Sheila E. Taube, Ph.D., Associate Director

The Cancer Diagnosis Program (CDP) stimulates and supports diagnostics research, resources, and improved technologies to guide treatment choices for cancer patients. The research portfolio includes investigator-initiated research that underlies new developments in diagnostics research, programs for developing new molecular technologies, and coordination and development of new biologic and informatics resources. The Program for the Assessment of Clinical Cancer Tests (PACCT) implements and coordinates the evaluation of new diagnostic technologies and their application to clinical decision making. PACCT is the mechanism by which CDP takes research from discovery through development to delivery. To accomplish CDP goals, the staff coordinates technology development activities with other NCI components, academic researchers, and industry; coordinates development of biologic and informatics resources with NCI programs, other federal agencies, and outside organizations; and maintains liaisons with the Food and Drug Administration (FDA) regarding development of new diagnostic devices. CDP staff devotes significant effort to evaluating research so they can advise the Division and NCI directors about scientific opportunities for developing new cancer diagnostics.

GRANTS

Identifying Chemosensitive Gliomas
Gliomas are malignant brain tumors that are usually fatal within a short time despite treatment. A major glioma subtype called oligodendroglioma, however, often responds to therapy. Long-term remissions are seen in about two-thirds of patients with oligodendrogliomas who are treated with a combination of procarbazine, lomustine, and vincristine (the PCV regimen). It has not been possible to routinely and consistently identify oligodendrogliomas using microscopy.

Now, NCI-supported researchers at the Massachusetts General Hospital, in collaboration with investigators in Ontario, Canada, have discovered that loss of a portion of chromosome 1 in oligodendroglioma tumor cells predicts response to PCV [1]. This finding has been confirmed by a second group of NCI-funded investigators at the Mayo Clinic [2]. There is intense interest in the potential of these chromosome abnormalities to guide treatment for oligodendroglioma patients. The predictive power of chromosome deletions is under investigation in a phase III trial that recently closed accrual [3], and CDP and the Cancer Therapy Evaluation Program are working with Clinical Co-operative Group members to design follow-up trials. These discoveries may help physicians recommend appropriate treatments.

The Glioma Marker Network (GMN), initiated via a 1988 Request for Application (RFA), has played a critical role in these discoveries. Through two rounds as an RFA-driven consortium, the Network designed marker studies of greater power and complexity than previously attempted, and developed an unparalleled resource of brain tumor specimens with centrally performed pathology reviews and associated clinical data. One important study mapped deletions on chromosomes 1p and 19q that are associated with sensitivity to PCV, and designed fluorescence in situ hybridization probes that provide a simple, highly reliable assay for these deletions [4]. In 1999 the GMN was reorganized as a program project grant. It is still a multi-institutional consortium with projects at the Mayo Clinic, University of California-San Francisco, Ohio State University, and M.D. Anderson Cancer Center. The program has active collaborations with the Radiation Therapy Oncology Group and the North Central Cancer Treatment Group, and continues to develop and expand the brain tumor tissue resource.

References 1. Cairncross JG, Ueki K, Zlatescu, MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. Journal of the National Cancer Institute 1988;90:1473-9. 2. Smith JS, Perry A, Borell TJ, et al. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas and mixed oligoastrocytomas. Journal of Clinical Oncology 2000;18:636-45. 3. Jenkins RB, Curran W, Scott CB, Cairncross G. Pilot evaluation of 1p and 19q deletions in anaplastic oligodendrogliomas collected by a National Cooperative Cancer Treatment group. American Journal of Clinical Oncology 2001;24:506-508. 4. Smith JS, Alderete B, Minn Y, et al. Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene 1999;18:4144-52. Collaborators The principal investigator at Massachusetts General Hospital is Dr. David N. Louis, collaborating with Dr. J. Gregory Cairncross at the University of Calgary and Foothills Medical Centre, Alberta, Canada. The lead investigator at the Mayo Clinic is Dr. Robert Jenkins, collaborating with other principal investigators of the NCI-supported Glioma Marker Network: Dr. Allan Yates (Ohio State University), Dr. Peter Burger (Johns Hopkins University) and Dr. Burt Feuerstein (University of California-San Francisco). Collaborators from the clinical trials organizations are Dr. Minesh Mehta (University of Wisconsin) of the RTOG, Dr. Kurt Jaeckle (Mayo Clinic) of the NCCTG, Dr. Stuart Grossman (Johns Hopkins University) of NABTT, and Dr. Alfred Yung (M.D. Anderson Cancer Center) of the NABTC.

TARGETED INITIATIVES

Access to Prostate Cancer Biospecimens for Research
In 2002, the Cooperative Prostate Cancer Tissue Resource (CPCTR) began accepting requests from the scientific community for prostate cancer tissue samples. The CPCTR is made up of four medical institutions that collect prostate tissue samples from tissue that remains after a tumor is surgically removed and annotate each sample with clinical information. These samples help cancer researchers answer questions related to prostate cancer development, diagnosis, and treatment. The CPCTR website explains how researchers may obtain research specimens. Tissue microarrays may be available in 2003.

References 1. Datta MW, Becich M, Bosland M, et al. Ethnicity-based analysis of prostatectomy specimens and PSA outcomes: Results from the NCI Cooperative Prostate Cancer Tissue Resource. U.S.-Canadian Academy of Pathology Meeting, Washington DC; March 22-28, 2003. 2. Melamed J, Datta MW, Becich M, et al. Prostate cancer pathologic parameters and clinical outcome: Results from the Cooperative Prostate Cancer Tissue Resource. U.S.-Canadian Academy of Pathology Meeting, Washington, DC; March 22-28, 2003. Collaborators CPCTR grantees

NCI Tissue Microarray Technology Accelerates Cancer Research
Tissue microarrays are paraffin blocks that contain samples from a large number of patients in an ordered array of small plugs taken from pathologic blocks. Microarrays provide an economical way to make large human specimen collections available to the research community, and allow researchers to study samples from many patients in one experiment. Several groups have used tissue arrays in their research since the 1998 publication by Dr. Olli Kallioniemi's group that described the technique.

The NCI has been instrumental in developing tissue microarrays to accelerate cancer research; for example, creating the Tissue Array Research Program (TARP) with the National Human Genome Research Institute in 2000. TARP provides researchers with tissue array slides containing 500-600 cases representing various tumor types. Slides from the arrays are distributed through the Cooperative Human Tissue Network. During the past 2 years, TARP has distributed nearly 3750 tissue microarray slides to 350 investigators throughout the United States. These arrays have helped researchers quickly determine the prevalence of their antibody reagent targets in various tumor types-an important step in developing diagnostic assays and tools for basic science.

The Cooperative Breast Cancer Tissue Resource (CBCTR) has enhanced the utility of tissue microarrays by producing a set of tissue microarrays designed by NCI statisticians to provide high statistical power for detecting differences in marker prevalence between tumor stages. This array allows researchers to detect changes in marker expression with progression from node-negative to node-positive breast cancer to metastatic disease. The CBCTR receives about five applications per month for progression array slides, and the requests increase as researchers learn about the availability of the arrayed specimens.

The NCI also supports other tissue microarray efforts. The National Surgical Adjuvant Breast and Bowel Project created a tissue array containing all specimens from its trial of anthracycline versus anthracycline followed by paclitaxel in breast cancer patients. Slides from this array will soon be available to the research community. The CPCTR is working with NCI statisticians to design useful tissue microarrays that will soon be in production. Plans are also underway in the CBCTR and CPCTR to design and produce arrays that can be used to assess prognostic markers.

References 1. Glass A, Donis-Keller H, Mies C, et al. The Cooperative Breast Cancer Tissue Resource: Archival tissue for the investigation of tumor markers. Clinical Cancer Research 2001;7:1843-9. 2. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Medicine 1998;4:844-7. Collaborators Glass A, Russo J, Russo I, Zehnbauer B, Milikowski C, Kleiner D, Moskaluk C, Paik S, Hewitt S, Kallioniemi, O.

Molecular Profiling Predicts Lung Cancer Prognosis
Up to 40% of stage I non-small-cell lung cancers recur despite surgical resection. The ability to identify patients likely to recur will allow development of strategies to improve therapy and provide information for patients likely to be cured with surgery alone. No diagnostic markers are available to help determine what treatment besides surgery will be effective for curing non-small-cell lung cancer.

Three Director's Challenge projects have reported gene expression profiles that identify clinically different subsets of stage I lung adenocarcinoma patients. Each research group identified a subset of patients with significantly worse outcomes than the majority of stage I lung adenocarcinoma patients. These results are particularly promising because each group used different analytical platforms and criteria to select specimens for analysis.

A study is being initiated to confirm these results in a separate large cohort of archived frozen lung adenocarcinomas with associated clinical outcome data. The proposed study of 500-600 tumors will be a collaboration between the Director's Challenge investigators and investigators from the lung Specialized Programs of Research Excellence and clinical cooperative groups. The study will use standardized protocols so generated data will be comparable.

If confirmed, these molecular signatures will be developed into clinical diagnostic tests that can inform patients and clinicians about the likelihood of cure by surgery alone. Such a test may also be useful in characterizing the likely behavior of small lesions identified by spiral computerized tomography scanning. Molecular profiling may lead to novel targets for developing new treatments or improving imaging modalities.

References 1. Beer DG, Kardia SL, Huang CC, et al. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nature Medicine 2002;8:816-24. 2. Bhattacharjee A, Richards WG, Staunton J, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proceedings of the National Academy of Sciences USA 2001;98:13790-5. 3. Garber ME, Troyanskaya OG, Schluens K, et al. Diversity of gene expression in adenocarcinoma of the lung. Proceedings of the National Academy of Sciences USA 2001;98:13784-9. Collaborators Samir Hanash, David Beer, Sharon Kardia, Thomas Giordano, et al., University of Michigan, Ann Arbor. Arindam Bhattacharjee, Matt Meyerson, Todd Golub, David Livingston, et al., Dana Farber Cancer Institute and MIT, Boston, MA. Mitch Garber, Matt van de Rijn, Charles Perou, Patrick Brown, David Botstein, et al., Stanford University, Palo Alto, CA.