dc.contributor.author | Leal, MF | |
dc.contributor.author | Haynes, BP | |
dc.contributor.author | Schuster, E | |
dc.contributor.author | Yeo, B | |
dc.contributor.author | Afentakis, M | |
dc.contributor.author | Zabaglo, L | |
dc.contributor.author | Martins, V | |
dc.contributor.author | Buus, R | |
dc.contributor.author | Dodson, A | |
dc.contributor.author | Cheang, MCU | |
dc.contributor.author | Smith, IE | |
dc.contributor.author | Martin, L-A | |
dc.contributor.author | Dowsett, M | |
dc.date.accessioned | 2019-10-14T08:48:50Z | |
dc.date.accessioned | 2019-12-06T14:23:18Z | |
dc.date.issued | 2019-12 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (24), pp. 7485 - 7496 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3438 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-19-1129 | |
dc.description.abstract | PURPOSE:To investigate the presence of ESR1 mutations in primary estrogen-receptor-positive (ER+) breast cancer treated with extended (>4 weeks) neoadjuvant (presurgical) aromatase inhibitor (NAI) therapy and to identify patients who may gain less benefit from aromatase inhibition (AI) alone based upon on-treatment changes in gene expression. EXPERIMENTAL DESIGN:We evaluated ER, progesterone receptor, and Ki67 by immunostaining, ESR1 mutations by droplet-digital PCR and expression of over 800 key breast cancer genes in paired pre- and post-NAI tumor samples from 87 ER+ breast cancer patients. RESULTS:Cell proliferation and estrogen-regulated genes (ERG) remained suppressed in most tumors indicative of persistent response to NAI. Enrichment of ESR1 mutations was found in five tumors and predominantly in patients receiving therapy for >6 months. ESR1-mutant tumors showed increased expression of ESR1 transcript and limited suppression of ERGs and proliferation-associated genes in response to NAI. ESR1 wild-type tumors with high residual proliferation (Ki67r ≥10%; 15/87 tumors) showed lower ESR1/ER expression pre- and post-therapy and lower ERGs. Tumors with ESR1 mutations or Ki67r ≥10% showed less inhibition of estrogen response, cell cycle, and E2F-target genes. CONCLUSIONS:Ligand-independent ER signaling, as a result of ESR1 mutation or reduced ER dependence, identified after extended NAI therapy, can guide early selection of patients who would benefit from combination therapy. | |
dc.format | Print-Electronic | |
dc.format.extent | 7485 - 7496 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.relation.replaces | https://repository.icr.ac.uk/handle/internal/3380 | |
dc.relation.replaces | internal/3380 | |
dc.relation.replaces | internal/3310 | |
dc.relation.replaces | https://repository.icr.ac.uk/handle/internal/3310 | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Breast Neoplasms | |
dc.subject | Estrogen Receptor alpha | |
dc.subject | Receptors, Progesterone | |
dc.subject | Aromatase Inhibitors | |
dc.subject | Neoplasm Staging | |
dc.subject | Treatment Outcome | |
dc.subject | Immunohistochemistry | |
dc.subject | Gene Expression Profiling | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Mutation | |
dc.subject | Aged | |
dc.subject | Aged, 80 and over | |
dc.subject | Middle Aged | |
dc.subject | Female | |
dc.subject | Biomarkers, Tumor | |
dc.title | Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-09-09 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-19-1129 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 24 | |
pubs.merge-from | internal/3310 | |
pubs.merge-from | https://repository.icr.ac.uk/handle/internal/3310 | |
pubs.notes | Not known | |
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/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
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/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 25 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Genomic Analysis – Clinical Trials | en_US |
icr.researchteam | Medicine (RMH Smith Cunningham) | en_US |
icr.researchteam | Endocrinology | en_US |
dc.contributor.icrauthor | Smith, Ian | |
dc.contributor.icrauthor | Buus, Richard | |
dc.contributor.icrauthor | Martin, Lesley-Ann | |
dc.contributor.icrauthor | Cheang, Chon | |
dc.contributor.icrauthor | Dowsett, Mitch | |