ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas
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Gabrielle Deniziaut1,*, Jean Christophe Tille2,*, François-Clément Bidard3, Sophie Vacher1, Anne Schnitzler1, Walid Chemlali1, Laurence Trémoulet1, Laetitia Fuhrmann1, Paul Cottu3, Roman Rouzier4, Ivan Bièche1, Anne Vincent-Salomon1,5
1Institut Curie, PSL Research University, Pathology-Genetics-Immunology Department, 75005 Paris, France
2Geneva University Hospital, Faculty of Medicine, Division of Clinical Pathology, 1205 Geneva, Switzerland
3Institut Curie, PSL Research University, Medical Oncology Department, 75005 Paris, France
4Institut Curie, Versailles Saint-Quentin University, Surgery Department, 92210 Saint-Cloud, France
5Institut Curie, PSL Research University, INSERM U934, 75005 Paris, France
*These authors have contributed equally to this work
Anne Vincent-Salomon, email: [email protected]
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
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.
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