dc.contributor.author | Schuster, EF | |
dc.contributor.author | Gellert, P | |
dc.contributor.author | Segal, CV | |
dc.contributor.author | López-Knowles, E | |
dc.contributor.author | Buus, R | |
dc.contributor.author | Cheang, MCU | |
dc.contributor.author | Morden, J | |
dc.contributor.author | Robertson, J | |
dc.contributor.author | Bliss, JM | |
dc.contributor.author | Smith, I | |
dc.contributor.author | Dowsett, M | |
dc.contributor.author | POETIC Trial Management Group and Trialists, | |
dc.date.accessioned | 2019-03-04T14:41:47Z | |
dc.date.issued | 2019-01 | |
dc.identifier.citation | JCO precision oncology, 2019, 3 | |
dc.identifier.issn | 2473-4284 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3115 | |
dc.identifier.eissn | 2473-4284 | |
dc.identifier.doi | 10.1200/po.18.00286 | |
dc.description.abstract | PURPOSE: Although aromatase inhibitor (AI) treatment is effective in estrogen receptor-positive postmenopausal breast cancer, resistance is common and incompletely explained. Genomic instability, as measured by somatic copy number alterations (SCNAs), is important in breast cancer development and prognosis. SCNAs to specific genes may drive intrinsic resistance, or high genomic instability may drive tumor heterogeneity, which allows differential response across tumors and surviving cells to evolve resistance to treatment rapidly. We therefore evaluated the relationship between SCNAs and intrinsic resistance to treatment as measured by a poor antiproliferative response. PATIENTS AND METHODS: SCNAs were determined by single nucleotide polymorphism array in baseline and surgery core-cuts from 73 postmenopausal patients randomly assigned to receive 2 weeks of preoperative AI or no AI in the Perioperative Endocrine Therapy-Individualizing Care (POETIC) trial. Fifty-six samples from the AI group included 28 poor responders (PrRs, less than 60% reduction in protein encoded by the MKI67 gene [Ki-67]) and 28 good responders (GdRs, greater than 75% reduction in Ki-67). Exome sequencing was available for 72 pairs of samples. RESULTS: Genomic instability correlated with Ki-67 expression at both baseline (P < .001) and surgery (P < .001) and was higher in PrRs (P = .048). The SCNA with the largest difference between GdRs and PrRs was loss of heterozygosity observed at 17p (false discovery rate, 0.08), which includes TP53. Nine of 28 PrRs had loss of wild-type TP53 as a result of mutations and loss of heterozygosity compared with three of 28 GdRs. In PrRs, somatic alterations of TP53 were associated with higher genomic instability, higher baseline Ki-67, and greater resistance to AI treatment compared with wild-type TP53. CONCLUSION: We observed that primary tumors with high genomic instability have an intrinsic resistance to AI treatment and do not require additional evolution to develop resistance to estrogen deprivation therapy. | |
dc.format | Electronic-eCollection | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC CLINICAL ONCOLOGY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | POETIC Trial Management Group and Trialists | |
dc.title | Genomic Instability and TP53 Genomic Alterations Associate With Poor Antiproliferative Response and Intrinsic Resistance to Aromatase Inhibitor Treatment. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-02-25 | |
rioxxterms.versionofrecord | 10.1200/po.18.00286 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | JCO precision oncology | |
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/Endocrine Therapy Resistance | |
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/Clinical Trials & Statistics Unit | |
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/Endocrine Therapy Resistance | |
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/Clinical Trials & Statistics Unit | |
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 | 3 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Endocrine Therapy Resistance | |
icr.researchteam | Clinical Trials & Statistics Unit | |
icr.researchteam | Genomic Analysis – Clinical Trials | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Endocrinology | |
dc.contributor.icrauthor | Schuster, Eugene | |
dc.contributor.icrauthor | Buus, Richard | |
dc.contributor.icrauthor | Cheang, Chon | |
dc.contributor.icrauthor | Bliss, Judith | |