Targeted next-generation sequencing identifies genomic abnormalities potentially driving the prognosis of early-stage invasive lobular breast carcinoma patients stratified according to a validated clinico-pathological model.
Biomarkers, Tumor
Breast Neoplasms
/ diagnosis
Carcinoma, Lobular
/ diagnosis
Cyclin-Dependent Kinase 4
/ genetics
Cyclin-Dependent Kinase 6
/ genetics
DNA Copy Number Variations
Female
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Humans
Middle Aged
Multivariate Analysis
Prognosis
Retrospective Studies
Risk
Sequence Analysis, DNA
Survival Analysis
Breast cancer
CDK4
Lobular
Next-generation sequencing
Prognosis
Transcriptome analysis
Journal
Breast (Edinburgh, Scotland)
ISSN: 1532-3080
Titre abrégé: Breast
Pays: Netherlands
ID NLM: 9213011
Informations de publication
Date de publication:
Apr 2020
Apr 2020
Historique:
received:
04
11
2019
revised:
14
01
2020
accepted:
20
01
2020
pubmed:
7
2
2020
medline:
15
12
2020
entrez:
7
2
2020
Statut:
ppublish
Résumé
The clinico-pathological and molecular factors that drive the prognosis of invasive lobular breast carcinoma (ILC) are not entirely explored. In this regard, the development and validation of a prognostic model for ILC and the investigation of the distribution of molecular abnormalities (focusing on CDK4/6 alterations) according to prognosis were the aims of this study. Two clinico-pathological multi-center data-sets of early-stage ILC patients (Training/Validation Set, TS/VS) were gathered. A 3-class model was developed according to the multivariate analysis for disease-free-survival (DFS) and externally validated. Mutational, copy number variation and transcriptomic analyses by targeted next generation sequencing (NGS) were performed (and validated with quantitative PCR) in an explorative cohort of patients with poor and good prognosis. Data from overall 773 patients (TS/VS: 491/282) were gathered. The developed model significantly discriminated low/intermediate/high risk in the TS (10-years DFS: 76.3%/67.6%/39.8%, respectively, p<0.0001) and in the VS (p<0.0001). In the explorative cohort for molecular analysis (34 patients), CDK4 gain was present exclusively in the poor prognosis group (35.0%, p = 0.03; OR 7.98, 95%CI 1.51-42.1, p = 0.014). Moreover, CDK4 and 6 overexpression showed a trend toward an association with poor prognosis (OR 2.7, 95%CI 0.4-18.1, p = 0.3; OR 3.29, 95%CI 0.56-19.25, p = 0.18). A risk stratification model, able to accurately separate early-stage ILC patients' prognosis into different risk classes according to clinico-pathological variables, allowed to investigate potential biomarkers of prognosis with targeted NGS. CDK4 gain is suggested for future validation as a prognostic biomarker and a potential therapeutic opportunity in ILC patients.
Identifiants
pubmed: 32028173
pii: S0960-9776(20)30035-7
doi: 10.1016/j.breast.2020.01.034
pmc: PMC7375560
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
CDK4 protein, human
EC 2.7.11.22
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
56-63Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.
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