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
Abstract 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 (...
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2020-08-01
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Online Access: | http://link.springer.com/article/10.1186/s13058-020-01324-4 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sasagu Kurozumi Mansour Alsaleem Cíntia J. Monteiro Kartikeya Bhardwaj Stacey E. P. Joosten Takaaki Fujii Ken Shirabe Andrew R. Green Ian O. Ellis Emad A. Rakha Nigel P. Mongan David M. Heery Wilbert Zwart Steffi Oesterreich Simon J. Johnston |
spellingShingle |
Sasagu Kurozumi Mansour Alsaleem Cíntia J. Monteiro Kartikeya Bhardwaj Stacey E. P. Joosten Takaaki Fujii Ken Shirabe Andrew R. Green Ian O. Ellis Emad A. Rakha Nigel P. Mongan David M. Heery Wilbert Zwart Steffi Oesterreich Simon J. Johnston 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 Lobular Breast cancer ERBB2 HER2 Mutation Prognosis |
author_facet |
Sasagu Kurozumi Mansour Alsaleem Cíntia J. Monteiro Kartikeya Bhardwaj Stacey E. P. Joosten Takaaki Fujii Ken Shirabe Andrew R. Green Ian O. Ellis Emad A. Rakha Nigel P. Mongan David M. Heery Wilbert Zwart Steffi Oesterreich Simon J. Johnston |
author_sort |
Sasagu Kurozumi |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2020-08-01 |
description |
Abstract 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. |
topic |
Lobular Breast cancer ERBB2 HER2 Mutation Prognosis |
url |
http://link.springer.com/article/10.1186/s13058-020-01324-4 |
work_keys_str_mv |
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doaj-d4597b94e0d64f6d896b2a13a644a68c2021-04-02T16:52:10ZengBMCBreast Cancer Research1465-542X2020-08-0122111110.1186/s13058-020-01324-4Targetable 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 datasetsSasagu Kurozumi0Mansour Alsaleem1Cíntia J. Monteiro2Kartikeya Bhardwaj3Stacey E. P. Joosten4Takaaki Fujii5Ken Shirabe6Andrew R. Green7Ian O. Ellis8Emad A. Rakha9Nigel P. Mongan10David M. Heery11Wilbert Zwart12Steffi Oesterreich13Simon J. Johnston14Nottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of NottinghamNottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of NottinghamNottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of NottinghamNottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of NottinghamDivision of Oncogenomics, Oncode Institute, Netherlands Cancer InstituteDepartment of General Surgical Science, Gunma University Graduate School of MedicineDepartment of General Surgical Science, Gunma University Graduate School of MedicineNottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of NottinghamNottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of NottinghamNottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of NottinghamSchool of Veterinary Medicine and Science, University of NottinghamGene Regulation and RNA Biology Laboratory, School of Pharmacy, University of NottinghamDivision of Oncogenomics, Oncode Institute, Netherlands Cancer InstituteWomens Cancer Research Center, UPMC Hillman Cancer Center and Magee-Women Research InstituteNottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of NottinghamAbstract 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.http://link.springer.com/article/10.1186/s13058-020-01324-4LobularBreast cancerERBB2HER2MutationPrognosis |