Abstract
BackgroundApproximately one in five breast cancers are driven by amplification and overexpression of the human epidermal growth factor receptor 2 (HER2) receptor kinase, and HER2-enriched (HER2E) is one of four major transcriptional subtypes of breast cancer. We set out to understand the genomics of HER2 amplification independent of subtype, and the underlying drivers and biology of HER2E tumors.MethodsWe investigated published genomic data from 3155 breast tumors and 5391 non-breast tumors.ResultsHER2 amplification is a distinct driver event seen in all breast cancer subtypes, rather than a subtype marker, with major characteristics restricted to amplification and overexpression of HER2 and neighboring genes. The HER2E subtype has a distinctive transcriptional landscape independent of HER2A that reflects androgen receptor signaling as replacement for estrogen receptor (ER)-driven tumorigenesis. HER2 amplification is also an event in 1.8% of non-breast tumors.ConclusionsThese discoveries reveal therapeutic opportunities for combining anti-HER2 therapy with anti-androgen agents in breast cancer, and highlight the potential for broader therapeutic use of HER2 inhibitors.
Highlights
One in five breast cancers are driven by amplification and overexpression of the human epidermal growth factor receptor 2 (HER2) receptor kinase, and HER2-enriched (HER2E) is one of four major transcriptional subtypes of breast cancer
We explored the genomics of HER2 amplification in 3155 breast tumors across three cohorts
We found HER2 amplification in other intrinsic subtypes, and used this to categorize the landscape of HER2 amplification, independent of subtype
Summary
One in five breast cancers are driven by amplification and overexpression of the human epidermal growth factor receptor 2 (HER2) receptor kinase, and HER2-enriched (HER2E) is one of four major transcriptional subtypes of breast cancer. Breast cancer has four well-established, transcriptional subtypes in the prediction analysis of microarray 50 (PAM50) scheme: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 (HER2)enriched (HER2E) [1]. These subtypes overlap with immunohistochemical (IHC) staining of three protein markers, estrogen receptor (ER), progesterone receptor (PR) and HER2, supplemented with in situ hybridization (ISH) of HER2. Recent reports have proposed “molecular apocrine” as an additional subtype of breast cancer, characterized by increased androgen signaling and apocrine differentiation [5,6,7]
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