Age-specific differences in oncogenic pathway deregulation seen in human breast tumors.

Abstract

PURPOSE: To define the biology driving the aggressive nature of breast cancer arising in young women. EXPERIMENTAL DESIGN: Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young <or=45 years; older >or=65 years), 411 eligible patients (n = 200<or=45 years; n = 211>or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. RESULTS: In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value. CONCLUSION: Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.

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Description

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Citation

Published Version (Please cite this version)

10.1371/journal.pone.0001373

Publication Info

Anders, Carey K, Chaitanya R Acharya, David S Hsu, Gloria Broadwater, Katherine Garman, John A Foekens, Yi Zhang, Yixin Wang, et al. (2008). Age-specific differences in oncogenic pathway deregulation seen in human breast tumors. PLoS One, 3(1). p. e1373. 10.1371/journal.pone.0001373 Retrieved from https://hdl.handle.net/10161/4481.

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Scholars@Duke

Acharya

Chaitanya Acharya

Research Associate, Senior

I utilize computational biology, machine learning and pre-clinical mouse models to study cancer. My long-term research interests involve developing a comprehensive understanding of immune response to changing tumor microenvironment and its role in tumor progression and resistance to therapy.

Marcom

Paul Kelly Marcom

Adjunct Professor in the Department of Medicine

Basic Science:
-Germline and somatic genetic changes in breast cancer.

Translational:
-Identification and management of individuals and families with hereditary cancer risk.
-Communication of cancer risk information to individuals and families.
-Breast cancer prevention.
-Optimizing management of early breast cancer.
-Treatment of metastatic breast cancer


Clinically, Dr. Marcom works as a medical oncologist in the multidisciplinary breast cancer clinic. He participates in clinical trials investigating new chemotherapeutic and biologic treatments. 

Marks

Jeffrey R. Marks

Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery

I have been engaged in basic and applied cancer research for over 28 years beginning with my post-doctoral fellowship under Arnold Levine at Princeton. Since being appointed to the faculty in the Department of Surgery at Duke, my primary interest has been towards understanding breast and ovarian cancer. I am a charter member of the NCI-Early Detection Research Network (EDRN) and have been an integral scientist in the breast and gynecologic collaborative group for 15 years including leading this group for a 5 year period. I am also a major contributor to the Cancer Genome Atlas and have worked in this context for the past 4 years. My research interests are in the molecular etiology of these diseases and understanding how key genetic events contribute to their onset and progression. My work has been very multi-disciplinary incorporating quantitative, population, genetic, and behavioral approaches.  I consider my specialty to be in the area of using human breast and ovarian cancer as the primary and only authentic model system to understand these diseases.  

Blackwell

Kimberly Lynn Blackwell

Adjunct Professor in the Department of Medicine

Breast cancer angiogenesis
Breast cancer in younger women
Hormonal therapy
Neoadjurant therapy for breast cancer

Current Clinical Investigations

Principal Investigator, A Phase I-II Study of Neoadjuvant Evacet/Paclitaxel/Hyperthermia in Locally Advanced Breast Cancer Patients.

Investigator, Development of Screening Markers for Breast Cancer using Circulating Immune Complexes: Collaborative Study with Diagen Medical Technologies.

Principal Investigator, Use of Plasma D-Dimer as a Predictive Marker in Colorectal Carcinoma: Correlative Science Study with Genentech, Inc.

Principal Investigator, A randomized, Phase II study of gabapentin or glutamine to prevent the peripheral neuropathy/myalgia associated with weekly taxol administration in metastatic breast and lung cancer.

Investigator, A Phase 2, Randomized, Double-Masked, Multicenter Study of Two Dose Levels of ERA-923 for the treatment of Metastatic Breast Cancer in Postmenopausal Women who have failed Tamoxifen therapy. Genetics Institute.

Investigator, A Phase I Study of Combined Doxil/Hyperthermia in Stage IV Breast Cancer.


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