Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers

Eugene F Schuster, Elena Lopez-Knowles, Anastasia Alataki, Lila Zabaglo, Elizabeth Folkerd, David Evans, Kally Sidhu, Maggie Chon U Cheang, Holly Tovey, Manuel Salto-Tellez, Perry Maxwell, John Robertson, Ian Smith, Judith M Bliss, Mitch Dowsett

Research output: Contribution to journalArticlepeer-review

Abstract

Aromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients will eventually relapse. Given the limited understanding of intrinsic resistance in these tumours, here we conduct a large-scale molecular analysis to identify features that impact on the response of ER + HER2- BC to AI. We compare the 15% of poorest responders (PRs, n = 177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant AI to good responders (GRs, n = 190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations. 
Original languageEnglish
Article number4017
Number of pages15
JournalNature Communications
Volume14
DOIs
Publication statusPublished - 07 Jul 2023

Keywords

  • Female
  • Aromatase Inhibitors - pharmacology - therapeutic use
  • Ki-67 Antigen - metabolism
  • Postmenopause
  • Receptor, ErbB-2 - genetics - metabolism
  • Receptors, Estrogen - genetics - metabolism
  • Neoplasm Recurrence, Local
  • Humans
  • Breast Neoplasms - drug therapy - genetics - metabolism

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