Julie R. Gralow, MD

On behalf of the Southwest Oncology Group
Co-Investigator: Peggy I. Porter, MD, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle

One way to improve treatment of breast cancer is to develop tests that predict for the likelihood of response or resistance to certain drugs. Such a test would allow physicians to select specific drugs with a high likelihood of benefit and avoid drugs unlikely to generate a response in certain patients. In another BCRF-funded study, the Southwest Oncology Group (SWOG) is studying the tumors of breast cancer patients previously treated with anti-tubulin drugs on clinical trials in an attempt to determine if there is a pattern that could predict for response or resistance to these drugs. Tissue samples were collected and preliminary analysis has been completed. To date, one marker, tau, has been found to highly correlate with benefit from the combination anti-tubulin regimen. The reconciling of the responses has been completed and the results will be submitted for presentation at the 2007 San Antonio Breast Cancer Symposium, with acknowledgement to BCRF for their generous support.

A second SWOG project is examining metastases involving the bone, common in advanced breast cancer patients. Bone metastases are very common in patients with breast cancer. The skeleton is the initial site of recurrence in 35 - 40% of patients. Up to 60 - 80% of patients with metastatic breast cancer eventually develop signs and symptoms related to bone involvement. Bisphosphonates are a diverse group of compounds, which have profound effects on bone mineralization and resorption. They are effective in treating conditions in which there is excessive bone resorption and osteoclast activity, including osteoporosis and Paget's disease of bone. Several randomized clinical trials in breast cancer patients with bone metastases have demonstrated the ability of bisphosphonates to reduce skeletal-related events and symptoms, including pathologic fractures, surgery, radiation, spinal cord compression, hypercalcemia, and pain.

There is a need for further investigation to determine whether bisphosphonates can influence the development of bone metastases and improve survival in early stage breast cancer. The Southwest Oncology Group (SWOG) has a newly activated study, S0307, which proposes to determine whether bisphosphonates can delay or prevent the occurrence of metastases in high-risk patients with breast cancer but who have no evidence of metastatic disease. Patients are required to also be receiving "standard" adjuvant systemic therapy.

The doses of bisphosphonates used in S0307 are two to ten times greater than those used to treat osteoporosis, and the effects of high-dose bisphosphonates on bone heath is uncertain. Bisphosphonates increase bone density and have been shown to reduce fracture rates in women with osteopenia and osteoporosis. Bone density is one important determinant of the strength of bone, however bone strength depends on both the quantity and the quality of bone. In order to determine if the effects of bisphosphonates are beneficial or detrimental to the skeleton, the researchers are conducting a companion study to evaluate a subset of premenopausal women at selected institutions who will undergo bone biopsies, bone density measurements by dual x-ray absorptimetry and biochemical markers of bone turnover before and after three years of high dose bisphosphonate treatment. Results of this sub-study will provide valuable information about skeletal effects of high-dose bisphosphonate use.

Sixty percent of all U.S. cancer patients are 65 years of age or older, and this number is expected to rise considerably in the next decade. There are many reasons why older patients may respond to cancer treatments differently than younger patients, including increasing numbers of general health problems, medications, and other age-related changes. Determining how best to treat older cancer patients, and determining the risks and benefits of cancer therapies in this population, is becoming increasingly critical. Approved cancer therapies are proven to be effective and safe through carefully conducted clinical trials. Unfortunately, older cancer patients rarely participate in clinical trials.

Because most cancer trials do not include sufficient numbers of older patients, there is not enough data to determine safety or efficacy for most cancer treatments in this population. The challenge of enrolling older cancer patients in clinical trials becomes more urgent as the number of older individuals in the United States increases. The Southwest Oncology Group (SWOG) is studying why older cancer patients either do or do not enroll on a cancer clinical trial. They hope to explore and define the barriers to clinical trials participation in older patients and develop successful interventions to overcome them.

A window of opportunity exits to forge new directions in cancer diagnosis, treatment and prevention, resulting from recent developments that create an unprecedented juncture in science and technology. New microarray technologies can identify genes and proteins involved in pathways that control cell proliferation, death, and differentiation. Evaluation of these genes and gene products in human tumors is the next critical step to assess their real clinical value. A new method for rapid evaluation of large numbers of tumor samples at the same time, called tissue microarray (TMA), has been developed. This high-throughput technique can greatly expand ability to test tumor markers identified through new array technologies, and rapidly translate molecular discoveries into clinical applications.

In the coming year, the researchers will expand construction of TMA blocks to include tumors collected as part of other SWOG trials. The SWOG staff will make sections of the TMA blocks available to investigators for use in translational research that has been approved by the Intergroup Breast Correlative Sciences Review Committee (IBCSRC). The IBCSRC has members of all clinical trial Groups contributing specimens, and has been empowered by the Groups and the NCI to set priorities and to approve the use of biological materials collected as part of Intergroup Breast Cancer protocols. The group will identify SWOG/Intergroup trials that would benefit from the construction of TMA, set priorities and requirements for use of TMA slides, review project proposals for TMA slides, and establish guidelines for data submission and analysis.

Mid-Year Progress Report:
For the study of tumors of breast cancer patients previously treated with anti-tubulin drugs on clinical trials, tissue samples were collected and analysis has been completed. One marker, tau, has been found to highly correlate with benefit from the combination anti-tubulin regimen. The conclusions were that the SWOG S0102 study demonstrated that the combination of two anti-tubulin agents, docetaxel and vinorelbine, is highly active as first-line chemotherapy in HER-2 negative metastatic breast cancer. Analysis of the tau marker confirmed a previous study that higher tau is associated with a better prognosis in metastatic patients treated with docetaxel and vinorelbine. This data was presented at the 2007 San Antonio Breast Cancer Symposium.

At this time, the bisphosphonates study has been reviewed and approved by SWOG, and data collection forms have been developed. The study will now go to CTEP (Cancer Trial Evaluation Program of the NCI) for review and potentially be ready to open and begin enrollment in April. Limited SWOG institutions are currently being evaluated for participation, with 3 sites confirmed (Seattle Cancer Care Alliance, University of Michigan, and Columbia University).

The study of barriers to clinical trial enrollment for older individuals is currently enrolling breast cancer, lung cancer and colorectal cancer patients at a limited number of institutions. The results of this study will indicate where and how to target efforts to increase clinical trial enrollment for older cancer patients, so that we may begin to rectify this important barrier to cancer research and treatment.

Drs. Gralow and Porter,with the support of BCRF, have continued to expand the SWOG TMA resource. They have constructed TMA blocks from 4 studies and continue to provide researchers with material to test hypotheses. Assays that have evaluated the prognostic and predictive value of HER2, TOP2A, p27, and cyclin E genes or proteins have confirmed that high level HER2 gene amplification is a prognostic marker for patients treated in the adjuvant setting with doxorubicin containing regimens and that p27 might be a promising prognostic marker, especially in women with ER-positive breast cancer. Results from these studies have been presented at the San Antonio Breast Cancer Symposium, American Society for Clinical Oncology and published in the Journal of the National Cancer Institute.

Additionally, a TMA for a trial of combined anti-tubulin therapy in metastatic breast cancer has been tested for protein expression. The study demonstrated that the combination of two anti-tubulin agents, docetaxel and vinorelbine, is highly active as first-line chemotherapy in HER-2 negative metastatic breast cancer and that tau protein is associated with a better prognosis in metastatic patients treated with docetaxel and vinorelbine. The results were presented at the San Antonio Breast Cancer Symposium in December 2007.

The resource being funded by BCRF supports the best use of specimens collected through SWOG-initiated trials. The Seattle team is working to develop and expand capabilities for producing high-quality TMA tissue sections and web-based images that are accessible to researchers nationwide.

Bio:
Julie Gralow majored in Biologic Sciences as an undergraduate at Stanford University, attended medical school at the University of Southern California in Los Angeles, and trained as a resident in Internal Medicine at Brigham and Women's Hospital in Boston. Her Medical Oncology fellowship training was performed at the University of Washington School of Medicine and the Fred Hutchinson Cancer Research Center.

As a breast cancer specialist and academician, Dr. Gralow's time is split between patient care, education, and clinical research. She is the principal investigator on several clinical trials related to breast cancer prevention and treatment, and is committed to patient education, outreach and wellness. She is co-chair of the Southwest Oncology Group’s Breast Cancer Committee, and serves as chair of the American Society of Clinical Oncology's Cancer Communications Committee.

Dr. Gralow is also Medical Director, Team Physician and co-founder of Team Survivor Northwest, an exercise and fitness program for women cancer survivors. She is co-author of "Breast Fitness: An Optimal Exercise and Health Plan for Reducing Your Risk of Breast Cancer".