liver enzymes were normal​.
  • Comprehensive molecular testing from tissue biopsy shows no actionable alterations​.
  • AI plus palbociclib (Ibrance) was initiated​.
    • Response: Therapy tolerated well with grade 2 neutropenia that did not require dose modification of palbociclib​.
  • Twenty months later, follow-up imaging showed increased size of both liver nodules and 2 new lung nodules, the largest measuring 0.9 cm​.
  • ECOG performance score was 0 and liver enzymes were normal.

Targeted OncologyTM: How has the new American Society of Clinical Oncology (ASCO) guidelines for ESR1 mutation testing change your considerations of treatment?

JOYCE O’SHAUGHNESSY, MD: The ASCO guidelines had a rapid communication after elacestrant (Orserdu) was approved by the FDA and they rapidly put out that we should be evaluating circulating tissues (ct) DNA or tumor tissue for ESR1 mutations, and that we should do that in the metastatic setting.1,2 We were given the green light to also do it serially, because it is an acquired mutation. Going back to primary breast cancer to look for an ESR1 mutation is not worth doing; you’re simply not going to find it. It’s not a truncal foundational mutation. It’s acquired under the selective pressure of an AI.

Joyce O’Shaughnessy, MD

Celebrating Women Chair in Breast Cancer Research​

Baylor University Medical Center​

Director, Breast Cancer Research Program​

Texas Oncology​

The US Oncology Network​

Joyce O’Shaughnessy, MD

Celebrating Women Chair in Breast Cancer Research​

Baylor University Medical Center​

Director, Breast Cancer Research Program​

Texas Oncology​

The US Oncology Network​

By the time you’re at second- or third-line therapy, you have [nearly half] of patients who have an ESR1 mutation. [However], in the first-line metastatic setting you might find it [approximately] 10% to 15% of the time, but as patients progress on the AI it’ll go to 30% to 50%. So that’s basically what the ASCO guidelines has allowed us to do now, is to get the ctDNA biopsy in the metastatic setting and to repeat it because of the availability now of an agent that targets an ESR1 mutation.

If there is progression on 3 or 4 years of adjuvant AI, is it still worth looking for an ESR1 mutation?

I’ll always get it because it gives me a chance to look at their PIK3CA and AKT [as well], and you might find it still. Then you can see if it’s also increasing in allelic frequency if you repeat [the biopsy] again upon disease progression. I get the biopsy on the first metastasis and then I get the ctDNA. You can find out all kinds of things [after that test. For example, you can see] if you have amplicons, cyclin D1 expression, amplicons coamplified with FGFR1 or it’s ligands…. I’m always looking for as much information as I can possibly get.

How does this testing affect your use of the CDK4/6 inhibitor with the AI?

Regardless, I’m going to give them a CDK4/6 inhibitor in the first line. The standard ASCO guidelines essentially are saying we have to know [if there is a] PIK3CA mutation, an ESR1 mutation, or a germline BRCA mutation. These are the [the important mutations] that we don’t want to miss.1 The HER2 mutations are also simply acquired, and you almost never find them in primary breast cancer. If you find HER2, we have the SUMMIT trial [NCT01953926], which shows that you can give the patient neratinib [Nertynx], fulvestrant [Faslodex], and trastuzumab deruxtecan [Enhertu].3

Is it possible to use other tests to find an ESR1 mutation in the patient’s disease?

Yes, you can. In the metastatic setting, if you have a biopsy [from a patient] and they’ve progressed on metastatic AI, but you haven’t done a biopsy in the metastatic setting, you could send that into next-generation sequencing [NGS] instead. It’s possible you’d find the ESR1 mutation there and not in the ctDNA. But in the EMERALD trial [NCT03778931], they used ctDNA evidence of an ESR1 mutation to define the ESR1 mutation cohort as positive [for the mutation].4

What are the mechanisms of resistance of ESR1 mutations?

What happens is…the ER mutates mainly in the ligand binding domain, right where estrogen or tamoxifen binds. They mutate there and become constituently active. They have a confirmational change and once they’re constituently active they don’t need a ligand.5 So, because of this, there was this thinking that [the receptors were resistant to the use of] endocrine therapy.

They were an autonomous entity that you couldn’t get on top of with any of our endocrine therapies because they were constituently active. [However], it turns out that if you have something that will buy into them, you can inhibit them, and that’s what the oral selective ER degraders [SERDs] are about. [These therapies are about] going after and inhibiting ERs, so it turns out that ESR1-driven breast cancer is ER-driven breast cancer.

ERs are driving it and they’re sensitive, so if you have the right agent [you can inhibit them], but before we didn’t have the right agent. AIs don’t work. Fulvestrant works very modestly. Tamoxifen doesn’t work. We haven’t had anything [until recently], so that’s why we didn’t think endocrine therapy worked [as well]. But it turns out that the oral SERDs can inhibit ESR1 mutations.5

How did the ESR1-mutated population respond to treatment on the SoFEA trial (NCT00253422)?

[These were in the] second line, before introducing the CDK4/6 inhibitors. [The SoFEA trial] was a randomization to fulvestrant vs exemestane [Aromasin]. What was seen in the ESR1 wild-type population [was that responses on] exemestane and fulvestrant were the same.6 They worked the same in the ESR1 wild-type [population]; in the ESR1 mutant [population] the exemestane was ineffective, but fulvestrant worked.

In terms of the oral SERDs, there are a number of them. They’re beginning to get culled down because some of the developments have stopped since they didn’t have signal-finding trial data that was worthy of pursuit. But there are about 4 of them still in development in the metastatic setting. Elacestrant was approved by the FDA earlier this year.2 So, we have 1 SERD available in terms of our practice availability.

References

1. Burstein HJ, DeMichele A, Somerfield MR, Henry NL; Biomarker Testing and Endocrine and Targeted Therapy in Metastatic Breast Cancer Expert Panels. Testing for ESR1 mutations to guide therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2023;41(18):3423-3425. doi:10.1200/JCO.23.00638

2. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. January 27, 2023. Accessed August 4, 2023. https://tinyurl.com/yvvafe4k

3. Jhaveri K, Goldman J, Hurvitz S, et al. Neratinib plus fulvestrant plus trastzuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial. J Clin Oncol. 2022;40(16):1028-1028. doi:10.1200/JCO.2022.40.16_suppl.1028

4. Bidard FC, Kaklamani VG, Neven P, Streich G, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD Trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338

5. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3

6. Johnston SR, Kilburn LS, Ellis P, et al; SoFEA investigators. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14(10):989-98. doi:10.1016/S1470-2045(13)70322-X

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