Friday, March 31

Clinical Validation of Biomarkers:
Biological and Analytical

8:00 – 8:30 Clinical Validation of Cancer Biomarkers with Diagnostic Potentials
Dr. William Clarke, Professor, Pathology, Johns Hopkins University
Cancer is a proteomic disease. The study of cancer proteomics not only allows better understanding of cancer biology, but it also provides the opportunities to identify proteomic biomarkers for cancer diagnostics. Since cancer is heterogeneous, it is unlikely that a single biomarker could be used to achieve its full clinical potentials in the early detection of cancer. Maximum clinical usefulness is likely to require a panel of biomarkers. Discovery of a cancer biomarker panel is relatively easy, however, clinical validation is difficult. Study design, patient selection, sample collection/processing and data analysis are important issues for a successful validation program. We want to extract as much information as possible from a limited number of samples and to avoid selecting biomarkers whose performances are influenced mostly by non-disease related artifacts in the data. With a successful clinical validation, potential biomarkers could be translated into clinical practice. Case studies will be presented to illustrate lessons learned from the clinical validation of biomarkers for the early detection of cancer.

8:30 – 9:00 Developmental Strategy for the Identification of Clinically Relevant Lung Cancer Biomarkers
Dr. Estelle Marrer, Biomarker Expert, Biomarker Development, Novartis Pharma AG
Lung cancer kills over 1 million patients a year, worldwide, being the most important "killer" among the different solid tissue tumors (American Cancer Society 1930-2001). Very striking is the fact that mortality due to lung cancer is still only slightly less than its incidence. Up-to-date there are no reliable biomarkers for the detection of lung cancer, it is therefore extremely difficult, if not impossible, to detect lung cancer at a very early and limited stage. Prospectively, since 2001, The Department of Pulmonary Gene Research (Hospital of Basel, Switzerland) has collected endo-bronchial biopsies of patients attending out-patient clinic for a suspicion of lung cancer or
investigation of an interstitial lung disease. Minute endo-bronchial biopsies (n = 82) and matched blood samples of patients with NSCLC (n = 67) and controls, with and without inflammatory lung disease, smokers and non smokers (n = 15) were hybridized on a high-sensitivity array (Novachip) without prior amplification. Biomarker identification has been performed using multivariate supervised between group analysis (BGA).

9:00 – 9:30 Biomarker Discovery and Validation with Rheumatoid Arthritis Registry
Dr. Danyi Wen, Scientist II, Inflammation, Millennium Pharmaceuticals, Inc.
Biomarkers play a pivotal role in drug discovery and development. Biomarkers include pharmcodynamic (PD) markers and disease markers. PD biomarkers are critical in characterizing pharmacodynamic effects of a compound in dose-escalating studies. Several PD assays were developed to support the drug discovery for rheumatoid arthritis (RA). Millennium Pharmaceuticals Inc. and Partners Health Care are carrying out “Rheumatoid Arthritis Registry” study. RA registry samples were used as resources for biomarker discovery and validation. How we use RA biomarker to support drug development will be discussed.

9:30 – 10:00 Validation of the ELISpot Assay for Use in Monitoring Vaccine Trials
Dr. Janet Lathey, Director, Virology/Immunology, SeraCare BioServices
Bioassay Development and Validation, especially for cell based assays is not always straight forward. Using the enzyme-linked immunospot (ELISpot) assay as a basis, this session will provide guidance for developing and validating a clinical trial assay. Specific aspects to be covered include: use of stimulated cells and a standard curve to evaluate Precision, Linearity, Range, Robustness, and LOD/LOQ; use of donor banks for evaluating Accuracy and Reproducibility; and proficiency testing for multiple laboratory evaluations.

10:00 – 11:00 Coffee Break in the Exhibit Hall with Poster Viewing 

Biomarkers to Monitor and Predict Response to Therapy

11:00 – 11:30 Inflammatory Disease Biomarkers May be Useful Predictors of Clinical Efficacy of Infliximab Plus MTX Therapy in MTX-Naïve Early Rheumatoid Arthritis Patients
Dr. Sudha Visvanathan, Principal Research Scientist, Clinical Pharmacology and Experimental Medicine, Centocor, Inc.
Objectives: To compare the timing and extent of change in serum biomarker levels between patients receiving methotrexate (MTX) alone and MTX plus infliximab (IFX), and to determine if such changes predict improvement in signs and symptoms and structural damage in a randomized, controlled trial. Conclusions: For the combined infliximab plus MTX group, MMP-3, at baseline showed a significant association with improvement in clinical response, both signs and symptoms and structural damage at 1 year. Detection of elevated levels of MMP-3, ICAM-1 and COL 2-3/4C long neoepitope at baseline can be used to identify patients that may show improvement in ACR-N after treatment with infliximab plus MTX for 1 year.

11:30 – 12:00 EGFR Mutations and Response to Therapy
Dr. Somasekar Seshagiri, Scientist, Molecular Biology, Genentech Inc.
We have determined EGFR mutations retrospectively in a subset of previously untreated patients with advanced NSCLC in the phase III TRIBUTE study randomized to carboplatin and paclitaxel with either erlotinib (TarcevaTM) or placebo. We find that the EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib and may predict greater likelihood of response to erlotinib plus chemotherapy.

12:00 – 12:30 The Functional Diffusion Map: A Noninvasive Imaging Biomarker for Early Prediction of Cancer Treatment Outcome
Dr. Brian Ross, Professor, Radiology & Biological Chemistry, University of Michigan
There is a vital need for a validated imaging approach for providing early quantitation of cancer treatment response allowing for individualization of patient care. The functional diffusion map (fDM) (Proc. Natl Acad. Sci 102, 5524, 2005) has been shown to be sensitive to tissue structure at the cellular level. During the course of successful therapeutic intervention, changes in cellular structure occurs preceding macroscopic changes such as a decrease in tumor volume. This talk will overview the fDM approach and present new data revealing its ability to stratify patents (n=39) with Grade III/IV gliomas into responders and nonresponders much earlier than currently possible. 

12:30 - 2:00 Lunch on Your Own or Technology Workshop (sponsorship available)

Biomarkers to Monitor and Predict Disease Progression

2:00 – 2:30 High PSA Nadir on Testosterone Inactivating Pharmaceuticals Accurately Predicts Early Progression to Bone Metastasis in Men with Prostate Cancer
Dr. Mark Scholz, Medical Director, Clinical Services, Prostate Oncology Specialists
Presentation of retrospective review of 159 men with varying stages of prostate cancer short of bone metastasis treated with testosterone blocking drugs prior 2000. Various factors predictive of early progression to bone metastasis were evaluated including gleason score, PSA, stage, PSA doubling time and PSA nadir with an ultrasensitive PSA assay. PSA nadir greater than 0.05 ng/ml was strongly predictive of early progression to bone metastasis 

2:30 – 3:00 Cell-Bound Complement Activation Products (CB-CAPs) for Monitoring Inflammatory Diseases
Dr. Joseph Ahearn, Director of Research, Medicine, University of Pittsburgh Arthritis Institute
Essentially all inflammatory diseases and processes involve activation of the complement cascade. Common human disorders such as myocardial infarction, stroke, transplant rejection, hepatitis C virus infection, and autoimmune disease all share complement activation as a component of disease pathogenesis. We have developed an extensive panel of assays for complement activation products deposited on surfaces of circulating blood cells from the erythroid, myeloid, and megakaryocyte lineages. Data generated from more than 10,000 assays and more than 20 diseases suggest this as a promising approach for patient selection and monitoring response in a broad range of clinical trials.

3:00 – 3:30 Real-Time Molecular Diagnosis for Patient Stratification of Lymph Node Surgery
Dr. Dave Hoon, Director, Member, Molecular Oncology, John Wayne Cancer Institute
Currently we are performing the first international randomized multicenter clinical trial in malignant melanoma whereby melanoma patients lymph nodes are upstaged by real time quantitative RT-PCR and randomized for complete node dissection. The study involves detecting occult metastatic tumor cells in paraffin embedded tissue sections of sentinel lymph nodes and upstaging after histopathology diagnosis. The mRNA biomarkers were previously shown in a Phase II study to upstage lymph nodes that were histopathology negative and shown to predict disease recurrence and overall survival. The study has opened up a new approach in molecular upstaging of tumor draining lymph nodes. We will discuss our recent and current trials. The current trial has accrued >150 patients for molecular biomarker stratification for elective surgery.

3:30 – 4:00 Quantitative End-Point LATE-PCR Assays for Monitoring Barretts Esophagus
Prof. Lawrence Wangh, Associate Professor, Biology, Brandeis University
Barrett's esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EA). EA represents about 1 percent of the cancers diagnosed in the US and it is one of the cancers whose incidence has been increasing steadily during the past three decades in the Western world. In addition to ploidy abnormalities detected by flow cytometry, loss of heterozygosity, LOH, involving the p16 gene in chromosome 9p, as well as LOH involving the p53 gene in chromosome 17p are among the earliest and most relevant genomic biomarkers of BE. Our two laboratories are employing Quantitative End-Point LATE-PCR, QE LATE-PCR, to detect LOH in these chromosomal regions. Each LATE-PCR assay generates both single-stranded and double-stranded DNA and the ratio of these products corrects for variability among replicate samples. In addition, QE LATE-PCR assays make use of single linear probes to distinguish SNP sites that are heterozygous in normal genomes from those that are hemizygous in genomes that have undergone LOH in a single-tube, end-point assay format. We anticipate that clinical assays based on the QE LATE-PCR strategy will be reliable, rapid, and relatively inexpensive compared to current assays for LOH and will thereby make it easier to identify and closely monitor those BE patients at highest risk for developing EA.

4:00 Close of Conference