WASHINGTON-Cutting-edge molecular research supported by the National Cancer Institute (NCI) promises revolutionary changes in the way physicians screen, diagnose, and treat breast cancer, NCI director Richard D. Klausner, MD, told the Senate appropriations subcommittee that oversees the NCI.
WASHINGTONCutting-edge molecular research supported by the National Cancer Institute (NCI) promises revolutionary changes in the way physicians screen, diagnose, and treat breast cancer, NCI director Richard D. Klausner, MD, told the Senate appropriations subcommittee that oversees the NCI.
"We have reached an exciting point where we have a molecular window on cancer, and our new strategy of looking at all aspects of breast cancer from a molecular view is bearing fruit," he said in a report submitted as part of his testimony on NCI’s fiscal year 2002 budget. "Our challenge is to translate this new knowledge into useful and effective screening, preventive, diagnostic, and treatment tools as quickly as possible."
Researchers in recent years have obtained the tools to detect molecular changes that occur in tumor cells, Dr. Klausner said. Such discoveries have expanded the fundamental understanding of cancer and revealed that significant molecular differences can exist in cancers given the same name. "It will be important to consider breast cancer not as one disease but as a collection of possibly heterogeneous diseases," he said. "Efforts are underway to distinctly classify tumors by a variety of parameters, including hormone-receptor status, histologic patterns, and the presence of oncogenes."
Currently, five NCI-supported Early Detection Research Network centers are investigating genetic approaches to the early detection and risk assessment of breast cancer, he said. Others are examining the gain, change, or loss of genetic material that occurs with the disease.
Studies include genes such as BRCA1, the Ki-ras oncogenes, and the p53 tumor-suppressor gene, which are abnormally elevated in breast cancer, and others that are inactivated by genetic changes, such as the DNA repair gene.
Research indicates that a single drop of nipple aspirate fluid can reveal differ-ences in protein peaks between normal and cancerous breast cells, Dr. Klausner said. Studies are now in progress to determine if the approach is valid in a large number of specimens and has potential as an early screening test.
The Diagnostic Challenge
Breast cancer’s most pressing diagnostic challenge involves therapeutic choices, particularly whether to give adjuvant therapy to patients with negative lymph nodes, Dr. Klausner said.
"Earlier detection of breast cancer is resulting in a shift to smaller tumors, and in over 50% of cases, there is no apparent spread to the axillary lymph nodes. About 70% of node-negative patients will actually be cured by definitive surgery plus local/regional radiotherapy. We do not know how to separate, with sufficient certainty, the patients with a high risk for recurrence from those whose cancer will not recur."
As more specific therapies such as trastuzumab (Herceptin) become available, the need to identify which patients will benefit from which treatments becomes more important, he added. "Decisions regarding which patients should be treated and the choice of treatment require greater understanding of the underlying biology of breast cancer and the specific lesion in the patient," he said.
Tumor classification based on morphology does not always predict the tumor’s clinical behavior, Dr. Klausner noted. "Molecular profiles are expected to provide more informative molecular
classification schemes by identifying clinically important tumor subsets within morphological classes," he said.
For example, investigators have developed molecular profiles for two subsets of node-negative breast cancers. One subset appears to have tumors arising from the luminal cells in breast glands and the other from basal cells. "Patients with basal cell tumors appear to have a significantly worse outcome and may represent those node-negative patients at greater risk for recurrence," he said.
Node-negative breast cancer patients whose disease recurs probably shed cancer cells from their primary tumor, and researchers are working on new techniques to detect and analyze alterations in tumors as a way of detecting residual disease. NCI will hold a meeting this fall to assess the state of the science in detecting minimal disease as a way to help it determine its research agenda.
The Institute has accelerated its program to discover and develop new imaging technologies that can identify biologic and molecular properties of precancerous and cancer cells to predict clinical course and response to treatment.
In one study, researchers are using positron emission tomography (PET), enhanced by administration of a chemical agent that indicates receptor status, to evaluate estrogen-receptor (ER)-positive women before and after they begin tamoxifen (Nolvadex) therapy. They hope to learn whether this approach predicts responsiveness to hormone therapy.
Other investigators are developing novel radiolabeled ER binding molecules for imaging and possible therapeutic use.
Trastuzumab is the prime example of a targeted therapeutic for breast cancer. Currently, NCI is sponsoring 10 trials involving the drug, and Genentech, its maker, is supporting five other studies.
"Based on discoveries in the research lab, there is a plethora of breast cancer targets with active agents under development," Dr. Klausner said. NCI has initiated several trials seeking to exploit these discoveries, and more are in development. In a phase III trial, researchers are investigating the use of an inhibitor of the enzyme matrix metalloproteinase in advanced breast cancer as a way to destroy supporting tissue around the tumor; the experimental inhibitor is administered after conventional chemotherapy.
Also under evaluation is one of the first selective estrogen-receptor degradation (SERD) agents. "Early work has shown activity in patients whose tumors are resistant to tamoxifen, and a large trial is planned by NCI to test this agent in early-stage disease," Dr. Klausner said.
An NCI-sponsored phase II trial will begin shortly that combines trastuzumab and chemotherapy with an agent that interferes with the epidermal growth factor (EGF) pathway.
Another agent soon to enter clinical trial is a humanized monoclonal antibody that interferes with angiogenesis in tumors by blocking vascular endothelial growth factor (VEGF). NCI has approved a phase III study to test this agent in combination with chemotherapy.
"The NCI has developed a new way to describe breast cancer as a series of clinical states that represent decision points for patients and physicians," Dr. Klausner said. "Each of these clinical states lends itself to a tailored management plan based on its collection of defining traits."