High Resolution Oligonucleotide Array-CGH and Hot Spot Mutations To Select Patients for Targeted Therapies.

Abstract

Abstract Background. A high number of genomic alterations (gene amplification, mutations) have been reported in breast cancers, and could potentially be targeted in early clinical trials. In the present molecular screening program, we aim at performing CGH array and hot spot mutations for 200 patients with metastatic breast cancer, in order to drive these patients in specific early clinical trials.Patients and Methods. Patients were selected to present a metastatic breast cancer under treatment in four French Centers. DNA was extracted by Qiagen method from either primary breast cancer or metastatic lesions. The hybridizations were done on 4*44K Agilent Array CGH. The analysis was done with Analytics v3.4.40 software. The file reported amplified zones (log2ratio>0.84 for biopsy, 1.58 for FNA) and focused on predefined genes that encode a candidate target. Hot spot mutations cover PI3K, AKT, PTEN genes. The primary endpoint was to determine how many patients were driven to a specific clinical trial because of molecular analyses. The secondary endpoints included PFS and response rates.Results. As june 12th, 109 patients were included in the molecular screening program. CGH array was feasible and could be interpreted within one month in 85 (78%) patients. Array-CGH identified high level amplification in 57 patients (67%). As expected, the two most frequent amplicons included ERBB2 (17q11-12, 24%) and FGFR1 (8p11, 16%).The accuracy to detect ERBB2 amplification was 90%. A significant number of patients presented rare gene amplifications including ERBB4 amplification (n=1), CCND1/FGF4 amplification (n=6), FGFR2 (n=2), EGFR (n=1), VEGFB (n=4), BCR (n=1)Interestingly, only 4 patients presented TOP2A amplification. Hot spot mutations for PI3KCA, AKT, PTEN is being performedConclusion. This preliminary analysis shows that array CGH allows to identify patients who are candidate for targeted agents in phase I/II trials. Accrual will continue until 200 patients. Selected patients will be included in clinical trials in second semester of 2009 after a target validation by IHC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5067.