Steady progress against HER2-positive breast cancer.

New England Journal of Medicine (Impact Factor: 54.42). 10/2011; 365(14):1336-8. DOI: 10.1056/NEJMe1101326
Source: PubMed
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    ABSTRACT: HER2-positive breast cancer accounts for 25% of all cases and has a poor prognosis. Although progress has been made in understanding signal transduction, little is known of how HER2 achieves gene regulation. We performed whole genome expression analysis on a HER2+ and HER2- breast cancer cell lines and compared these results to expression in 812 primary tumors stratified by their HER2 expression level. Chip-on-chip with anti-RNA polymerase II was compared among breast cancer cell lines to identify genes that are potentially activated by HER2. The expression levels of these HER2-dependent POL II binding genes were determined for the 812 HER2+/- breast cancer tissues. Genes differentially expressed between HER2+/- cell lines were generally regulated in the same direction as in breast cancer tissues. We identified genes that had POLII binding in HER2+ cell lines, but without significant gene expression. Of 737 such genes "poised" for expression in cell lines, 113 genes were significantly differentially expressed in breast tumors in a HER2-dependent manner. Pathway analysis of these 113 genes revealed that a large group of genes were associated with stem cell and progenitor cell control as indicated by networks centered on NANOG, SOX2, OCT3/4. HER2 directs POL II binding to a large number of genes in breast cancer cells. A "poised" class of genes in HER2+ cell lines with POLII binding and low RNA expression but is differentially expressed in primary tumors, strongly suggests a role of the microenvironment and further suggests a role for stem cells proliferation in HER2-regulated breast cancer tissue.
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    Clinical Trials 08/2013; DOI:10.1177/1740774513497125 · 1.94 Impact Factor
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    ABSTRACT: The developmental pathway from discovery to clinical practice for biomarkers and biomarker-directed therapies is complex. While several issues need careful consideration, two critical issues that surround the validation of biomarkers are the choice of clinical trial design (which is based on the strength of the preliminary evidence and marker prevalence) and the biomarker assay related issues surrounding the marker assessment methods such as the reliability and reproducibility of the assay. This review focuses on trial designs for marker validation, both in the setting of early phase trials for initial validation, as well as in the context of larger definitive trials. Designs for biomarker validation are broadly classified as retrospective (i.e., using data from previously well-conducted, randomized, controlled trials) or prospective (enrichment, allcomers or adaptive). We believe that the systematic evaluation and implementation of these design strategies are essential to accelerate the clinical validation of biomarker-guided therapy, thereby taking us a step closer to the goal of personalized medicine.
    12/2011; 1(12):1629-1636. DOI:10.4155/CLI.11.152