Alterations in the cell cycle checkpoint pathway in breast cancer.

Abstract

126 Background: Breast cancer is a molecularly diverse disease with molecular subtypes defined by ER, PR and HER2 status. Dysregulation of the cell cycle pathway through activation of cyclin D1 and/or inactivation of CDKN2A is a mechanism of tumor progression in breast cancer and drugs targeting CDK4/6 is undergoing investigation in this disease with promising preliminary results. We investigated several key genetic alterations in cell cycle regulatory proteins in advanced breast cancer patient samples to identify potential targets for cell cycle related treatment options. Methods: A comprehensive genomic profiling was performed on 37 breast cancer samples with the majority being metastatic. Testing included targeted exome sequencing of 562 genes in tumor and paired normal DNA. Results: Patients’ ages ranged from 27-66 years. Analysis of cell cycle regulatory genes revealed focal amplification of cyclin D1/D2 or CDKN2A loss in 9/37 (24%) of cases, of which, 45% were hormone receptor (HR) positive, HER2 negative, 33% were HR positive, HER2 positive and 22% were triple negative (TNBC) subtype. Loss of RB1 was analyzed since it negatively regulates response to CDK4/6 inhibitors. Loss of RB1 was noted in 4/37 (10.8%) of cases, all of which were TNBCs. Only a single TNBC with RB1 loss had concurrent CDK4 amplification and loss of CDKN2A. No evidence of CCNE1 amplification was found in any samples. Incidence of CDK4 and CDK6 amplification was found in samples with cyclin D1 amplification or CDKN2A loss. Our cohort included a single male TNBC patient who harbored cyclin D1 amplification as well as CDKN2A loss. Overall, amplification of cyclin D1, cyclin D2, CDK4 and CDK6 was found in 16%, 5.4%, 2.7% and 2.7% respectively. Loss of CDKN2A was noted in 5.4% of tumors profiled. Conclusions: Exome sequencing identified subsets of patients with mutated cell cycle associated genes that may benefit from CDK 4/6 inhibitors. Our data suggests loss of RB1 is more frequent in TNBC subtype which may confer resistance to CDK4/6 inhibitors. Our analysis suggests that in addition to HR positive, HER2 negative patients, a subset of HR positive, HER2 positive patients could be sensitive to CDK4/6 inhibitors due to activation of the cell cycle pathway as evidenced by mutations in key genes.