NE Oncology Issue – September 2014

Saba NF et al. ASCO 2014:e17053

Background

Preclinical studies have demonstrated that treatment with inhibitors of epidermal growth factor receptor (EGFR) and cyclooxygenase 2 (COX-2) results in synergistic inhibition of head and neck squamous cell carcinoma (HNSCC) tumourigenesis. Saba and colleagues employed the nCOunter nanoString platform to analyze expression data in baseline and post-therapy samples in order to identify genomic signatures that may help to predict treatment outcome in patients with premalignant head and neck lesions.1

Study design

  • A preassembled gene expression panel provided by nCounter nanoString and consisting of 236 cancerrelated and internal reference genes was used to perform gene expression analysis.
  • Baseline and post therapy samples from two patients who had been treated with celecoxib and erlotinib on a phase I chemoprevention trial were compared:
    • One patient was a responder who had severe dysplasia at baseline that was reduced to mild dysplasia 3 months after treatment, with no diagnosis of HNSCC as of 1 year after treatment;
    • The second patient was a nonresponder who had moderate dysplasia at baseline and 3 months after treatment, with diagnosis of HNSCC as of 1 year after treatment.
  • For both patients, the baseline expression of a subset of 28 genes was compared between a biopsy versus a cytobrush sample.

Key findings

  • In the responder patient, gene profiles at baseline versus 3 months post treatment showed differential increased expression of CDC2, ATM, NTRK3, BRCA2, and IGFBP6 genes.
    • In the nonresponder patient, gene profiles at baseline versus 3 months post treatment showed significantly decreased expression of the same genes.
  • In the responder patient, gene profiles at baseline versus 3 months post treatment showed decreased expression of NOTCH1, TFGB, ETS1, FGFR1, HCK, CDH1, and TNSF10.
    • In the nonresponder patient, gene profiles at baseline versus 3 months post treatment showed significantly increased expression of the same genes.
  • A significant, positive correlation was observed between baseline expression of the subset of 28 genes in biopsied and cytobrush specimens in the responder (r = 0.454, p = 0.015) and nonresponder (r = 0.52, p = 0.004) patients.

Key conclusions

  • A potential set of gene expression biomarkers that differentiates between patients with premalignant lesions of the head and neck who respond to treatment with inhibitors of EGFR and COX-2 versus patients who do not respond was identified.
  • An association in gene expression profiles in biopsy and cytobrush samples was observed using nanoString technology.
  • Gene expression profiling has potential value as a predictive tool for assessing response in chemoprevention trials.

Reference: 1. Saba NF, Rossi MR, Dwivedi B, et al. Predictive value of gene expression signatures in premalignant lesions of the head and neck for response
to chemoprevention with EGFR and COX-2 inhibitors. J Clin Oncol (ASCO Annual Meeting) 2014; 32 (Suppl);abstr e17053.

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Canadian Perspectives

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Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

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David Macdonald, MD, FRCPC

Dr. David Macdonald is a hematologist at the QEII Health Sciences Centre in Halifax, Nova Scotia, and Assistant Professor in the Division of Hematology at Dalhousie University’s Faculty of Medicine. Dr. Macdonald chairs the Hematology Cancer Site Team for Cancer Care Nova Scotia. His interests are in hematologic malignancies and, in particular, lymphoproliferative disorders. He has done a Clinical Trials Fellowship with the National Cancer Institute of Canada – Clinical Trials Groups and is actively engaged in clinical trials research. Dr. Macdonald has also completed a clinical fellowship in the lymphoma group at the British Columbia Cancer Agency in Vancouver, and he maintains a clinical research program in lymphoma.

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Jeffrey Rothenstein, MD, FRCPC

Dr. Jeffrey Rothenstein is a medical oncologist at the R.S. McLaughlin Durham Regional Cancer Centre in Oshawa and an Adjunct Assistant Professor in the Department of Oncology at Queen’s University in Kingston, Ontario. He completed his internal medicine and medical oncology training at the University of Toronto. Dr. Rothenstein’s main clinical focus is on the management of thoracic and gastrointestinal malignancies. He is the lung cancer site group leader at the R.S. McLaughlin Durham Regional Cancer Center.

Investigator Commentaries

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Stephan Stilgenbauer, MD

Dr. Stephan Stilgenbauer is Associate Professor and Deputy Chairman at the Department of Internal Medicine III (Hematology, Oncology, Rheumatology and Infectious Diseases) at Ulm University, Germany. He received his medical training at Heidelberg Medical School and was trained in internal medicine and hematology-oncology at the Universities of Heidelberg and Ulm. He spent a postdoctoral fellowship at the German Cancer Research Center (DKFZ) in Heidelberg. His research focus is on the molecular pathogenesis of hematological malignancies and translation of this research into novel treatment strategies. Dr. Stilgenbauer has authored or co-authored numerous original articles, reviews, and book chapters in journals such as The New England Journal of Medicine, The Lancet, Nature Medicine, the Proceedings of the National Academy of Sciences of the United States of America, Journal of Clinical Oncology, Blood, Leukemia, Haematologica, among others.

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C. Tom Kouroukis, MD

Dr. C. Tom Kouroukis graduated from the University of Toronto and completed training in Internal Medicine, Hematology and MSc (Health Research Methodology) training at McGill and McMaster Universities. He was awarded a National Cancer Institute of Canada Clinical Research Fellowship. He is a hematologist at the Juravinski Cancer Centre/Hamilton Health Science, Chair of the Hematology Disease Site Team, Head of the Division of Malignant Hematology, and Associate Professor in the Department of Oncology. He is Co-chair of the Hematology Cancer Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative and Chair of the Stem Cell Committee of Cancer Care Ontario. His research interests include the care of older patients with hematological cancers, the impact and evaluation of co-morbidity in older cancer patients, clinical trials, and practice guideline development.

Expert Commentaries

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Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

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Dietger Niederwieser, MD
Dr. Dietger Niederwieser is the Head of the Department of Hematology and Oncology at the University Hospital of Leipzig in Germany. He completed his medical degree and postgraduate training in internal medicine and hemato-oncology at the University of Innsbruck in Austria. His research interests include leukemia, myelodysplastic syndrome, renal cell carcinoma, Hodgkin lymphoma, allogeneic stem cell transplantation, and graft versus host disease and he is currently involved in a variety of clinical trials in these areas. Dr. Niederwieser is President of the Worldwide Network for Blood and Marrow Transplantation, past President of the European Group for Bone and Marrow Transplantation (EBMT), and a former Chair of the EBMT Chronic Leukemia Working Party. He is a member of several scientific societies, including the European Hematology Association, the American Society of Hematology, and the American Society of Clinical Oncology and he serves as an external reviewer for universities in Europe and the United States. Dr. Niederwieser is the author or co-author of numerous articles (<390) published in international peer-reviewed journals, such as The New England Journal of Medicine, Blood, the Journal of Clinical Oncology, the Journal of the American Medical Association, Nature Clinical Practice Oncology, Annals of Oncology, Leukemia, and Bone Marrow Transplantation.

Case Study

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Barbara Melosky, MD, FRCP(C)

Dr. Barbara Melosky is a Clinical Associate Professor of Medicine at the University of British Columbia and a medical oncologist at the British Columbia Cancer Agency in Vancouver. She graduated from medical school at the University of Manitoba, and did a residency in internal medicine and an oncology fellowship at the University of British Columbia. Dr. Melosky is currently working in the fields of lung and gastrointestinal malignancies with a special interest in the side effects of targeted therapy. She sits on the Executive Committee for the Lung Disease Site NCIC Clinical Trials Group and is the annual Chair of the Canadian Lung Cancer Conference.