P3-01-11: Increased Gene Copy Number of c-KIT and VEGFR2 at 4q12 in Primary Breast Cancer Is Related to an Aggressive Phenotype and Impaired Prognosis.

Abstract

Abstract Introduction: Triple-negative breast cancer (TNBC) accounts for approximately 15% of all female breast cancer and is associated with aggressive clinical behaviour. No targeted treatments are available for TNBC. Drugs inhibiting tyrosine kinases, such as vascular endothelial growth factor receptor 2 (VEGFR2) and c-KIT, have however shown some promising results for patients with TNBC. The aim of the present study was to investigate whether gains and/or amplifications of VEGFR2 and c-KIT occur in TNBC. These genes may constitute novel candidate biomarkers for selecting TNBC patients for treatment with tyrosine kinase inhibitors. Material & Methods: Fluorescence in situ hybridization (FISH) was used to quantify gene copy numbers of VEGFR2 and c-KIT in 83 primary human breast cancers, of which 31 were classified as TNBC. Gains were defined as ≥4 gene copies in more than 40% of the cancer cells, while amplification was defined as gene copy/CEP ratio >2 in more than 10% of the cancer cells. A tumour was considered FISH positive for c-KIT and/or VEGFR2 if it displayed copy number gain and/or amplification. Immunohistochemical (IHC) staining was performed for assessment of c-KIT protein expression. Results: Ten (32%) of the TNBCs were VEGFR2 FISH positive and nine (29%) were c-KIT FISH positive, whereas non-TNBCs were FISH positive for VEGFR2 and c-KIT in nine (18%) cases for both genes. No significant difference in frequency between TNBCs and non-TNBCs was found. There was a correlation between FISH positivity for VEGFR2 and c-KIT (c2 test, P<0.001), and VEGFR2 and c-KIT FISH positivity correlated to ER/PgR negativity and high Nottingham histological grade (NHG). A significantly worse breast cancer specific survival (BCSS) was seen for FISH positive cases in the whole cohort as well as among untreated patients and non-TNBCs, but not among TNBC cases. Discussion: The high correlation between VEGFR2 and c-KIT FISH positivity suggests that the genes are co-amplified. Increased copy number of both genes was related to aggressive disease and a worse prognosis, and thus has the potential of functioning as a novel predictive biomarker for selected targeted therapy particularly in the difficult-to-treat TNBC patient category. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-11.