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.
Highlights
The human epidermal growth factor receptor (HER) family is composed of four transmembrane receptors: EGFR/HER1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4 [1]
We retrospectively retrieved 529 tumors diagnosed as a primary breast invasive lobular breast carcinomas (ILC) excised from women treated at the Institut Curie (France) from 2005 to 2008
The corresponding clinicopathological characteristics are shown in Table 1; 51 tumors (93%) were estrogen receptors (ER)-positive, 40 tumors (73%) were progesterone receptors (PR)-positive and 53 tumors (96%) were E-cadherin-negative, while the median age at time of diagnosis was 62 years
Summary
The human epidermal growth factor receptor (HER) family is composed of four transmembrane receptors: EGFR/HER1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4 [1] These proteins have an extra-cellular domain that can bind different growth factors, a single hydrophobic transmembrane segment (α-helix), and an intracellular portion that includes a protein kinase domain [2, 3]. The intracellular kinase activity is activated by the binding of extracellular ligands and/or homo- or hetero dimerization of the receptor with another member of the family [3]. When activated, these receptors stimulate multiple downstream signaling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase, and lead to cell growth and survival [4]. ERBB3 displays no significant intracellular kinase activity and signals through heterodimerization, mainly with ERBB2 [6, 7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
