Rates
of the most common form of breast cancer dropped a startling 15 percent from
August 2002 to December 2003, researchers reported yesterday.
The
reason, they believe, may be because during that time, millions of women
abandoned hormone treatment for the symptoms of menopause after a large national
study concluded that the hormones slightly increased breast cancer risk.
The
new analysis of breast cancer rates, by researchers from the M. D. Anderson
Cancer Center in Houston and presented at a breast cancer conference in San
Antonio, was based on a recent report by the National Cancer Institute on the
cancer's incidence.
Investigators
cautioned that they would like to see the findings confirmed in other studies,
including, perhaps, in data from Canada and Europe, and they would like to see
what happens in the next few years.
''Epidemiology
can never prove causality,'' said Dr. Peter Ravdin, a medical oncologist at the
M.D. Anderson center and one of the authors of the analysis.
But,
he said, the hormone hypothesis seemed to perfectly explain the data and he and
his colleagues could find no other explanation.
Donald
Berry, head of the division of quantitative science at the cancer center and the
senior investigator for the analysis, called the connection between the drop in
rates and hormone use ''astounding.''
Over
all, for women of all ages and all breast cancer types, the incidence of the
cancer, the second leading killer of women, dropped by 7 percent in 2003, or
about 14,000 cases, the researchers said. It was the first time that breast
cancer rates had fallen significantly, something experts said was especially
remarkable because the rates had slowly inched up, year by year, since 1945.
But
the decrease was most striking for women with so-called estrogen-positive
tumors, which account for 70 percent of all breast cancers.
In
July 2002, the Women's Health Initiative, a large clinical trial looking at the
use of one menopause drug, Prempro, made by Wyeth, found that women taking the
drug had slightly higher breast cancer rates. The study's findings were a shock
to many women and their doctors. Until then, many had assumed that Prempro
simply replaced the lost hormones of youth. Within six months, the drug's sales
had fallen by 50 percent.
Scientists
knew that hormones could fuel the growth of estrogen-positive tumors, which
carry receptors for estrogen on their cell surfaces. The hypothesis is that when
women stopped taking menopausal hormones, tiny cancers already in their breasts
were deprived of estrogen and stopped growing, never reaching a stage where they
could have been seen on mammograms.
Other
cancers may have regressed, making them undetectable. And, possibly, without
hormones, cancers that would have gotten started may never have grown at all.
''This
could well be the study of the year in cancer,'' said Dr. Otis Brawley, director
of the Georgia Cancer Center at Emory University. He added that it also might
help explain why breast cancer rates were lower for black women than for white
women -- blacks, he said, were less likely to use hormones for menopause.
Dr.
Brawley also said the findings might explain why cancer in black women was more
lethal. Hormone-initiated cancers, he said, might be less deadly than those that
arise on their own.
Candace
Steele, a Wyeth spokeswoman, said in an e-mail message that ''breast cancer is a
complex disease and the causes are not known.
At
this point, she said, ''it is simply inappropriate to make any speculative
statements'' based on the analysis.
And,
she added, ''clearly, more studies are warranted.''
Dr.
Berry said that the biggest effect overall was seen in women ages 50 to 69. That,
he added, is the group most likely to have been taking menopausal hormones. In
them, the incidence of breast cancer, including the type that grows in response
to estrogen and the one that does not, fell by 12 percent in 2003, the latest
year for which data is available.
The
findings of the new analysis were supported by a separate study in California.
That study, published in the Nov. 20 issue of the Journal of Clinical Oncology,
found an even bigger drop in rates in that state and a correspondingly bigger
drop in hormone use starting in July 2002.
Other
researchers, who saw Dr. Berry's analysis in advance of its presentation
yesterday, said they found the hypothesis convincing.
Susan
Ellenberg, a professor of biostatistics at the University of Pennsylvania, said
the work was provocative. And, she added, ''I certainly don't see any obvious
thing that says, 'Oh, this can't be right,' or any obvious flaws.''
Until
2002, as many as a third of American women over age 50 were taking menopausal
hormones. The drugs could relieve symptoms like hot flashes, and were thought to
protect against heart disease. Because the pills were known to slow bone loss,
some women used them to prevent osteoporosis. Some women and doctors also
believed, without any good evidence, that the pills could keep skin youthful,
preserve memory and make women energetic.
The
use of estrogen to treat menopause took off in 1966, when a doctor, Robert
Wilson, wrote the best-selling book ''Feminine Forever'' and flew across the
country promoting it. He insisted that estrogen could keep women young, healthy
and attractive. Women would be replacing a hormone they had lost at menopause
just as diabetics replace the insulin their pancreas fails to make.
Before
long, the menopause drugs, and in particular Prempro, from Wyeth, a combination
of estrogen and progestins, became one of the most popular drugs in history.
The
reversal of fortune came in July 2002 when the Women's Health Initiative was
halted. Its accumulating data indicated that Prempro was associated with a
slight increase in breast cancer and in heart attacks, strokes and blood clots.
The drug slightly decreased the risk of hip fractures and colon cancer, but
those benefits were not enough to overcome its risks, the researchers said.
Health authorities cautioned that similar pills must be regarded as having the
same risks as Prempro until proven otherwise.
The
very next year, 2003, the National Cancer Institute reported recently, there was
a huge decline in breast cancer incidence. It was, Dr. Ravdin said, the largest
decline for a single cancer in a single year that he was aware of. He and his
colleagues wondered what was going on. The cancer kills an estimated 40,000
women a year and any decline in incidence can be important.
''We
looked at all the possible explanations,'' Dr. Berry said. He ticked them off:
less mammography screening. But there was no sign of that. Increased use of
drugs like tamoxifen that can prevent breast cancer; no evidence of that.
''There
was some notion that it might be statins, but that was essentially debunked,''
Dr. Berry said.
After
July 2002, Dr. Berry said, the rate ''dropped each month and it is exactly where
you would expect it to be'' if the declining use of menopausal hormones were the
reason.
Dr.
Barnett Kramer, the associate director for disease prevention at the National
Institutes of Health, said that hormones were certainly the most plausible
explanation for such an immediate effect on incidence. Most breast cancer is
fueled by estrogen and studies have found that removing estrogen, with drugs
like tamoxifen that block the hormone, sharply reduces breast cancer rates
within a year.
That
was also the conclusion of Christina Clarke, an epidemiologist at the Northern
California Cancer Center, and her colleagues, when they analyzed the cancer's
rates in California. The investigators used data they had collected for a
National Cancer Institute's program and data from Kaiser Permanente, the health
insurer.
Dr.
Clarke said that they had data through 2004 and so could ask whether the
decrease in cancer incidence in 2003 continued the next year. It did, she said,
although it slowed somewhat, as might be expected.
The
investigators found that the breast cancer incidence fell even more in
California than in the rest of the country -- the overall drop was 11 percent in
2003, compared with 7 percent nationally. And, Dr. Clarke said, more women in
California also had been using hormone therapy than women in other states.
Kaiser
Permanente's prescriptions for hormone combinations like Prempro fell by
two-thirds in 2003 and prescriptions for estrogen alone dropped by one-third, Dr.
Clarke and her colleagues reported. (Estrogen without progestin can cause cancer
of the uterine lining so should only be used by women whose uteruses have been
removed. While there is some question about whether estrogen alone increases
breast cancer risk, the Women's Health Initiative did not find such an effect.)
The
heaviest users of hormone therapy were women in affluent places like Marin
County, where high breast cancer rates had long troubled women and researchers.
Women in those areas also largely abandoned the treatments after the 2002 report
and their cancer rates declined accordingly, Dr. Clarke said.
Dr.
Marcia Stefanick, a professor of medicine at Stanford University and chairwoman
of the steering committee for the Women's Health Initiative, said she found the
hormone argument persuasive and felt it helped clear up the mystery in Marin
County.
''Everyone
kept saying, What is it? What's in the environment?'' she said. Now, she said,
it is becoming clear. ''The best explanation is hormone therapy.''