Many Paths, One Goal: Eliminating Breast Cancer
Three new approaches are helping IU Cancer Center physicians and
scientists advance in their quest against breast cancer.
Pink ribbons aren't just for little girls' pigtails anymore. They
now appear as a symbol of strength and hope against most women's
worst nightmare: breast cancer. Statistics on a woman's odds of
breast cancer vary from year to year, depending on what group or
sources are cited. But by any measure the disease is a killer, touching
women from every walk of life.
Researchers at the Indiana University School of Medicine long have
taken the lead in bettering diagnosis, treatment and understanding
of the disease. At the IU Cancer Center, a National Cancer Institute-designated
facility and the only one of its kind in Indiana, a diverse group
of individuals collaborates to unlock the disease process and lay
it open to new, more effective approaches.
Anti-Angiogenesis: Starving The Tumor
1976: A young doctor fresh into the first year of his residency
spent half an hour in a hospital stairwell sobbing. Not because
his workload was overwhelming, which it was, or because his hours
were inhumane, which they were. He cried that day, for the first
of many times to come in his career, because he had to tell a patient
that she had cancer. She was only twenty-two years old, had three
children and had just learned the bad news.
"She just looked at me and asked, 'Who's going to take care
of my children?'" George W. Sledge Jr., MD, remembers.
Twenty-five years later in his office in the IU Cancer Center where
he leads the adult oncology program, Dr. Sledge apologizes for getting
emotional when recalling the case and adds, "That's when I
knew I wanted to help people with cancer."
The course of his career led Dr. Sledge, now the Ballve-Lantero
Professor of Oncology, into the fight against breast cancer. Today
his focus is anti-angiogenesis; he and his team are developing ways
to arrest tumors by cutting off their blood supply.
Any collection of tumor cells releases hormones, also called growth
factors, into their environment. These vascular endothelial growth
factors (VEGF) signal the blood vessels nearby to sprout new vessels
that attach to the tumor, feed it and allow it to grow. Since every
tumor larger than 1-2 mm3 requires its own blood supply, Dr. Sledge
aims to attack cancer at what may be its most vulnerable spot, this
circulatory lifeline.
"The approach is broadly applicable to any tumor," he
says, and testing has already started on breast, lung and colorectal
cancers.
His weapon of choice is Avastin (bevacizumab), an antibody developed
by Genentech, which inhibits angiogenesis by attaching itself to
VEGF and preventing it from binding to the receptors on the blood
vessels. Without the correct signal from the growth factor, the
blood vessels attempting to connect with the tumor stop developing.
Lacking its own sufficient blood supply, the tumor can't grow and
sometimes even shrinks.
Avastin is designed to work together with traditional chemotherapy
drugs called taxanes, which attack the structural elements of cancer
cells, rendering them inflexible and preventing them from successfully
dividing and multiplying.
Indiana University ran the first Phase I and Phase II trials with
Avastin, first enrolling general cancer patients and then, more
specifically, breast cancer patients for whom prior chemotherapy
treatment had failed.
The first nationwide Phase III trial with Avastin began in December,
led by Kathy D. Miller, MD, assistant professor of hematology/oncology
at IUSM, and coordinated by the Eastern Cooperative Oncology Group
(ECOG).
"This trial is for patients with newly diagnosed metastatic
breast cancer who have not had prior chemotherapy for recurrent
disease," Dr. Miller says of the trial that will enroll roughly
650 patients over the next three or four years. It will investigate
to what extent adding Avastin to standard chemotherapy will enhance
its effectiveness.
"It's a synergistic effect," Dr. Sledge notes. "Two
plus two equals five - together they work better than either one
alone."
Dr. Sledge remembers seeing the Avastin results for the first time.
"My research nurse and I were comparing the two films, seeing
the lump on one and the hole on the other one where the lump used
to be - we just broke into grins," he says, a smile stretching
across his face as he recalls the discovery.
"There's the intellectual thrill of seeing that science works,"
Dr. Sledge says of what drives him still today. "But then there's
the human feeling of knowing that ten minutes later you're going
to walk into the patient's room and say, 'You're going to live a
bit longer.'"
Ductal Lavage: Searching for the Bad Seed
Many women diagnosed with breast cancer remember the frightening
moment when they first felt the little lump that wasn't there before.
By the time it's large enough to detect, that lump has its own blood
supply and its cancerous cells have a means to spread.
Self-exams, mammograms, and even ultrasound have made strides toward
early detection, but they all require a tumor to already exist.
A new procedure at the IU Cancer Center makes it possible to find
evidence of the very earliest stages of cancer formation.
Ductal lavage gets its name from the French word meaning to wash
or rinse. Based on the same principle as traditional nipple aspiration,
in which a suction device is used to extract fluid out of the ducts,
ductal lavage harvests thousands of cells from fluid-emitting ducts
where most breast cancers are thought to originate. The cells are
analyzed for abnormal cell growth and the cancer risk assessed.
Anna Maria Storniolo, MD, a professor of clinical medicine who
heads the Catherine Peachy Breast Cancer Prevention Program at the
IU Breast Care and Research Center, directs the high risk breast
cancer screening clinic that administers ductal lavage.
"As many as ninety-five percent of cancers begin in the ductal
system of the breasts," Dr. Storniolo says. "We need to
go where the money is."
Ductal lavage is reserved for women at extremely high risk, as
assessed in the clinic by a variety of methods. When appropriate,
women receive the test along with a complete evaluation and counseling
to help them cope with anxiety, learn risk-reduction behaviors and
determine genetic history.
Robert J. Goulet Jr., MD, associate professor and medical director
of IU's Breast Care Center, administers the test. "Until recently
we were one of only a few centers in the United States to use the
ductal lavage," he says. "We're very excited about this
advancement in diagnosis and the potential it holds for treatment."
The test involves little or no discomfort. A topical anesthetic
is applied to the nipple and a pump is used to determine which ducts
are fluid-producing. A tiny catheter is then inserted into the productive
duct to introduce a small amount of lidocaine and saline solution.
The patient massages her breast to move the fluid through the ductal
system. After several minutes the clinician retracts the sample
through the catheter into a collection tube. This method harvests
an average of nearly 14,000 cells per duct, compared with nipple
aspiration that garners only 120 cells for the entire breast.
"The soup of cells that come out is a gold mine of potential
clinical material that has never before been this easily accessible
to us," Dr. Storniolo explains. "What are the molecular
signals that cause a cell to go from benign to cancerous? We look
at the cell that's gone haywire, the one that's operating under
very abnormal control signals."
Aside from assessing the level of abnormal cell growth in a woman's
ductal cells, the procedure also allows for repeated evaluation
and tracking of very specific areas of the breast. Dr. Storniolo
sees no end to the possibilities. "I can see a future where
we can give drugs just to that area of the breast," she says.
Synthesome: The DNA Machine
Knowing how to treat breast cancer and where to look for it are
vital to keeping the disease in check. But unraveling the mystery
of what causes cells to become cancerous could hold the key to a
cure.
In January 2002, Linda Malkas, PhD, professor of medicine and the
Vera Bradley Chair Designee of Breast Cancer Research, came to IUSM
from the University of Maryland at Baltimore School of Medicine,
where she and her research team have been investigating the mammalian
DNA synthesome.
Dr. Malkas discovered what she calls "the machine that makes
DNA" in a test tube twelve years ago. Watching the multiprotein
DNA replication in progress allows researchers to witness the beginnings
of cancer which manifest as the cell's uncontrolled proliferation
and the accumulation of genetic damage.
"I wondered if the replication machine in breast cancer cells
is particularly prone to error," Dr. Malkas says, adding that
her research so far has supported this theory.
In particular, one component of the synthesome exhibits structural
changes in connection with cancerous cell production. The protein
proliferating cell nuclear antigen (PCNA) has been studied for the
last twenty years as a whole entity, but the structural alteration
in the replication complex consisting of only forty peptides has
never been investigated in detail.
Dr. Malkas and her team discovered that PCNA in non-malignant breast
cells expresses its protein complete with a positive translation
modification group (PTM) which helps regulate cell activity. In
malignant cells, PCNA also creates the protein but the PTM group
is not present, which she believes contributes to the cell's inability
to control itself.
"This PCNA is a real malignancy marker," Dr. Malkas explains.
"Chemotherapy doesn't discriminate between malignant and non-malignant
cells, but this will help us go after things unique to malignancies."
The potential for her research is amplified by other advances in
the field, particularly ductal lavage. "We can make better
diagnoses with lavage and can find new therapeutic targets,"
Dr. Malkas says.
Dr. Malkas shares a selfless passion and enthusiasm for research
in the battle against breast cancer with her IU colleagues, including
her husband, Robert Hickey, PhD, associate professor of medicine
in the Division of Hematology/Oncology, whose expertise lies in
the field of proteomics, the study of the set of proteins produced
by an organism, tissue or cell.
"I got my first look at the horror of cancer when my father
died of it eighteen years ago," Dr. Malkas remembers. "I
don't care if anybody remembers my name. If I can make a few less
tears in the world wrought by cancer, and if someone finds through
my work something that makes a dent in this disease - then I'll
know why I lived."
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