Abstract
HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal–basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage–fusion–bridge mechanism.
Highlights
HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are available
A total of 289 HER2positive (HER2 þ ) breast cancer (BC) with frozen tumour samples identified from the French PHARE/SIGNAL programs[19,20] were analysed
We used gene expression as an operational basis to classify HER2 þ tumours into four groups that were further characterized in terms of interdependent genomic variables
Summary
HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are available. Luminal breast cancers express HR while basal breast cancers do not Because of this heterogeneity, due to various cell-of-origins and molecular alterations, the response of breast cancer patients to therapy is variable and difficult to predict[2]. Overexpression of the ERBB2/HER2 protein kinase receptor has enabled patients with HER2-positive tumour to benefit from antibody-based (for example, trastuzumab) and anti-kinase-based (for example, lapatinib) therapies that target this receptor[3,4,5,6,7]. They may be included in the HER2-enriched or luminal molecular subtypes, depending on whether they express ER, and this has a consequence on their response to targeted therapies. HER2-positive breast cancers vary in their genome alterations, gene expression programs, and cell-of-origin and this impacts on their microenvironment[17,18], prognosis and response to treatment. Gene sets specific to the mammary stem cells (MaSCs), luminal progenitor (pLum) and luminal mature (mLum) populations[26] were analysed, showing an increasing expression gradient from groups A to D for pLum and a corresponding decreasing gradient for mLum (Supplementary Fig. 2a–c)
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