Abstract P1-08-12: p53 status and 17q21.3 amplicon formation in HER2-positive breast cancer
Authors: G Tan, M Seeliger, J Cohen
Journal: Cancer Research (2017)

Abstract Breast cancers that overexpress HER2/neu are associated with poor clinical outcome. Treatment of HER2-positive breast cancers with trastuzumab, a monoclonal antibody that antagonizes HER2 receptor signaling, increases patient overall and disease-free survival. While targeted therapy is reasonably effective, resistance to trastuzumab remains a problem, particularly in the case of metastatic disease. Tumor suppressor p53 is the most commonly mutated gene in human cancer and mutations that lead to the stabilization and accumulation of p53 in HER2-positive breast cancers are associated with worse clinical outcome. Another feature of HER2-enriched breast cancers are amplifications of the HER2 locus on chromosome 17q21.3. Table 1 Wildtype p53Mutated p53No amplification12.8%63.9%17q21.3 amplification13.1%8.7%Table 1: Among 58 cases, Her2-positive tumors with mutated p53 (n=37, 63.9%) occurred at a 4.9-fold higher frequency than amplification of the 17q21.3 gene set (n=8, 13.1%), with significant mutual exclusivity (p=0.005), The patient genomic data set was obtained from the Breast Invasive Carcinoma Study conducted by the TCGA Network (Nature, 2012) and visualized using cBioPortal (MSKCC), Copy alterations of genes were assessed using GISTIC2.0 (Broad Institute) via cBioPortal. We studied the genomic profiles of 58 HER2-positive breast tumor samples using cBioPortal to determine p53 mutation status. 74.1% of samples expressed mutant p53 and a large fraction of mutations occurred in the key DNA binding domain. We assessed the amplification status of 24 genes within the chromosome 17q21.3 locus as an indicator of amplicon formation, and found that 21.8% of breast tumors demonstrated copy number amplification (Table 2). Mutant p53 tumors with no amplicon formation occurred 5 times more frequently than tumors with only 17q21.3 amplicon formation. These alterations tended to occur exclusive of one another (p=0.005, Table 1). Separately, using gene expression data from Kaplan-Meier Plotter, we observed that alterations in gene expression within the 17q21.3 amplicon can have differential effects on the survival of HER2-positive breast cancer patients (Table 2). Table 217q21.3 Gene SetHazard RatioP-valueCOL1A11.760.01MBTD10.530.01SPATA200.650.04UBE2Z0.680.07EME10.650.08Table 2: List of relevant genes within the chromosome 17q21.3 amplicon. Genes in this amplicon can influence both beneficial and hazardous survival outcomes in HER2-positive breast cancer patients (n=208). Hazard ratios (HR) were determined from gene expression data available through Kaplan-Meier Plotter (Gyorffy, 2010). Our data shows that HER2-positive breast cancers can be divided into p53 mutant and non-mutant subsets with p53 mutations relatively exclusive to 17q21.3 gene amplification. However, p53 mutation status and 17q21.3 copy number have a variety of effects on patient outcome. We are interested in understanding the interaction between these two genetic alterations and whether subdividing HER2-positive breast cancer into these subtypes will improve our ability to provide effective therapy to patients. Citation Format: Tan G, Seeliger M, Cohen J. p53 status and 17q21.3 amplicon formation in HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-08-12.