ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

// Gabrielle Deniziaut 1, * , Jean Christophe Tille 2, * , François-Clément Bidard 3 , Sophie Vacher 1 , Anne Schnitzler 1 , Walid Chemlali 1 , Laurence Trémoulet 1 , Laetitia Fuhrmann 1 , Paul Cottu 3 , Roman Rouzier 4 , Ivan Bièche 1 , Anne Vincent-Salomon 1, 5 1 Institut Curie, PSL Research University, Pathology-Genetics-Immunology Department, 75005 Paris, France 2 Geneva University Hospital, Faculty of Medicine, Division of Clinical Pathology, 1205 Geneva, Switzerland 3 Institut Curie, PSL Research University, Medical Oncology Department, 75005 Paris, France 4 Institut Curie, Versailles Saint-Quentin University, Surgery Department, 92210 Saint-Cloud, France 5 Institut Curie, PSL Research University, INSERM U934, 75005 Paris, France * These authors have contributed equally to this work Correspondence to: Anne Vincent-Salomon, email: anne.salomon@curie.fr Keywords: ERBB2 mutations, ERBB3 mutations, invasive lobular breast carcinoma, sequencing, anti-ERBB2 targeted agents Received: March 30, 2016     Accepted: August 21, 2016     Published: September 02, 2016 ABSTRACT ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively. Our study aims to determine ERBB2 and ERBB3 mutations frequencies in grade 3 and/or ERBB2-positive invasive lobular breast carcinomas (ILC). All the 529 ILC surgically-excised registered at Institut Curie in the years 2005 to 2008 were reviewed. Thirty-nine grade 3 ERBB2-negative ILC and 16 ERBB2-positive ILC were retrieved and subjected to Sanger sequencing of the ERBB2 and ERBB3 activation mutation hotspots ( ERBB2 : exons 8, 17, 19, 20, 21; ERBB3 : exons 3, 6, 7, 8). Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]). No ERBB2 mutation was found among the 16 ERBB2-positive ILC. No ERBB3 mutation was found in any of the 55 ILC. ERBB2 mutations were statistically associated with solid ILC features (p=0.01). Survival analyses showed no significant prognostic impact of ERBB2 mutations. Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening.