Abstract S4-03: Exome sequencing reveals clinically actionable mutations in the pathogenesis and metastasis of triple negative breast cancer

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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.

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... In addition, there are few systematic studies of recurrent and/or metastatic disease, though some studies are now being conducted. 48,49 To further understand tumor evolution and therapeutic resistance in breast cancer, it will be imperative to catalogue the mutations present in those tumors that are metastatic at diagnosis or that recur after primary treatment. ...
Remarkable progress in sequencing technology over the past 20 years has made it possible to comprehensively profile tumors and identify clinically relevant genomic alterations. In breast cancer, the most common malignancy affecting women, we are now increasingly able to use this technology to help specify the use of therapies that target key molecular and genetic dependencies. Large sequencing studies have confirmed the role of well-known cancer-related genes and have also revealed numerous other genes that are recurrently mutated in breast cancer. This growing understanding of patient-to-patient variability at the genomic level in breast cancer is advancing our ability to direct the appropriate treatment to the appropriate patient at the appropriate time-a hallmark of "precision cancer medicine." This review focuses on the technological advances that have catalyzed these developments, the landscape of mutations in breast cancer, the clinical impact of genomic profiling, and the incorporation of genomic information into clinical care and clinical trials.
... [22][23][24][25]. We presented data at the 2013 San Antonio Breast Cancer Symposium identifying gene mutations associated with progression free survival (PFS) in metastatic breast cancer [26]. Patients with WNK1 mutations had a median PFS of 1.4 months compared to 7.3 months (P = 0.03) in those with the wild type gene. ...
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Next generation sequencing (NGS) coupled with sophisticated bioinformatics tools yields an unprecedented amount of information regarding tumor genetics, with the potential to reveal insights into tumor behavior. NGS and other multiplex genomic assays are rapidly spilling from the laboratory into the clinic through numerous commercial and academic entities. This raises the important question as to whether we are ready to use these data in clinical decision-making. While genetic lesions are clearly targeted by a new generation of biological cancer therapies, and certain regulatory approvals are actually coupled to single gene assays, we still do not know if the vast information on other genomic alterations is worth the added cost, or even worse, the inappropriate and unproven assignment of patients to treatment with an unapproved drug carrying potentially serious side effects. On the other hand, the trend toward a precision medicine pathway is clearly accelerating, and clinical trials validating pathway-driven personalized cancer therapeutics will be necessary in both the community and academic settings. Lower cost and wider availability of NGS now raises a debate over the merit of routine tumor genome-wide analysis.
Triple-negative breast cancer (TNBC) has a poor prognosis with limited treatment options. Genomic analysis of TNBCs offers the opportunity to decode TNBC into biologically relevant subtypes with unique molecular targets. With further research, these findings may be translated into effective targeted therapeutic options. Clin Cancer Res; 21(7); 1511–3. ©2014 AACR. See related article by Burstein et al. p. 1688
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