Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

Nat Commun. 2016 May 13;7:11579. doi: 10.1038/ncomms11579.

Abstract

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast / pathology
  • Breast Neoplasms / blood
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / mortality
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics*
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Estradiol / therapeutic use
  • Estrogen Receptor Antagonists / pharmacology*
  • Estrogen Receptor Antagonists / therapeutic use
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / genetics*
  • Estrogens / metabolism
  • Female
  • Fulvestrant
  • Humans
  • Indazoles / pharmacology
  • Indazoles / therapeutic use
  • Middle Aged
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use

Substances

  • 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
  • DNA, Neoplasm
  • Estrogen Receptor Antagonists
  • Estrogen Receptor alpha
  • Estrogens
  • Indazoles
  • Protein Kinase Inhibitors
  • Sulfonamides
  • estrogen receptor alpha, human
  • Fulvestrant
  • Estradiol
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human