Identification, clinical-pathological characteristics and treatment outcomes of patients with metastatic breast cancer and somatic human epidermal growth factor receptor 2 (ERBB2) mutations
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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.
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.
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).
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.
KeywordsBreast cancer Somatic mutations Metastasis Human epidermal growth factor receptor 2
Distant disease-free survival
Human epidermal growth factor receptor 2 amplification positive/negative
Human epidermal growth factor receptor 2 mutation positive/negative
Formalin fixed paraffin embedded
Invasive ductal carcinoma
Invasive lobular carcinomas
Metastatic breast cancer
Residual cancer burden
Single nucleotide variants
Tumour infiltrating lymphocytes
Time to progression
University Hospitals Leuven
Human epidermal growth factor receptor 2
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).
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).
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.
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