TY - JOUR
T1 - Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers
AU - Schuster, Eugene F
AU - Lopez-Knowles, Elena
AU - Alataki, Anastasia
AU - Zabaglo, Lila
AU - Folkerd, Elizabeth
AU - Evans, David
AU - Sidhu, Kally
AU - Cheang, Maggie Chon U
AU - Tovey, Holly
AU - Salto-Tellez, Manuel
AU - Maxwell, Perry
AU - Robertson, John
AU - Smith, Ian
AU - Bliss, Judith M
AU - Dowsett, Mitch
PY - 2023/7/7
Y1 - 2023/7/7
N2 - 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.
AB - 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.
KW - Female
KW - Aromatase Inhibitors - pharmacology - therapeutic use
KW - Ki-67 Antigen - metabolism
KW - Postmenopause
KW - Receptor, ErbB-2 - genetics - metabolism
KW - Receptors, Estrogen - genetics - metabolism
KW - Neoplasm Recurrence, Local
KW - Humans
KW - Breast Neoplasms - drug therapy - genetics - metabolism
U2 - 10.1038/s41467-023-39613-z
DO - 10.1038/s41467-023-39613-z
M3 - Article
C2 - 37419892
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
M1 - 4017
ER -
