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Abstract
Around, 30–40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer.
Highlights
The identification of molecular cancer drivers has considerably improved clinical outcomes in oncology
Gasdermin B (GSDMB) over-expression is associated with poor prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer
We have previously reported that relative high expression of GSDMB, but no other GSDM genes, in breast tumours is associated with poor survival in unselected breast cancer cases [34]
Summary
The identification of molecular cancer drivers has considerably improved clinical outcomes in oncology. Inhibition of the human epidermal growth factor receptor 2 (HER2; ERBB2 gene) represents a paradigm in breast cancer oncology. Over-expression of ERBB2 occurs in approximately 20% of breast tumours [1, 2]. The amplification of chromosome 17q12-q21, which includes ERBB2, defines an intrinsic molecular cancer subtype associated with relatively aggressive tumour behaviour and poor clinical outcome [3]. The development of targeted anti-HER2 therapies based principally on humanized antibodies (such as trastuzumab, trastuzumab emtansine -T-DM1 or pertuzumab) and tyrosine kinase inhibitors (such as lapatinib) has dramatically improved the outcome of women with early and advanced stage HER2-positive breast cancer [4,5,6,7,8,9,10,11]. Trastuzumab response rate is limited to approximately 15–26% [12, 13], which indicates the involvement of other molecules and/or signalling pathways that influence outcome in this setting [14]
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