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Breast Cancer Research and Treatment

, Volume 174, Issue 1, pp 55–63 | Cite as

Identification, clinical-pathological characteristics and treatment outcomes of patients with metastatic breast cancer and somatic human epidermal growth factor receptor 2 (ERBB2) mutations

  • Lynn Jongen
  • Giuseppe Floris
  • Bram Boeckx
  • Dominiek Smeets
  • Diether Lambrechts
  • Sara Vander Borght
  • Annouschka Laenen
  • Grace Mann
  • Richard E. CutlerJr.
  • Alshad S. Lalani
  • Patrick Neven
  • Hans WildiersEmail author
Preclinical study
  • 118 Downloads

Abstract

Purpose

The human epidermal growth factor receptor 2 (ERBB2) may harbour somatic mutations that drive breast tumorigenesis. Here, we study prevalence, tumour characteristics and disease outcome of ERBB2 mutations in a large unselected cohort of metastatic breast cancer (mBC) patients.

Methods

We retrospectively included all mBC patients with sufficient primary breast tumour, diagnosed between 2000 and 2015 (n = 775). Genomic DNA was subjected to a targeted-resequencing assay to identify hotspot mutations in exon 8, 17, 19, 20, and 21 of ERBB2. We studied demographics, tumour characteristics, median distant disease-free survival (DDFS), using a time-to-event analysis and time to progression (TTP) and overall survival (OS) upon metastasis, using Kaplan–Meier and log-rank statistics to assess differences between ERBB2-mutation statuses.

Results

ERBB2 mutations were observed in 1.8% of the samples (13/721). Patient and tumour characteristics were independent of ERBB2 mutations. Luminal ERBB2-mutated (ERBB2mut+) cases (n = 5) had a shorter DDFS than ERBB2mut cases (median DDFS 0.8 vs. > 4.0 years, p = 0.02). ER-positive ERBB2mut+ patients who received an aromatase inhibitor (AI) as first-line treatment (stage IV disease) had a worse TTP vs. ERBB2mut patients (n = 3 vs. 156; median TTP 103 vs. 311 days, p = 0.04). OS for all subtypes was lower for ERBB2mut+ vs. ERBB2mut cases (n = 11 vs. 669; median OS 1.1 vs. 2.3 years, p = 0.46).

Conclusion

ERBB2mut+ are rare in patients in whom mBC developed and no evidence was found for an association with specific types of BC or patient characteristics, although outcomes of ERBB2mut+ carriers might be worse. The latter, however, needs to be validated in larger populations.

Keywords

Breast cancer Somatic mutations Metastasis Human epidermal growth factor receptor 2 

Abbreviations

AI

Aromatase inhibitor

DDFS

Distant disease-free survival

ERBB2amp+/−

Human epidermal growth factor receptor 2 amplification positive/negative

ERBB2mut+/−

Human epidermal growth factor receptor 2 mutation positive/negative

FFPE

Formalin fixed paraffin embedded

IDC

Invasive ductal carcinoma

ILC

Invasive lobular carcinomas

mBC

Metastatic breast cancer

OS

Overall survival

PR

Progesterone receptor

RCB

Residual cancer burden

SNVs

Single nucleotide variants

TILs

Tumour infiltrating lymphocytes

TNBC

Triple-negative BC

TTP

Time to progression

UHL

University Hospitals Leuven

ER

Oestrogen receptor

ERBB2

Human epidermal growth factor receptor 2

Notes

Acknowledgements

The authors would like to thank Sarah Cumps and Wilfried Versin for their training and technical assistants in histology at the Department of Imaging and Pathology, Translational Cell & Tissue Research of the KU Leuven. We further thank Gilian Peuteman, Evy Vanderheyden, and Thomas Van Brussel from the VIB Center for Cancer Biology, laboratory of Translational Genetics, for performing the DNA extractions, and the sequencing. We would like to acknowledge Chantal Remmerie, from the Multidisciplinary Breast Centre of University Hospitals Leuven for setting up the database of the patients with breast cancer. The computational resources used in this work were provided by the Flemish Supercomputer Center (VSC), funded by the Hercules Foundation and the Flemish Government, Department of Economy, Science and Innovation (EWI).

Funding

The work was supported by Puma Biotechnologies Inc..

Compliance with ethical standards

Conflict of interest

HW is recipient of The Research Foundation - Flanders (FWO). HW received consulting fees, travel support, and research support from Puma Biotechnologies, Inc (all provided to his institute), and he received speaker’s fees, consulting fees, travel support, and research support from Roche (all provided to his institute). LJ received a grant from Puma Biotechnologies, Inc. GM, AL, and RC received salary and have ownership interest in Puma Biotechnologies, Inc. PN received speaker’s fees, consulting fees, travel support, and research support from Roche (all provided to his institute). PN is on the advisory board of Novartis, AstraZeneca, Lilly, and Pfizer (all consulting fees are provided to his institute).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committee (University Hospitals Leuven, Belgium) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Patients were only included if they provided a written informed consent at time of diagnosis for future research on their resected tumour tissue. This article does not contain any studies with animals performed by any of the authors.

Supplementary material

10549_2018_5049_MOESM1_ESM.doc (181 kb)
Supplementary material 1 (DOC 181 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Lynn Jongen
    • 1
  • Giuseppe Floris
    • 2
    • 3
  • Bram Boeckx
    • 4
    • 5
  • Dominiek Smeets
    • 4
    • 5
  • Diether Lambrechts
    • 4
    • 5
  • Sara Vander Borght
    • 3
    • 4
  • Annouschka Laenen
    • 6
  • Grace Mann
    • 7
  • Richard E. CutlerJr.
    • 7
  • Alshad S. Lalani
    • 7
  • Patrick Neven
    • 1
    • 8
  • Hans Wildiers
    • 1
    • 9
    Email author
  1. 1.Department of OncologyKU Leuven - University of LeuvenLeuvenBelgium
  2. 2.Laboratory of Translational Cell & Tissue Research, Department of Imaging and PathologyKU Leuven - University of LeuvenLeuvenBelgium
  3. 3.Department of PathologyUniversity Hospitals LeuvenLeuvenBelgium
  4. 4.Department of Human GeneticsKU Leuven - University of LeuvenLeuvenBelgium
  5. 5.Laboratory of Translational GeneticsVIB Center for Cancer BiologyLeuvenBelgium
  6. 6.Interuniversity Centre for Biostatistics and Statistical BioinformaticsLeuvenBelgium
  7. 7.Puma Biotechnology, Inc.Los AngelesUSA
  8. 8.Department of Gynaecology and Obstetrics, University Hospitals LeuvenKU Leuven - University of LeuvenLeuvenBelgium
  9. 9.Department of General Medical Oncology, University Hospitals LeuvenKU Leuven - University of LeuvenLeuvenBelgium

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