Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2-targeted therapy.

Case Report A 58-year-old woman was evaluated at our institution for management of treatment-refractory breast cancer. She had a 5-year history of an initially estrogen receptor (ER), progesterone receptor (PR)–positive and human epidermal growth factor receptor 2 (HER2)–amplified pT1a, pN0, pMx invasive ductal breast carcinoma treated with standard local therapies and without any adjuvant systemic treatment. Subsequently she developed what appeared to be a primary triple-negative (ER/PR/HER2) disease with features of inflammatory breast cancer. Physical exam demonstrated erythema, warmth, and induration extending cephalic from her medial left breast to her lateral left neck (Figs 1A and 2A). She was experiencing dysphagia, attributed to infiltration of the tumor into the infrahyoid muscles. The disease proved to be refractory to multiple systemic therapies, including combination regimens with taxanes (Taxotere, sanofi-aventis, Bridgewater, NJ), bevacizumab (Avastin, Genentech, South San Francisco, CA), dasatinib (Sprycel, Bristol-Myers Squibb, Princeton, NJ), ixabepilone (Ixempra, Bristol-Myers Squibb) and gemcitabine (Gemzar, Eli Lilly, Indianapolis, IN). This lack of response to cytotoxic chemotherapy is typical of inflammatory breast cancer. After progressive disease, a new diagnostic skin biopsy was performed to re-evaluate standard biomarkers and to permit sequencing of a broad range of genes known to be associated with cancer within a single integrated assay. Pathologic examination revealed breast carcinoma in the dermal tissue with associated lymphovascular invasion (Figs 3A [low magnification] and 3B [higher magnification]), and these findings along with the clinical presentation fulfilled the diagnostic criteria for inflammatory breast carcinoma. Biomarker testing was performed, and the tumor was again negative for ER/PR staining by immunohistochemistry and negative for ERBB2 amplification by fluorescent in situ hybridization (FISH). Accordingly, the patient was considered ineligible for HER2-targeted therapy. At this time, this cutaneous sample of recurrent tumor was submitted for diagnostic next generation sequencing (NGS) by a Clinical Laboratories Improvement Amendments–certified commercial laboratory, where the entire coding regions of 182 cancer-related genes were sequenced, along with 36 introns of 14 genes frequently involved in gene fusions. Consistent with the prior FISH-based test for the recurrent disease, NGS demonstrated no evidence of an ERBB2 copy number gain (amplification), instead revealing two distinct ERBB2 mutations (V777L and S310F, both at 47% allele frequency). Both mutations have previously been described in breast cancer in Catalog of Somatic Mutations in Cancer (COSMIC; December 2012). Mutations in PIK3CA (K111E at 30%) and TP53 (C229fs*10 at 38%) were also identified. The percent of tumor in this sample was estimated to be 50%, and the consistency of allele frequency of the ERBB2 mutations with this histologic assessment of purity suggests these mutations are ubiquitous within the tumor. In vitro studies using established cell lines suggested that both of the identified ERBB2 mutations activate HER2 by either affecting HER2 autophosphorylation or phosphorylation of downstream substrates. The V777L mutation is in the kinase domain of HER2 and is associated with aberrant and enhanced activation of downstream signaling pathways in breast cancer cells. The S310F mutation is in the extracellular domain and has also recently been demonstrated to be activating in lung cancer cells. It has also