A pathway-based approach to identify molecular biomarkers in cancer.

Many examples highlight the power of gene expression profiles, or signatures, to provide an understanding of biological phenotypes. This is best seen in the context of cancer, where expression signatures have tremendous power to identify new cancer subtypes and to predict clinical outcomes. Gene expression profiles have been developed to personalize medicine, accurately predicting disease recurrence and tumor response to therapy.

Retraction: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570-80.

To the Editor: We would like to retract our article, "A Genomic Strategy to Refine Prognosis in Early-Stage Non-Small-Cell Lung Cancer,"(1) which was published in the Journal on August 10, 2006. Using a sample set from a study by the American College of Surgeons Oncology Group (ACOSOG) and a collection of samples from a study by the Cancer and Leukemia Group B (CALGB), we have tried and failed to reproduce results supporting the validation of the lung metagene model described in the article. We deeply regret the effect of this action on the work of other investigators.

Refocusing the war on cancer: the critical role of personalized treatment.

Despite very substantial investment and effort over the past 30 years, the overall survival rate of cancer patients has changed little. We propose that without a truly robust mechanism for selecting the right treatment for the right patient at the right time-the central concepts of personalized medicine-we will continue to see only incremental improvements and have little hope for substantial survival gains. We suggest that it is now imperative that future clinical trials be designed with a plan to incorporate biomarker development.

The lung cancer exercise training study: a randomized trial of aerobic training, resistance training, or both in postsurgical lung cancer patients: rationale and design.

Background: The Lung Cancer Exercise Training Study (LUNGEVITY) is a randomized trial to investigate the efficacy of different types of exercise training on cardiorespiratory fitness (VO2peak), patient-reported outcomes, and the organ components that govern VO2peak in post-operative non-small cell lung cancer (NSCLC) patients.

Methods/design: Using a single-center, randomized design, 160 subjects (40 patients/study arm) with histologically confirmed stage I-IIIA NSCLC following curative-intent complete surgical resection at Duke University Medical Center (DUMC) will be potentially eligible for this trial. Following baseline assessments, eligible participants will be randomly assigned to one of four conditions: (1) aerobic training alone, (2) resistance training alone, (3) the combination of aerobic and resistance training, or (4) attention-control (progressive stretching).

A pathway-based classification of human breast cancer.

The hallmark of human cancer is heterogeneity, reflecting the complexity and variability of the vast array of somatic mutations acquired during oncogenesis. An ability to dissect this heterogeneity, to identify subgroups that represent common mechanisms of disease, will be critical to understanding the complexities of genetic alterations and to provide a framework to develop rational therapeutic strategies. Here, we describe a classification scheme for human breast cancer making use of patterns of pathway activity to build on previous subtype characterizations using intrinsic gene expression signatures, to provide a functional interpretation of the gene expression data that can be linked to therapeutic options.

Age- and sex-specific genomic profiles in non-small cell lung cancer.

Context: Gene expression profiling may be useful in examining differences underlying age- and sex-specific outcomes in non-small cell lung cancer (NSCLC).

Objective: To describe clinically relevant differences in the underlying biology of NSCLC based on patient age and sex.

Design, Setting, And Patients: Retrospective analysis of 787 patients with predominantly early stage NSCLC performed at Duke University, Durham, North Carolina, from July 2008 to June 2009.

Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma.

Purpose: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities are the result of a common biological phenotype, such as regulatory pathways.

Experimental Design: Lung cancer cell lines with corresponding gene expression data and genes associated with an embryonic stem cell identity were used to develop a signature of embryonic stemness (ES) activity specific to lung adenocarcinoma.

A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia.

Purpose: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients.

Experimental Design: We used gene expression profiling methods to generate predictors of therapy response and prognosis.

Age-specific differences in oncogenic pathway dysregulation and anthracycline sensitivity in patients with acute myeloid leukemia.

Purpose: To define the biology driving the aggressive nature of acute myeloid leukemia (AML) in elderly patients.

Patients And Methods: Clinically annotated microarray data from 425 patients with newly diagnosed de novo AML from two publicly available data sets were analyzed after age-specific cohorts (young or= 55 years; n = 144) were prospectively identified. Gene expression analysis was conducted utilizing gene set enrichment analysis, and by applying previously defined and tested signature profiles reflecting dysregulation of oncogenic signaling pathways, altered tumor environment, and signatures of chemotherapy sensitivity.

Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation.

Objective: Polycythemia vera (PV) is characterized by erythrocytosis associated with the presence of the activating JAK2(V617F) mutation in a variable proportion of hematopoietic cells. JAK2(V617F) is detected in other myeloproliferative neoplasms, does not appear to be the PV-initiating event, and its specific role in deregulated erythropoiesis in PV is incompletely understood. We investigated the pathogenesis of PV to characterize abnormal proliferation and apoptosis responses and aberrant oncogenic pathway activation in primary PV erythroid precursors.

Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential.

Human cancers result from a complex series of genetic alterations, resulting in heterogeneous disease states. Dissecting this heterogeneity is critical for understanding underlying mechanisms and providing opportunities for therapeutics matching the complexity. Mouse models of cancer have generally been used to reduce this complexity and focus on the role of single genes.

Utilization of genomic signatures to identify phenotype-specific drugs.

Genetic and genomic studies highlight the substantial complexity and heterogeneity of human cancers and emphasize the general lack of therapeutics that can match this complexity. With the goal of expanding opportunities for drug discovery, we describe an approach that makes use of a phenotype-based screen combined with the use of multiple cancer cell lines. In particular, we have used the NCI-60 cancer cell line panel that includes drug sensitivity measures for over 40,000 compounds assayed on 59 independent cells lines.

An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer.

Introduction: Perhaps the major challenge in developing more effective therapeutic strategies for the treatment of breast cancer patients is confronting the heterogeneity of the disease, recognizing that breast cancer is not one disease but multiple disorders with distinct underlying mechanisms. Gene-expression profiling studies have been used to dissect this complexity, and our previous studies identified a series of intrinsic subtypes of breast cancer that define distinct populations of patients with respect to survival. Additional work has also used signatures of oncogenic pathway deregulation to dissect breast cancer heterogeneity as well as to suggest therapeutic opportunities linked to pathway activation.

Gene expression profiles of tumor biology provide a novel approach to prognosis and may guide the selection of therapeutic targets in multiple myeloma.

Purpose: Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) comprise heterogeneous disorders with incompletely understood molecular defects and variable clinical features. We performed gene expression profiling (GEP) with microarray data to better dissect the molecular phenotypes, sensitivity to particular chemotherapeutic agents, and prognoses of these diseases.

Methods: Using gene expression and clinical data from 877 patients ranging from normal plasma cells (NPC) to relapsed MM (RMM), we applied gene expression signatures reflecting deregulation of oncogenic pathways and tumor microenvironment to highlight molecular changes that occur as NPCs transition to MM, create a high-risk MGUS gene signature, and subgroup International Staging System (ISS) stages into more prognostically accurate clusters of patients.

Translating genomics into clinical practice: applications in lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of death from cancer worldwide and has a poor overall survival across all stages of disease. The recent advancement of gene expression technology addresses the phenotypic complexity of many diseases, including NSCLC. These genomic approaches have shown great promise in NSCLC in helping to improve risk stratification, prognosis, and the clinician's ability to match the right therapy to an individual patient.

Report on EU-USA workshop: how systems biology can advance cancer research (27 October 2008).

The main conclusion is that systems biology approaches can indeed advance cancer research, having already proved successful in a very wide variety of cancer-related areas, and are likely to prove superior to many current research strategies. Major points include: Systems biology and computational approaches can make important contributions to research and development in key clinical aspects of cancer and of cancer treatment, and should be developed for understanding and application to diagnosis, biomarkers, cancer progression, drug development and treatment strategies. Development of new measurement technologies is central to successful systems approaches, and should be strongly encouraged.

A genomic strategy to elucidate modules of oncogenic pathway signaling networks.

Recent studies have emphasized the importance of pathway-specific interpretations for understanding the functional relevance of gene alterations in human cancers. Although signaling activities are often conceptualized as linear events, in reality, they reflect the activity of complex functional networks assembled from modules that each respond to input signals. To acquire a deeper understanding of this network structure, we developed an approach to deconstruct pathways into modules represented by gene expression signatures.

Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer.

We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2-8, and PAX9) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the TTF-1 and NKX2-8 pathways identified a cluster of patients with poor survival, representing approximately 20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power.