Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer

Abstract

Acquired ESR1 mutations are a major mechanism of resistance to aromatase inhibitors (AI). We developed ultra-high sensitivity multiplexed digital PCR assays for ESR1 mutations in circulating tumor DNA (ctDNA) and used these to investigate the clinical relevance and origin of ESR1 mutations in a cohort of 171 women with advanced breast cancer. ESR1 mutation status in ctDNA showed high concordance with contemporaneous tumor biopsies, and could be assessed in samples shipped at room temperature in preservative tubes without loss of accuracy. ESR1 mutations were found exclusively in patients with estrogen receptor positive breast cancer previously exposed to AI. Patients with ESR1 mutations had a substantially shorter progression-free survival on subsequent AI-based therapy (HR 3.1, 95%CI 1.9-23.1, log rank p=0.0041). ESR1 mutation prevalence differed markedly between patients that were first exposed to AI during the adjuvant and metastatic settings (5.8% (3/52) vs 36.4% (16/44) respectively, p=0.0002). In an independent cohort, ESR1 mutations were identified in 0% (0/32, 95%CI 0-10.9%) tumor biopsies taken after progression on adjuvant AI. In a patient with serial samples taken during metastatic treatment, ESR1 mutation was selected during metastatic AI therapy, to become the dominant clone in the cancer. ESR1 mutations can be robustly identified with ctDNA analysis and predict for resistance to subsequent AI therapy. ESR1 mutations are rarely acquired during adjuvant AI therapy, but are commonly selected by therapy for metastatic disease, providing evidence that the mechanisms of resistance to targeted therapy may be substantially different between the treatment of micro-metastatic and overt metastatic cancer.

WITHDRAWN: Prognostic value of circulating tumor DNA in breast cancers

“…Recently, multiple studies have investigated the correlation between the presence of ctDNA and prognosis among breast cancer patients. An overwhelming majority of the evidence has shown a correlation between poor prognosis and the presence of ctDNA in breast cancer [17][18][19][20], but several studies have failed to draw similar conclusions [21][22]. Therefore, the prognostic value of ctDNA in breast cancer patients remains controversial.…”

The Role of Genomic Profiling in Advanced Breast Cancer: The Two Faces of Janus

“…Clinical data suggest that patients with acquired ESR1 mutations following treatment with aromatase inhibitors may retain sensitivity to a higher dose of selective estrogen receptor modulators or CDK4/6 inhibition. [51][52][53] These observations have sparked interest in the correct sequencing of subsequent endocrine agents, as well as development of more potent estrogen receptor antagonists. In the near future, we are anticipating more clinical applications involving ESR1 mutations for the management of ER (+) breast cancer.…”

Molecular Diagnostics in Breast Cancer Routine Practice

“…Aromatase inhibitor treatment in the metastatic setting rather than in the adjuvant setting induces ESR1 mutations. 28 The pan-phosphatidylinositol 3-kinase (PI3K) inhibitor pictilisib and the CDK4/6-inhibitor palbociclib do not seem to be effective in ESR1 mutated patients, 29 and ESR1 mutations did not indicate impaired survival on fulvestrant compared to ESR1 wildtype. On examestane, however, ESR1 mutations do seem to indicate worse prognosis.…”