Breast cancer prevention meets success
with new agents and a new thinking.
By Erik
Ness
Few women get a more dramatic introduction to
breast cancer prevention than Sharon Anderson.
Nearly 15 years ago her identical twin Karen was nursing
her fourth child when she noticed a lump in her breast.
Karen’s doctor thought it was a blocked milk duct, but
after a few visits scheduled a mammogram. At the time
doctors excised the lump, cancer had spread to 17 of 21
lymph nodes.
Karen lived in west Kansas but sought further treatment
at the University of Kansas Medical Center, near
her sister Sharon. After Carol Fabian, MD, director of
the hospital’s Breast Cancer Prevention Center, finished
her first visit with Karen, she turned to Sharon. “Be here
tomorrow at 8,” she said firmly. “You are having your first
mammogram.”
Sharon Anderson was only 35 at the time, and no one
had ever mentioned mammograms before. Now the
veteran of four clinical trials, she’s helping her daughter’s
generation fight cancer before it happens. One trial told
her she carried the BRCA2 gene (a genetic mutation that
markedly increases a woman’s risk of breast and ovarian
cancers), and she had the recommended oophorectomy
(removal of the ovaries). She took the osteoporosis drug
Evista® (raloxifene) for five years in the STAR (Study of
Tamoxifen And Raloxifene) trial, which compared the
effects of two breast cancer risk-reducing drugs. Now
she’s in a trial testing the aromatase inhibitor Aromasin®
(exemestane).
‘‘With time, we will hopefully come up with a combination of medical and lifestyle
interventions that reduce the risk of breast cancer. It will be similar to treatment, so that
an individual woman walks in and, depending on her profile, there are various options
for her."
—Victor G . V ogel , MD
Despite four trials testing drugs known for side effects,
she has never had a problem. “I never did like taking
medicine. I guess I just think my body should be able
to take care of itself,” says Anderson, who also exercises regularly and watches her diet.
In this new era, complex cancers like breast cancer
probably won’t decrease as dramatically as cervical cancer,
which may be practically eliminated with the new human
papillomavirus vaccine. But the puzzling tangle of genetic
and lifestyle factors that lead to breast cancer is finally
starting to loosen. And the search for chemoprevention—drugs or nutrients that could slow down cancer or
even prevent it altogether—is beginning to yield fruit.
Last year, leading British cancer epidemiologist Jack
Cuzick, PhD, argued in the journal Lancet Oncology that
it was time for oncologists “to catch up with the cardiologists,”
who have cut deaths from heart disease in the
United States by half using drugs like statins and a prevention
mindset.
"Across the board it’s better to prevent a disease," argues
Worta McCaskill-Stevens, MD, of the Division of Cancer
Prevention at the National Cancer Institute. “With time,
we will hopefully come up with a combination of medical
and lifestyle interventions that reduce the risk of breast
cancer. It will be similar to treatment, so that an individual
woman walks in and, depending on her profile, there are
various options for her.”
What ’s Your Risk
Cancer prevention begins with figuring out your risk.
You may have taken available online tests (www.cancer.gov/bcrisktool) that ask your age, how many immediate
relatives have had breast cancer, age at menarche and
age at first childbirth. Your answers get plugged into a
complex equation developed by NCI biostatistics guru
Mitchell Gail, MD, PhD, and out pops your likelihood of developing breast cancer in the next five years.
The strength of the Gail model is that it’s accurate with
very little information. (It works better for white women;
the model is still being calibrated for other ethnic groups.)
But if it tells you that five out of 100 women may develop
breast cancer, it can’t tell you which 5. Defining high risk
is complex, but one commonly accepted measure of being
at high risk of developing breast cancer in the next five
years is a Gail score of 1.67 percent or greater. The Gail
risk score is used in some prevention studies to determine
eligibility.
A Star Is Born
After tamoxifen was released in the 1970s, doctors
noticed breast cancer patients who took the drug, which
inhibits estrogen activity, were less likely to develop a
second cancer in the opposite breast. Research among
high-risk women eventually revealed tamoxifen cut the
risk of breast cancer in half over a period of five years. The
well-known Breast Cancer Prevention Trial reported by
the National Surgical Adjuvant Breast and Bowel Project
found that of 13,175 high-risk women, 244 women in the
placebo group developed breast cancer compared with 124
women taking tamoxifen.
In 1998, tamoxifen was approved for breast cancer prevention
in high-risk women, though its main use has been
to prevent recurrence of breast cancer. Serious possible
side effects—blood clots in older patients and a slightly
increased risk of uterine cancer—alarmed high-risk, but
otherwise healthy, women. In fact, for women over 65
with an only somewhat elevated breast cancer risk compared
with the general population, the risk of side effects may actually outweigh the benefit.
‘‘[The FDA’s approval decision for Evista in breast cancer prevention] is moving at the pace of government. It’s regrettable that we aren’t using the agents that we do
have. There are half a million women taking Evista for osteoporosis, so they and their
doctors are obviously comfortable with it."
—Victor G. Vogel , MD
Evista works a lot like tamoxifen, so a massive comparison
of the two began in 1999 involving nearly 20,000
high-risk women without a personal history of invasive
cancer. The results of the STAR trial were released
last year and showed Evista gave comparable protection
with fewer blood clots and uterine cancers. Eli Lilly and
Company submitted an application to the Food and Drug
Administration in December 2006 for an additional
approval of Evista for the reduction of breast cancer risk in
postmenopausal women. The FDA’s decision is expected before the end of the year.
"It’s moving at the pace of government,” says Victor
G. Vogel, MD, director of the Breast Cancer Prevention
Program at Magee-Womens Hospital in Pittsburgh. “It’s
regrettable that we aren’t using the agents that we do have.
There are a half million women taking Evista for osteoporosis,
so they and their doctors are obviously comfortable with it."
Dr. Fabian says the STAR trial resulted in a draw.
While Evista has fewer side effects overall, it doesn’t seem
to be as good as tamoxifen in reducing noninvasive breast
cancer (ductal carcinoma in situ and lobular carcinoma in
situ). “When you get a mixed message like this, it’s very
difficult to explain that to patients,” she says.
Cheryl Pilate illustrates the problem. When her mother
was diagnosed with breast cancer at an early age, Pilate
was referred to Dr. Fabian’s clinic for high-risk patients.
At first everything looked clear, but then they began to see
alarming changes in Pilate’s breast tissue with a sampling
procedure called random periareolar fine needle aspiration.
The test results suggested she had 10 times the risk of her peers, which “broke through the little shell of denial that we
all keep,” says Pilate. “It really scared me.”
Removing her ovaries was an option, but Pilate wanted to go
through menopause naturally. She also considered tamoxifen. The
side effects worried her, but her biggest concern was efficacy. “My
lifetime risk was astronomically high. How does it help me to cut it
in half?” She finally decided on a bilateral prophylactic mastectomy.“It was the best thing I’ve ever done in my whole life. I woke up in
a state of elation and euphoria. It might seem radical to some, but
to me it seemed the least invasive.”
Next on the prevention horizon is a class of drugs called aromatase
inhibitors, or AIs, which include Aromasin, Arimidex®
(anastrozole) and Femara® (letrozole), for use in postmenopausal
women who get estrogen not from their ovaries but as a byproduct
of other processes in the adrenal gland and fat tissue (such as the
breast). AIs interrupt this estrogen production, and based on how
well they work with chemotherapy could provide an additional
reduction in risk over tamoxifen and Evista.
The IBIS-2 prevention trial is an international study testing
Arimidex for breast cancer prevention, and the ExCel trial
in Spain, Canada and the United States is looking at Aromasin.
STELLAR, a large-scale U.S. study comparing Femara and Evista,
was expected to start recruiting in April. But the trial, expected to
cost $100 million, is currently on hold because of budget cuts to the
National Cancer Institute.
“I don’t think there is any question but that the AIs are going to
be more active than tamoxifen,” says Dr. Fabian. But she also wonders
if enough high-risk women will be willing to live with potential
side effects, such as bone loss and reduced libido or vaginal dryness.“That’s even worse than hot flashes,” she says. Designing drugs with
fewer side effects, or that can be taken for shorter periods of time,
is a significant challenge. The long-term effects of AIs are not yet
known since they have not been in use as long as tamoxifen.
Optimal Prevention
Using clues called biomarkers, scientists hope to improve their
powers of prediction. Single genes like BRCA1 and BRCA2 are
clear biomarkers. Others that suggest breast cancer risk include
mammographic density (how much of the image is white) and the
level of hormones, such as testosterone, estradiol and the growth
hormone IGF-1. High-risk clinics also perform biopsies that
look for what’s called atypical hyperplasia—essentially too many cells—which can be a precursor
to breast cancer.
A less-invasive biomarker
would be welcomed, but what’s
really needed is one that reliably
indicates risk and response to
treatment. Dr. Fabian is confident
we’re within a few years
of being able to use biomarkers
like atypical hyperplasia to
reduce the participant number,
time and cost of breast cancer prevention trials. “We have this vast
array of things that are promising,” she says, but “you can’t spend
$200 million on each one.”
And the roster of potential agents for breast cancer prevention
alone is huge. Among those working their way through clinical
trials are arzoxifene (works like tamoxifen); the statin Zocor®
(simvastatin); anti-inflammatory agent Clinoril® (sulindac); and all
three AIs. Dozens more have caught investigators’ eyes. And many
potential prevention regimens combine several compounds and
may even work in combination with modified hormone replacement
therapy.
‘‘It's just a matter of translating
what we already do and know for cardiovascular disease into what we
can do and know now for preventive
oncology.’’
—Victor G. Vogel , MD
“I think it’s all about the agent,” says Dr. Vogel. “We’re on our
way to finding the optimal agent, but we haven’t found it yet.”
From a public health perspective, Dr. McCaskill-Stevens says prevention is extremely
important and physicians must
have a medical intervention.
Prevention also means oncologists
and their patients need to
occasionally pull back from the
relentless pursuit of malignancy
and see the whole patient.
“More than 75 percent of
women who get breast cancer
today will never die from their
disease,” says Dr. Fabian. “We have to seriously think about prevention
of other diseases that we might induce with treatment.
Prevention and survivorship are part of the same continuum.”
Researchers have established that the prevention paradigm works
with early detection, screening interventions and reducing risk
factors, says Dr. Vogel. “It’s just a matter of translating what we
already do and know for cardiovascular disease into what we can do
and know now for preventive oncology.”
Part of the challenge is getting the medical finance industry to
pay for preventive services. “As soon as you start paying for these
services, doctors will start providing them,” says Dr. Vogel. “The
pressure for mammographic screening to be used across the board
did not come from the medical community. It came from the advocate
community.”
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