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Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first-line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors, particularly those that may inform targeted therapies. Genes mutated in multiple tumors included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Notable genes involved in focal structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 was detected in 2 of 6 African Americans. RNA sequencing revealed consistent overexpression of the FOXM1 gene when tumor gene expression was compared with nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer with all the others, we detected expression patterns unique to each patient's tumor. Integrative DNA/RNA analysis provided evidence for deregulation of mutated genes, including the monoallelic expression of TP53 mutations. Finally, molecular alterations in several cancers supported targeted therapeutic intervention on clinical trials with known inhibitors, particularly for alterations in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. In conclusion, whole genome and transcriptome profiling of mTNBC have provided insights into somatic events occurring in this difficult to treat cancer. These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials in this irremediable cancer. Mol Cancer Ther; 12(1); 104–16. ©2012 AACR.

Introduction: The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy, especially with a K-ras mutation is poor with median survival of less than one year. The purpose of this study was to perform whole genome sequencing (WGS) to identify therapeutically actionable somatic events in mCRC patient samples, so as to select targeted treatment strategies for individual patients. Methods: IRB approval was obtained and 3 patients have been enrolled. All had > 2 prior regimens and had known K-ras mutations (age 73, 45 and 50 years, all were male). Percutaneous needle biopsies of liver metastases were performed with whole blood collection for the extraction of constitutional DNA. WGS was performed using Illumina paired end chemistry on HiSeq2000 sequencing system, which yielded coverage of greater than 30X for both the normal and tumor samples. Somatic genomic alterations (point mutations and indels, copy number alterations, translocations and rearrangements) were analyzed using our custom pipeline for paired analysis. Results: In all 3 samples sufficient DNA was extracted for sequencing. WGS and bioinformatics analysis took 3–4 weeks for completion. We found that all 3 tumor samples had KRAS mutations, while 2 samples had mutations in the APC gene and the PIK3CA gene. Other genes with therapeutic implications in single tumor samples were INPPL1, INPP4B and SMAD4. No EGFR amplifications were detected in our sample set. The concomitant mutations in MAPK (K-ras) and PI3K (PIK3CA, INPPL1, INPP4B) pathways suggest that combination therapies might be required for effective treatment of these tumors. In two instances, tumors were sent to a CLIA laboratory to allow for clinical validation of genomic events. Conclusions: WGS is feasible from DNA obtained from percutaneous biopsies in a clinical setting. Our study has revealed a series of therapeutically actionable events in mCRC and prospective clinical trials are needed to validate this approach. Funded by the Bisgrove-Scottsdale Healthcare and TGEN foundations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A183.