ctDNA Has High Sensitivity ESR1 Mutations in Metastatic Breast Cancer

ctDNA may be the best method to detect ESR1 mutations in patients with metastatic breast cancer.

After a patient with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer experiences disease progression on frontline therapy, it is essential that they be tested for an ESR1 mutation. ctDNA testing is the best way to do that, according to a physician assistant from Maimonides Cancer Center.

About ESR1 Mutations in Metastatic Breast Cancer

While ESR1 mutations are rare in untreated patients, they occur in approximately 40% of patients after they received endocrine therapy. These mutations occur in the ligand binding disease and make the disease resistant to aromatase inhibitors.¹

“It changes the shape so that the ligand cannot bind to the receptor, and it cannot do what it is supposed to do. The cancer starts to corroborate, and it causes progression of the disease,” Yan Pronin, PA-C, a physician assistant at Maimonides Cancer Center explained.

At a recent Community Case Forum, Pronin and colleagues discussed second-line treatment for ER-positive, HER2-negative metastatic breast cancer.

More specifically, ESR1 mutations alter the shape of the estrogen receptor, resulting in the receptor having a decreased affinity for ligands such as estrogen, selective estrogen receptor modulators, and selective estrogen receptor degraders (SERDs).¹

ctDNA Versus Tissue Biopsy for ESR1 Mutations

Elacestrant (Orserdu) was FDA-approved to treat patients with ESR1-mutant metastatic breast cancer in the second line, highlighting the importance of testing patients whose disease recurs or progresses on frontline endocrine therapy to see if they have the mutation. If they do, hormone therapies likely will not be effective.

READ MORE: ESR1 Testing Is Crucial in Second-line HR+, HER2- Metastatic Breast Cancer

Pronin polled attendees about what type of samples are sent for testing when patients in their practice with ER-positive, HER2-negative metastatic breast cancer experience recurrence on first-line therapy with a CDK4/6 inhibitor and aromatase inhibitor. Answers were:

• Tumor tissue (archival tumor tissue): 12.5%
• Tumor tissue (fresh biopsy): 25%
• Blood (for liquid biopsy/ctDNA testing): 62.5%
• I do not order molecular testing: 0%

Prior studies have used ctDNA to prove that hormone therapies lose their efficacy in treating metastatic breast cancer once it develops an ESR1 mutation. Data from the SoFEA trial (NCT00253422) and the EFFECT trial (NCT03778931) both showed that patients with ESR1-mutant disease, as detected via ctDNA, tended to show a trend toward inferior progression-free survival (PFS) and overall survival (OS) with exemestane or fulvestrant.²

“Tissue biopsy is old school. It’s low sensitivity, it’s a very invasive procedure… it’s very high cost and requires more material, and its storage is also more complicated than liquid biopsy, which is just a blood test. It’s very easy and high sensitivity with ESR1 mutations. It’s minimally invasive, low cost and requires less tumor and has very simple preservation,” Pronin said. “That’s why we recommend ctDNA.”

References

1. 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 Aug 15;23(1):85. doi: 10.1186/s13058-021-01462-3

2. Turner NC, Swift C, Kilburn L, et al. ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor-Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFFECT Trials. Cancer Clinical Res. Oct 1;26(19):5172-5177. doi: 10.1158/1078-0432.CCR-20-0224.