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Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets

Kurozumi, Sasagu; Alsaleem, Mansour; Monteiro, Cintia J.; Bhardwaj, Kartikeya; Joosten, Stacey E.P.; Fujii, Takaaki; Shirabe, Ken; Green, Andrew R.; Ellis, Ian O.; Rakha, Emad A.; Mongan, Nigel P.; Heery, David M.; Zwart, Wilbert; Oesterreich, Steffi; Johnston, Simon J.

Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets Thumbnail


Authors

Sasagu Kurozumi

Mansour Alsaleem

Cintia J. Monteiro

Kartikeya Bhardwaj

Stacey E.P. Joosten

Takaaki Fujii

Ken Shirabe

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

NIGEL MONGAN nigel.mongan@nottingham.ac.uk
Professor of Oncology

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DAVID HEERY david.heery@nottingham.ac.uk
Professor of Eucaryotic Gene Regulation

Wilbert Zwart

Steffi Oesterreich

Simon J. Johnston



Abstract

© 2020 The Author(s). Background: Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets. Methods: We performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC (N = 279) and invasive ductal carcinoma (IDC, N = 1301) using METABRIC, TCGA, and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade, and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in silico model of response to neratinib derived from breast cancer cell lines. Results: ILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% of ERBB2-mutated cases. Mutations in ERBB2 were enriched in ILC vs. IDC cases (5.7%, N = 16 vs. 1.4%, N = 18, p < 0.0001) and clustered in the tyrosine kinase domain of HER2. ERBB3 mutations were not enriched in ILC (1.1%, N = 3 vs. 1.8%, N = 23; p = 0.604). Median OS for patients with ERBB2-mutant ILC tumors was 66 months vs. 211 months for ERBB2 wild-type (p = 0.0001), and 159 vs. 166 months (p = 0.733) for IDC tumors. Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS - but only in ILC (hazard ratio, HR = 3.7, 95% CI 1.2-11.0; p = 0.021). Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC = 2.3, 95% CI 1.04-5.05; p = 0.040). Conclusions: Targetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes. Biomarker-led clinical trials of adjuvant HER-targeted therapy are warranted for patients with ERBB2-mutated primary ILC.

Citation

Kurozumi, S., Alsaleem, M., Monteiro, C. J., Bhardwaj, K., Joosten, S. E., Fujii, T., …Johnston, S. J. (2020). Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets. Breast Cancer Research, 22, Article 85. https://doi.org/10.1186/s13058-020-01324-4

Journal Article Type Article
Acceptance Date Jul 26, 2020
Online Publication Date Aug 11, 2020
Publication Date 2020-12
Deposit Date Sep 1, 2020
Publicly Available Date Sep 1, 2020
Journal Breast Cancer Research
Print ISSN 1465-5411
Electronic ISSN 1465-542X
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 22
Article Number 85
DOI https://doi.org/10.1186/s13058-020-01324-4
Keywords Cancer Research; Oncology
Public URL https://nottingham-repository.worktribe.com/output/4807918
Publisher URL https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-020-01324-4

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Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets (1.6 Mb)
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