Abstract P6-07-13: New insights on HER2 amplification from the constitutional and somatic standpoints: Results from the ICGC and SIGNAL/Phare studies

Background: HER2-positive (HER2+) breast cancers are defined by the amplification and/or overexpression of the human epidermal growth factor receptor (HER2/ERBB2) gene on chromosome region 17q12. Although anti-HER2 targeted therapies have greatly improved treatment of HER2+ breast cancer, the magnitude of benefit varies widely between patients. Deciphering the genomic and genetic heterogeneity of HER2+ breast cancer may provide a basis to better understand their natural history, opening new avenues of treatment. Methods: As part of the ICGC Breast Cancer Working Group effort, we combined whole genome sequencing and transcriptomic analyses of 64 HER2+ primary invasive carcinomas, and a genome wide association study (GWAS) of over 9.836 breast cancer patients in the prospective SIGNAL/PHARE cohort (NCT00381901 – RECF1098). Results: Using WGS data we precisely delineate the ERBB2 amplicon as a 106 kb region involving six genes and show that the amplification mechanism was consistent with breakage-fusion-bridge (BFB) cycles. Four RNA expression-based groups were identified, displaying specific genomic alterations in terms of amplification, rearrangements and mutations. On other hand, GWAS analyses failed to identify any constitutional variants associated with HER2 amplification. Discussion: By combining whole genome sequencing and expression analysis, we provide evidence showing that HER2+ tumours display considerably more molecular heterogeneity than previously reported. These results are reinforced with the lack of association between any genetic variants and HER2 amplification from GWAS analyses. Taken as a whole, these results suggest that HER2+ breast cancers do not represent per se a homogeneous subtype, but are distributed along the whole breast cancer spectrum, from ER-positive luminal to ER-negative basal phenotype. Genome alterations present in HER2+ tumors are in accordance with these phenotypes, and it is likely that the HER2 amplification is a secondary event in the course of tumorigenesis, not favored by any particular constitutional or somatic genetic variants. Citation Format: Vincent-Salomon A, Ferrari A, Pivot X, Macgrogan G, Arnould L, Treilleux I, Romieux G, Sertier A-S, Thomas E, Tonon L, Boyault S, Kielbassa J, Letexier V, Pauporte I, Birbaum D, Saintigny P, Cox D, Viari A. New insights on HER2 amplification from the constitutional and somatic standpoints: Results from the ICGC and SIGNAL/Phare studies. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-13.