Abstract 8: Genomic analyses of heterogeneous HER2 3+ invasive ductal carcinomas of the breast
Authors: Gauthier Arnaud , Lambros Maryou , Rodrigues Daniel N. , Arnould Laurent , Lacroix-Tikri Magali , Penault-Llorca Frédérique , Baranzelli Marie-Christine , Sastre Xavier , Natrajan Rachael , Delattre Olivier , Cottu Paul , Reis-Filho Jorge Sergio , Vincent-Salomon Anne 
Published: August 2012

Abstract
Aims: HER2 gene amplification is observed in 9% to 15% of breast carcinomas. According to current guidelines, cases with &gt;10% but &lt;30% of cells displaying complete membrane staining are considered of equivocal HER2 status. In a minority of HER2-positive cancers, however, HER2 overexpression and gene amplification are restricted to a subpopulation of cancer cells of the tumor bulk (i.e. HER2 intra-tumor heterogeneity). We investigated cases displaying heterogeneous HER2 overexpression and gene amplification (i.e. overexpression/ amplification in &gt;10% but less than 100% of the cancer cells) i) to determine whether the HER2-positive and HER2-negative components are clonal and ii) to define the genomic differences between the HER2-positive and HER2-negative components. Material and methods: Fourty-four cases were collected consecutively among five French hospitals and for which initial reports mentioned HER2 heterogeneity. Diagnosis of HER2 heterogeneity was re-assessed by immunohistochemistry and chromogenic and/ or fluorescence in situ hybridization. Each component was microdissected (laser capture microdissection) from representative tissue sections stained with an anti-HER2 antibody (Herceptest). After DNA extraction, the DNA samples from the HER2-positive and HER2-negative components of each case were subjected to microarray-based comparative genomic hybridization (aCGH), using a platform with 50Kb resolution. Results: Out of 44 cases, the HER2-positive and HER2-negative components from 13 cases yielded DNA of sufficient quantity and quality and were subjected to aCGH analysis. Tumors were preferentially ductal carcinomas of no special type (83%), of histological grade 3, ER positive (83%), and lymph node positive (70%). In 11 of the 13 pairs (85%), the only significant difference among the genomic profiles was the presence of the region of amplification located at the 17q12-q21 locus encompassing the HER2 gene in the HER2-positive component. Unsupervised clustering of aCGH data demonstrated strikingly similar patterns of copy number profiles in different components of each tumour. In cases that were ER-positive, both the HER2-positive and HER2-negative components harboured alterations associated with ER-positive (luminal) carcinomas, such as gains of 1q+, losses of 16q, and amplifications of 8p12 and 11q13. Conclusions: Albeit rare, our results demonstrate that HER2 can be heterogeneously overexpressed and amplified in breast cancers, and this phenomenon appears to be more prevalent in ER-positive breast carcinomas. Based on the similarities of their genomic profiles, the HER2-positive and HER2-negative components from each case are clonal and are likely to have diverged relatively early in the tumor evolution.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 8. doi:1538-7445.AM2012-8