Triple negative breast cancer (TNBC) represents a particularly aggressive and difficult to treat form of breast cancer. No specific genetic alterations have been described as characteristic of the disease, with the exception of association with BRCA1/2, EGFR, and KRAS mutations. In this study, we sought to define clinically actionable mutations in untreated metastatic tumors as well as compare the mutational status of metastatic samples with germ-line and primary tumors using whole exome sequencing.
We prospectively enrolled 38 patients with newly diagnosed metastatic TNBC and collected matched specimens of germ-line DNA, primary tumor and metastatic tumor. Median DFI from time of initial primary diagnosis to recurrence was 18 months (IQR = 1-24 months) and 9 patients presented with de novo metastatic disease. 34/38 patients went on to receive first-line treatment with nab-paclitaxel, carboplatin, and bevacizumab and ORR/PFS/OS are available.
Sites of TNBC metastatic tissue (n = 31) included: liver (10), chest wall (13), non-regional lymph nodes (4), and lung (4). 7 patients had inadequate metastatic tumor for sequencing. We performed whole-exome sequencing for all samples using the Agilent solution-based system of exon capture, which uses RNA baits to target all protein coding genes (CCDS database), as well as ∼700 human miRNAs from miRBase (v13). In all, we generated over 10 GB of sequencing data using high throughput sequencing on the Illumina platform.
We observed striking genetic heterogeneity among the metastatic and primary tumors. There was no single driver mutation that was common to the metastatic tumors indicating the diverse genetic pathways that contribute to metastasis. Early analysis suggests that mutations in APC and MTOR occur more frequently in metastatic tumors than in primary tumors. Nonsense mutations of ER were detected in both primary and metastatic tumors but not in germ-line DNA. EGFR and HER2 mutations were not found in any of the primary or metastatic TNBC samples.
This data provides the most comprehensive genetic portrait of metastatic and primary TNBC to date, and represents a significant first step in identifying the genetic causes of the disease, drivers of recurrence, and potential therapeutic targets. Full results, including the primary versus metastatic tumor mutational analysis will be presented.
This study was funded by a Susan G. Komen Grant SAC 100001.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S4-03.