dc.contributor.author | Bergamino, MA | |
dc.contributor.author | López-Knowles, E | |
dc.contributor.author | Morani, G | |
dc.contributor.author | Tovey, H | |
dc.contributor.author | Kilburn, L | |
dc.contributor.author | Schuster, EF | |
dc.contributor.author | Alataki, A | |
dc.contributor.author | Hills, M | |
dc.contributor.author | Xiao, H | |
dc.contributor.author | Holcombe, C | |
dc.contributor.author | Skene, A | |
dc.contributor.author | Robertson, JF | |
dc.contributor.author | Smith, IE | |
dc.contributor.author | Bliss, JM | |
dc.contributor.author | Dowsett, M | |
dc.contributor.author | Cheang, MCU | |
dc.contributor.author | POETIC investigators, | |
dc.date.accessioned | 2022-08-16T10:56:10Z | |
dc.date.available | 2022-08-16T10:56:10Z | |
dc.date.issued | 2022-08-16 | |
dc.identifier.citation | EBioMedicine, 2022, | |
dc.identifier.issn | 2352-3964 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5270 | |
dc.description.abstract | BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks' presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14-5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. FUNDING: Cancer Research UK (CRUK/07/015). | |
dc.language.iso | eng | |
dc.publisher | ELSEVIER | |
dc.relation.ispartof | EBioMedicine | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.title | HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-07-22 | |
dc.date.updated | 2022-08-16T10:52:20Z | |
rioxxterms.version | VoR | |
rioxxterms.licenseref.startdate | 2022-08-16 | |
rioxxterms.type | Journal Article/Review | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology | |
pubs.publication-status | Published online | |
icr.researchteam | Molecular Oncology | |
dc.contributor.icrauthor | Tovey, Holly | |
dc.contributor.icrauthor | Kilburn, Lucy | |
dc.contributor.icrauthor | Schuster, Eugene | |
dc.contributor.icrauthor | Alataki, Anastasia | |
dc.contributor.icrauthor | Bliss, Judith | |
dc.contributor.icrauthor | Cheang, Chon | |
icr.provenance | Deposited by Dr Elena Lopez Knowles on 2022-08-16. Deposit type is initial. No. of files: 1. Files: 1-s2.0-S2352396422003875-main.pdf | |