WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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The demonstration that the HER2 gene is amplified in breast cancer heralded the "genomic era" which ultimately led to major clinical advances for HER2-positive disease. The HER2 discovery was based on a search for cancer specific anomalies in the cellular homologs of the acutely transforming retroviral oncogenes described in birds and mammals. However HER2 gene amplification is now recognized to be only one of a large number of somatic mutations that occur in breast cancer, most of which have been identified through genomic screening techniques. Large scale tumor DNA resequencing projects, focused on a small number of tumors and the analysis of many genes, suggest that by the time breast cancer enters the terminal phase approaching ten or eleven individual somatic mutations may have accumulated. Similarly, array comparative hybridization experiments have uncovered multiple gene amplification and deletion events. The complexity of these changes has given rise to the concept of a "cancer genome atlas" in which all the recurring mutations in cancer are documented in publicly available data bases to assist clinical investigation and translational medicine. Understanding the clinical and biological significance of these somatic changes must represent one of the most important challenges facing breast cancer researchers today because when complete, a functionally annotated breast cancer genome atlas will provide predictive/prognostic biomarkers and therapeutic opportunities that will transform our approach to this common disease.

In the last ten years my clinical and laboratory efforts have therefore focused on the development of a luminal (hormone receptor positive) breast cancer genome atlas. In the early years our focus was on developing and promoting clinical collaborations, clinical trials and establishment of high quality (snap frozen) tumor specimen banks that are essential for genomic research. During these efforts we established a body of work on the practice of treating postmenopausal women with large palpable hormone receptor rich tumors with four months of an aromatase inhibitor before surgery. This treatment has now become a standard of care when a low toxicity approach is indicated for promoting breast conservation in older patients. This benefit to patients has driven our subsequent clinical trial success. Most recently our grant application collaborations have extended to include the American College of Surgeons Oncology Group with the activation of the national neoadjuvant endocrine therapy trial Z1031 that I lead as principal investigator. We have also established links with several UK centers with tissue banks from similar types of studies. The ultimate goal of these intensely collaborative efforts is to create specimen banks and biomarker data from thousands of patients to create sufficient statistical power to robustly link genomic screens to clinical outcomes so we can eventually focus our basic science efforts on lethal genetic events that offer the best new opportunities for therapeutic intervention.

From the scientific perspective our neoadjuvant trials allow a determination of the estrogen dependence of individual tumors and since the therapy is mechanistically simple - estrogen withdrawal though aromatase inhibition - biomarker research should be inherently more likely to produce a robust response predictor than efforts to predict, for example, the effectiveness of multi-agent chemotherapy. Our medium-term scientific goal is therefore to compare individual tumor genomic profiles with information on primary tumor aromatase inhibitor responsiveness to determine the constellation of genetic events that underlie estrogen-independent growth/endocrine therapy resistance. Over the last year, as a result of multiple nested grants from the NIH in the form of an R01, an Avon Foundation/NCI partner in progress award and Komen support from two CRAFT awards we have been able to complete a phase 2 trial of 115 patients who received four months of the aromatase inhibitor letrozole. We are in the process of completing a comprehensive analysis of the tumor samples accrued, including "whole genome" gene expression chips, high resolution array comparative hybridization analysis and candidate gene sequencing. In addition we have also begun to apply these techniques to samples from the Z1031 trial where the final sample size is 375 patients. Finally we have recently developed collaboration with the NHGRI and the Washington University Genome Center for large scale candidate gene sequencing of tumor DNA samples from both the R01 funded trial and Z1031. These long term efforts are finally reaching fruition and an initial publication on the complex amplicon structure of luminal breast cancer and the impact of individual gene amplification events on response to neoadjuvant aromatase inhibition and long-term outcomes is planned for mid 2007.

Our eventual goal is to deliverer new clinical grade diagnostic tests based on our genomic discoveries. To focus on this problem we developed a U01 to fund collaborations between Washington University, the University of Utah, and the University of North Carolina, Chapel Hill. This funded project focuses on developing a qPCR based biological classification of breast cancer. A patent by the three universities has been filed on our initial findings and licensing negotiations are proceeding. The gene lists we are currently generating, particularly those from the marriage of expression profiling and array comparative hybridization, also suggest a host of new therapeutic targets are ready to be exploited. Functional characterization of these genes has begun and will be a major new focus in my laboratory for the next five years.

Cross-talk between signal transduction pathways and ER signaling in endocrine resistant breast cancer, with opportunities for targeted intervention. Ellis M, Ma C Femara and the future: tailoring treatment and combination therapies with Femara. Breast Cancer Res Treat 2007;105 Suppl 1:105-15

Education

1978-1980	2nd MB, King's College, University of London, UK
1980-1981	BSc (hons), St. Mary's Hospital Medical School, University of London, UK
1981-1984	MB, BChir, Queens' College & School of Clinical Medicine, University of Cambridge, UK
1986	MRCP, Royal College of Physicians, London, Regents Park London, UK
1988-1991	PhD, Royal Postgraduate Medical School, University of London, UK

Professional Training

1984-1985	House Officer, General Surgery, Cambridge University House Officer Rotations, UK
1985	Senior House Officer, Gastroenterology, Hammersmith Hospital, London, UK
1985-1986	Senior House Officer, Radiotherapy & Oncology, Pulmonary Medicine, Churchill Hospital, Oxford, UK
1986-1988	Registrar, General & Pulmonary Medicine, Gastroenterology, Hammersmith Medical Registrar Rotations, London, UK
1988-1991	Research Fellow, Gene Expression Laboratory, Imperial Cancer Research Fund, London, UK
1991-1992	MRC Travelling Research Fellow, Lombardi Comprehensive Cancer Center, Washington, DC
1992-1994	Medical Oncology Fellow, Georgetown University Hospital, Washington, DC

Academic Positions

1994-1996	Instructor, Division of Hematology & Oncology, Department of Medicine, Georgetown University, Washington, DC
1996-2000	Assistant Professor, Division of Hematology & Oncology, Department of Medicine, Georgetown University, Washington, DC
2000-2003	Associate Professor, Division of Hematology, Oncology & Transplantion, Department of Medicine, Duke University, Durham, NC
2003-present	Associate Professor, Division of Oncology, Department of Medicine, Washington University, St Louis, MO
2003-present	Head, Section of Medical Oncology, Division of Oncology, Department of Medicine, Washington University, St Louis, MO
2003-present	Co-Director, Clinical and Translational Research, Siteman Comprehensive Cancer Center, St. Louis, MO
2003-present	Director, Breast Health Program, Washington University and Barnes-Jewish Hospital, St. Louis, MO
2003-present	Anheuser Busch Professor of Medical Oncology, Washington University, St. Louis, MO
2007-present	McDonnell International Scholars Academy, Washington University University Ambassador to Brazil and the University of Campinas

Appointments

1996, 1999, 2001	Study Section, Department of Veterans Affairs
1997-2001	Member, Breast Cancer Working Group of the Solid Tumor Correlative Science Committee of the Cancer & Lymphoma Group B (CALGB)
1998	Expert Advisor, Endocrinologic and Metabolic Drugs Advisory Committee #69, Food and Drug Administration
1999	Subcommittee member for "Cell Growth Signaling Pathways: Cell Biology Aspects", Program Committee, American Association for Cancer Research
1999	Chairperson, Minisymposium "Protein kinases in tumor progression/regression", AACR Annual meeting
2001-2005	Chairman, Breast Cancer Working Group, Solid Tumor Correlative Science Committee, Cancer and Lymphoma Group B (CALGB)
2001-present	Cadre Member, Breast Cancer Committee, Cancer and Lymphoma Group B (CALGB)
2002-2003	Review panel, NCI/AVON/SPORE Partners in Progress Award Program
2002	Member, Breast Cancer Working Group, Program for the Assessment of Cancer Clinical Tests (PACCT), National Institutes of Heath
2003	Primary Grant Reviewer, UK Breast Cancer Campaign
2003-2007	Primary Grant Reviewer, CALGB Fellowship and Junior Faculty Awards
2003-2006	External Advisory Board, UCSF Spore in Breast Cancer
2003-2007	External Advisory Board for UCSF SPORE in Breast Cancer
2004-2006	Member, Program Committee, ASCO
2004-present	Member, Breast Cancer Committee, American College of Surgeons Oncology Group
2005-present	Vice Chair, Breast Cancer Committee, Cancer and Lymphoma Group B (CALGB)
2005-2006	NCI Breast Cancer SPORE Study Section
2005-2006	NCI Breast Cancer SPORE study section
2005-2007	Clinical Trial Reviewer for Cancer Research, UK
2005-2006	Breakthrough Cancer UK Grant Review
2006	Chair, Fresh Frozen Working Group for the BIG/NCI Cooperative Groups
2006	Cancer Research UK, Fellowship Awards
2007-present	Chairman, Medical Oncology Committee, ACOSOG
2007-present	External Reviewer for Developmental Projects, MD Anderson SPORE in Breast Cancer
2007-present	Scientific Advisory Board, AVON Foundation

Editorial Boards

2003-2005	Journal of Clinical Oncology
2002-present	Endocrine Related Cancer
2004-present	Breast Cancer Research and Treatment
2003-present	Biomed Central (BMC) Cancer
2000-present	Contributing Editor, Breast Cancer, a Year Book quarterly

Board Certification

2004	Board Certification in Internal Medicine
2005	Board Certification in Medical Oncology

Honors & Awards

2001	Fellow, Royal College of Physicians, Regents Park, London, UK

Updated: March 21, 2008