Abstract P4-05-13: PTEN deletion is linked to adverse phenotype and poor prognosis in breast cancer

Abstract

Abstract Deletions of chromosome 10q23, including the PTEN (phosphatase and tensin homolog) locus, are known to occur in breast cancer, but systematic analyses of its clinical relevance are lacking. We thus analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a PTEN-specific probe, and found deletions in 19% of no special type, 9% of lobular, 46% of medullary and 4% of tubular cancers. 98.7% of deletions were heterozygous and 1.3% were homozygous. PTEN deletion was significantly linked to advanced tumor stage (p=0.0054), high tumor grade (p<0.0001), high tumor cell proliferation (Ki67 Labeling Index; p<0.0001), and shortened overall survival (p=0.0090). PTEN deletions were inversely associated with features of luminal type breast cancers (ER/PR positivity, CCND1 amplification). PTEN deletions were strongly linked to amplification of genes involved in the PTEN/AKT pathway such as MYC (p=0.0430) and HER2 (p=0.0065). Remarkably the combined analysis of MYC, HER2, and PTEN aberrations suggested that aberrations of multiple PTEN/AKT pathway genes have a strong additive effect on breast cancer prognosis. Cancers with two or three of these aberrations behaved significantly worse than cancers with none or one of these changes (p<0,0001). The particularly poor prognosis of patients with HER2 amplification and PTEN deletions challenges the concept of PTEN deletions interfering with trastuzumab therapy. In conclusion, PTEN deletion occurs in a relevant fraction of breast cancers, and is linked to aggressive tumors. Reduced PTEN function cooperates with MYC and HER2 activation in conferring aggressive phenotype to cancer cells. Citation Format: Eike Burandt, Martina Kluth, Valerie Kopperschmidt, Anja Mittenzwei, Annette Lebeau, Volkmar Müller, Isabell Witzel, Fritz Jänicke, Stefan Geist, Peter Paluchowski, Christian Wilke, Uwe Heilenkötter, Rainer Krech, Albert von d Assen, Ronald Simon, Patrick Lebok. PTEN deletion is linked to adverse phenotype and poor prognosis in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-05-13.