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
"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
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
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
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
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