Evaluation of endocrine resistance using ESR1 genotyping of circulating tumor cells and plasma DNA

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Tilak K. Sundaresan
  • Taronish D. Dubash
  • Aditya Bardia
  • Ben S. Wittner
  • Nicola Aceto
  • Erin J. Silva
  • Douglas B. Fox
  • Matthew Liebers
  • Ravi Kapur
  • John Iafrate
  • Mehmet Toner
  • Shyamala Maheswaran
  • Daniel A. Haber

Detail(s)

Original languageEnglish
Pages (from-to)43-52
Journal / PublicationBreast Cancer Research and Treatment
Volume188
Issue number1
Online published8 Jun 2021
Publication statusPublished - Jul 2021
Externally publishedYes

Abstract

Purpose  Therapeutic efficacy of hormonal therapies to target estrogen receptor (ER)-positive breast cancer is limited by the acquisition of ligand-independent ESR1 mutations, which confer treatment resistance to aromatase inhibitors (AIs). Monitoring for the emergence of such mutations may enable individualized therapy. We thus assessed CTC- and ctDNA-based detection of ESR1 mutations with the aim of evaluating non-invasive approaches for the determination of endocrine resistance. 
Patients and methods  In a prospective cohort of 55 women with hormone receptor-positive metastatic breast cancer, we isolated circulating tumor cells (CTCs) and developed a high-sensitivity method for the detection of ESR1 mutations in these CTCs. In patients with sufficient plasma for the simultaneous extraction of circulating tumor DNA (ctDNA), we performed a parallel analysis of ESR1 mutations using multiplex droplet digital PCR (ddPCR) and examined the agreement between these two platforms. Finally, we isolated single CTCs from a subset of these patients and reviewed RNA expression to explore alternate methods of evaluating endocrine responsiveness. 
Results  High-sensitivity ESR1 sequencing from CTCs revealed mono- and oligoclonal mutations in 22% of patients. These were concordant with plasma DNA sequencing in 95% of cases. Emergence of ESR1 mutations was correlated both with time to metastatic relapse and duration of AI therapy following such recurrence. The Presence of an ESR1 mutation, compared to ESR1 wild type, was associated with markedly shorter Progression-Free Survival on AI-based therapies (p=0.0006), but unaltered to other non-AI-based therapies (p=0.73). Compared with ESR1 mutant cases, AI-resistant CTCs with wild-type ESR1 showed an elevated ER-coactivator RNA signature, consistent with their predicted response to second-line hormonal therapies. 
Conclusion  Blood-based serial monitoring may guide the selection of precision therapeutics for women with AI-resistant ER-positive breast cancer.

Research Area(s)

  • Acquired ESR1 mutations, AI resistance ER + breast cancer, Circulating tumor cells (CTCs), Circulating tumor DNA (ctDNA), High-sensitivity ESR1 sequencing

Citation Format(s)

Evaluation of endocrine resistance using ESR1 genotyping of circulating tumor cells and plasma DNA. / Sundaresan, Tilak K.; Dubash, Taronish D.; Zheng, Zongli; Bardia, Aditya; Wittner, Ben S.; Aceto, Nicola; Silva, Erin J.; Fox, Douglas B.; Liebers, Matthew; Kapur, Ravi; Iafrate, John; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A.

In: Breast Cancer Research and Treatment, Vol. 188, No. 1, 07.2021, p. 43-52.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review