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Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Rueda, Oscar M 
Sammut, Stephen-John 
Seoane, Jose A 
Caswell-Jin, Jennifer L 

Abstract

The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1-6. It is therefore essential to identify patients who have a high risk of late relapse7-9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.

Description

Keywords

Breast Neoplasms, Disease Progression, Female, Humans, Models, Biological, Neoplasm Metastasis, Neoplasm Recurrence, Local, Organ Specificity, Prognosis, Receptor, ErbB-2, Receptors, Estrogen, Time Factors, Triple Negative Breast Neoplasms

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

567

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (CB4140)
Cancer Research UK (20544)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research Uk (None)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research UK (C507/A16278)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Department of Health (via National Institute for Health Research (NIHR)) (unknown)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
Cancer Research UK (A25117)
Cancer Research UK (C14303/A17197)
Cancer Research UK (C9545/A29580_do not transfer)
Cancer Research UK (25815)
Cancer Research UK (CRUK) travel grant (SWAH/047) 282 to visit Prof. Curtis’ Lab. C.R. is supported by award MTM2015-71217-R. Ca.C. is 283 supported by CRUK, ECMC and NIHR. C.C. is supported by the National Institutes 284 of Health through the NIH Director’s Pioneer Award (DP1-CA238296) and the Breast 285 Cancer Research Foundation.