Sequential somatic mutations upon secondary anti-HER2 treatment resistance in metastatic ERBB2S310F mutated extramammary Paget’s disease
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Thierry M. Nordmann1, Olivia Messerli-Odermatt1, Larissa Meier1, Sara Micaletto1, Thomas Coppetti1, Mirjam Nägeli1, Jivko Kamarachev1, Ken Kudura2, Sandra N. Freiberger3, Tamara Rordorf4, Joanna Mangana1, Ralph Braun1 and Reinhard Dummer1
1 Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
2 Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland
3 Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
4 Department of Oncology, University Hospital Zurich, Zurich, Switzerland
|Thierry M. Nordmann,||email:||[email protected]|
Keywords: ERBB2 protein; Paget disease; extramammary; trastuzumab; lapatinib
Received: July 10, 2019 Accepted: September 24, 2019 Published: November 19, 2019
Metastatic extramammary Paget’s disease is a rare adenocarcinoma with poor prognosis. Several reports of human epidermal growth factor receptor 2 alterations point to its pathogenic role in the disease. However, the occurrence of treatment resistance to anti-HER2 therapy demand the need for further knowledge. We report of a patient with metastatic penoscrotal extramammary Paget’s disease, with an ERBB2S310F mutation, in which near complete response was achieved upon treatment with trastuzumab and carboplatin. However, after 10 cycles of trastuzumab and carboplatin, widespread metastasis re-occurred. Analysis of a newly developing metastasis revealed additional genomic alterations including ERBB3A232V and PIK3CAG106V point mutations as well as MET and CDK6 amplification, providing a potential mechanism of acquired treatment resistance. Therefore, ERBB family inhibitor afatinib was initiated. Unfortunately, the patient succumbed to disease-related complications shortly after treatment initiation. This is the first report of ERBB2S310F mutated, metastatic extramammary Paget’s disease with secondary resistance to trastuzumab / carboplatin, potentially due to additional acquired genomic alterations. This case contributes to the growing evidence of HER2 in the pathogenesis of metastatic extramammary Paget’s disease and emphasizes the importance of repetitive, genomic analysis in rare diseases.
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