New York Times, October 27, 2008

THE EVIDENCE GAP
Quickly Vetted, Treatment Is Offered to Patients

By REED ABELSON

After a surgeon removed a cancerous lump from Karen Medlock’s breast in November, he recommended radiation, a routine next step meant to keep cancer from recurring.

But he did not send her for the kind of radiation most women have received for decades.

Instead, the surgeon referred her to a center in Oakland, Calif., specializing in a newer form of treatment where radioactive “seeds” are inserted in the tumor site. It could be completed in only five days instead of the six weeks typically required for conventional treatment, which irradiates the entire breast using external beams.

To Ms. Medlock, it seemed an obvious choice. The newer treatment — given through a system called MammoSite — has been performed on about 45,000 breast cancer patients in this country since the Food and Drug Administration cleared it for use in 2002.

Only when Ms. Medlock, 49, sought a second opinion did she learn a startling truth: MammoSite is still highly experimental.

The MammoSite system is among the thousands of devices the F.D.A. lets onto the market each year after only cursory review and with no clear evidence that they help patients. Doctors are free to use those products as they see fit, without telling patients that the devices are not proved. And because the doctors are frequently paid more by Medicare as a way to compensate them for the extra time and expense of adopting new procedures, these unproven products can become widely adopted.

F.D.A. officials defend the quick-review process as a way to promote innovation. Because most new products are simply an improvement on an existing device, they say, there is rarely need for a full review.

Demanding lengthy study of such devices would be “very, very inappropriate and a waste of resources,” said Dr. Daniel G. Schultz, the director of the F.D.A.’s Center for Devices and Radiological Health.

The agency let MammoSite on the market on the basis of a study involving only 25 women that did not answer the fundamental question of how effective it is against breast cancer. Six years later, many cancer specialists say there is still no conclusive proof that it works as well as conventional radiation. The F.D.A. says it did require a label warning that the system had not been shown to be a substitute for conventional radiation.

Dr. Valery Uhl, the radiation oncologist who provided Ms. Medlock’s second opinion, outlined the evidence behind the available treatments. Ms. Medlock chose conventional external-beam radiation because of its well-documented record of success in preventing the return of cancer. To use an unproven therapy like MammoSite, Dr. Uhl said, “makes me really nervous.”

Critics say the F.D.A.’s process for reviewing medical technology, under which medical devices have become a $75 billion-a-year industry in this country, is often too lax. More devices, they say, should get the same scrutiny applied to new drugs. While that process is not perfect, a new drug is typically studied in hundreds or even thousands of patients before the F.D.A. will approve it as safe and effective.

But under the fast-track review for most devices, a product’s effectiveness is never directly established. Regulators simply determine if the device does what its maker says it does — in MammoSite’s case, that it delivers radiation — and whether it poses any undue safety risks.

“Nobody is looking to see whether they help patients,” said Diane C. Robertson, an executive with the ECRI Institute, a nonprofit group in Plymouth Meeting, Pa., that evaluates new devices for insurers and hospitals. “We’re never going to wisely allocate resources in health care unless we start to focus on what’s best for patients.”

In response to a Congressional request to study the effectiveness of the F.D.A.’s device-review process, the nonpartisan Government Accountability Office is expected to release a report next month.

Critics say that when the F.D.A. clears a device, the public may wrongly assume that the government has proof it is medically effective. F.D.A. approval has been “widely misinterpreted,” said Dr. Jay R. Harris, the chairman of radiation oncology at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston.

Differing Opinions

Dr. Dennis R. Hill, the doctor who originally saw Ms. Medlock, scoffs at the notion that MammoSite is in any way experimental. “It is a proven method,” he said. He said the oncologist who told Ms. Medlock it was experimental was skeptical because she provides only traditional radiation.

But the oncologist in question, Dr. Uhl, says she has performed many radioactive-seed treatments but wants to make sure patients are fully informed about the range of options.

Of the 250,000 women in this country who are found to have breast cancer each year, around 200,000 are candidates for radiation treatment if they choose to undergo a lumpectomy or partial removal of a breast. Most still get conventional radiation.

MammoSite proponents say that is because most doctors simply recommend the treatments they know best. “There is a natural bias for radiation oncologists to do what they have been doing,” said David Harding, an executive at Hologic Inc., the company in Bedford, Mass., that markets MammoSite.

Many prominent specialists, though, say the gold standard remains conventional radiation, for which breast cancer local recurrence rates are 3 percent or less at five years. Success in preventing cancer recurrence is measured in long intervals of 5 or 10 years or more, and there has been little long-term study of MammoSite.

Even a radiation oncologist who is a leading proponent of the MammoSite treatment, Dr. Frank A. Vicini, wants to know how it compares with traditional radiation. He is directing a national study of MammoSite’s effectiveness, but he cautions that it could take decades to conclude whether it should be used in lieu of conventional radiation.

“We have to make sure patients know we don’t have 30-year data,” said Dr. Vicini, the chief of oncological services for Beaumont Hospitals in Royal Oak, Mich. “We simply don’t.”

A System From the Past

The nation’s system for regulating medical devices was set up more than three decades ago, when devices played a much smaller role in medicine. A growing chorus of doctors, consumer advocates and health insurance executives say it is overdue for an overhaul.

The process has become “a barrier to evidence development,” said Dr. Winifred S. Hayes, whose firm, Hayes Inc., evaluates new health care technologies.

Although federal drug regulation dates back more than 100 years, medical devices did not come under the government’s purview until 1976, after Congress responded to deaths linked to the Dalkon Shield, an intrauterine contraceptive device.
Because the new law would not apply to devices on the market before 1976, Congress did not want makers of newer products to be at a competitive disadvantage. So lawmakers provided the quick review process for any new product deemed “substantially equivalent” to something already on the market. That expedited process became known as a 510(k) review under the relevant section of the law.

But critics say that what Congress intended as a way to let simple devices quickly enter the market has expanded so much that even critical therapies are cleared without enough research.

“It is supposed to be for the Band-aids of the world,” said Diana Zuckerman, president of the National Research Center for Women and Families, a Washington advocacy group. “The 510(k) process should have been used less and less. It’s being used more.”

But defenders of the F.D.A. process, including the officials in charge of it, argue that tighter gatekeeping could deprive patients of promising alternatives. And they contend that most new medical devices introduced each year involve minor modifications to mundane items like thermometers.

To be sure, sophisticated devices like a new artificial hip or a novel heart stent do go through the same evidence-based scrutiny given to new drugs. Of the 41 medical devices that went through that full review last year and in which the F.D.A. reached a decision, 27 received approval.

But during those same 12 months, the F.D.A. reviewed 3,052 devices under the more cursory 510(k) process and cleared 2,640 of them. Critics, though, say MammoSite is significantly different from anything on the market.

On one level, MammoSite was simply the latest version of brachytherapy, a technique that delivers radiation inside the body through seeds. Brachytherapy is widely used to treat prostate cancer because it allows high doses of radiation to be directed to a small area.

MammoSite was developed as a way to deliver brachytherapy for breast cancer, but more simply. For example, earlier versions of brachytherapy required multiple catheters.

With MammoSite, a surgeon inserts a single balloon catheter in the cavity from which the tumor has been removed. The catheter remains in place during the five days that radioactive seeds are inserted into the balloon, twice a day, using a computer-controlled system. After the treatments, the catheter and the balloon are removed, and there is no remaining radiation.

The main “substantially equivalent” product that MammoSite’s maker cited in its F.D.A. application was something called GliaSite, which itself reached the market in 2001 through a 510(k) review. Like MammoSite, it uses a catheter with a small balloon to deliver radiation.

But critics point out that GliaSite is aimed at a far different disease — advanced brain cancer — and it is often tried for patients who do not have the luxury of choosing another treatment. Hologic, which acquired MammoSite and was not involved in the original application process, declined to comment on the F.D.A. process.

The F.D.A. says MammoSite was hardly a radically new technology, because radiation is a standard therapy in treating breast cancer and brachytherapy is an established technique. F.D.A. officials also cite MammoSite’s label as evidence they have warned doctors the treatment is unproved.

“At the end of the day, doctors have to read what’s on the label and make a clinical decision,” Dr. Schultz said.
Still, critics of the 510(k) system point to the sometimes disastrous consequences of letting a device be widely used without adequate study.

Under a 510(k) review, for example, the F.D.A. in 1996 cleared Protegen, a synthetic sling implanted under a woman’s bladder to prevent stress incontinence. No clinical research was required to see how it would work, and Protegen was recalled in 1999 because of a high rate of complications.

Dr. Schultz, the F.D.A. official, said that even when using the fast-track review process, the agency always considers potential risks to patients.

Financial Factors

MammoSite’s proponents say its main advantage is that the shorter course of treatment and reduced exposure to radiation mean more women will consider radiation. Without some form of radiation, the alternative is complete removal of the breast through a mastectomy. Many women and doctors are persuaded by this argument.

But critics, say some of MammoSite’s popularity is a result of the relatively high reimbursements paid by insurers.
Surgeons traditionally do not play a role in a patient’s radiation therapy. But with MammoSite, they can earn several thousand dollars when they insert the balloon catheter that the radiologist uses to administer the radioactive seeds. That money, critics say, encourages some surgeons to recommend the treatment.

What’s more, Medicare initially set the total payments for MammoSite, including the surgeon’s fee, by one estimate at nearly $20,000 — almost twice the amount paid for conventional radiation. That was in keeping with Medicare’s practice of offering more generous payments for new treatments to encourage investment in equipment and training involved in a new procedure.

In keeping with Medicare’s practice, though, the payments have shrunk in recent years. Hologic says Medicare is expected to pay around $15,000 for the treatment next year, compared with $12,000 for conventional radiation. Commercial insurers typically follow Medicare’s lead on reimbursements.

In at least some cases, it is the patient who pushes for MammoSite. After Ida Daugherty, 59, was found to have breast cancer last May, a doctor advised her to consider the MammoSite treatment after her operation. But the specialist she consulted advised against it, telling her, “I don’t feel the results are in.”

After Ms. Daugherty looked at the available research, though, she chose to get MammoSite treatments in July at Beaumont, where Dr. Vicini works.

“I really didn’t want to do six weeks,” Ms. Daugherty said. She worried that the radiation might weaken her bones enough to cause a broken rib — a possible side effect.

Weighing Evidence

The debate now among cancer specialists is whether there is enough evidence to feel comfortable recommending the treatment to women who are not part of a clinical study.

In its marketing materials, Hologic refers to five-year data indicating that women seem to do as well with MammoSite as with conventional therapy. But the cited study involved only 43 patients enrolled in the first clinical trial of the device, 25 of whom were included in the evidence provided the F.D.A.

“We all know there is no sufficient evidence to offer it outside a trial because no one knows whether it is equivalent,” said Dr. Silvia Formenti, the chairwoman of radiation oncology at New York University Medical Center.

Dr. Formenti is wary of pushing any new treatment too aggressively because she recalls another formerly popular breast cancer treatment: high-dose chemotherapy coupled with a bone marrow transplant. In the 1990s, tens of thousands of women with advanced breast cancer were subjected to the toxic effects of that treatment before discovering that it was no more effective than conventional therapies.

Other doctors see no need for further study of MammoSite, saying the practical evidence is already compelling.
“I’m a big believer and proponent and practitioner of brachytherapy,” said Dr. Bradley R. Prestidge, the chief executive of the Texas Cancer Clinic, in San Antonio, which says it has performed more than 600 MammoSite treatments, the most in the country.

Of those 600 patients, Dr. Prestidge said, only three women have had a cancer recurrence, a lower rate than in his patients with conventional radiation.

The clinical trial being led by Dr. Vicini of Beaumont is meant to provide more than anecdotal evidence. The study will look at different techniques, including MammoSite, in which radiation is delivered to only part of the breast. He says the goal is to study 4,300 patients and results are expected in 2015.

“Doing the right thing is collecting the data,” Dr. Vicini said.

New York Times, September 4, 2008

Researchers See Promise in New Test for Tumors

By THE ASSOCIATED PRESS

MILWAUKEE (AP) — A radioactive tracer that “lights up” cancer hiding inside dense breasts showed promise in its first big test against mammograms, revealing more tumors and giving fewer false alarms, doctors reported Wednesday.

The experimental method, molecular breast imaging, or M.B.I., would not replace mammograms for women at average risk for cancer. But it might become an additional tool for higher-risk women with a lot of dense tissue that makes tumors hard to spot on mammograms, and at a lower cost than magnetic resonance imaging, or M.R.I. About one-fourth of women 40 and older have dense breasts.

“M.B.I. is a promising technology” that is already in advanced testing, said Carrie Hruska, a biomedical engineer at the Mayo Clinic in Rochester, Minn., which has been working on it for six years.

Ms. Hruska gave results in a telephone news briefing on Wednesday and will present them this week at an American Society of Clinical Oncology conference in Washington.

Mammograms, a type of X-ray, are now the chief way to check for breast cancer. M.B.I. uses radiation, too, but in a different way. Women are given an intravenous dose of a short-acting tracer that is absorbed more by abnormal cells than by healthy ones. Special cameras collect the “glow” these cells give off, and doctors look at the picture to spot tumors.

Researchers tried both methods on 940 women who had dense breasts and a high risk of cancer because of family history or other reasons.

Thirteen tumors were found in 12 women: eight by M.B.I. alone, one by mammography alone, two by both methods and two by neither. (The two missed tumors were found on subsequent annual mammograms, physical exams or other imaging tests.)

Looked at another way, M.B.I. found 10 of 13 tumors, missing 3; mammograms detected 3 of 13 tumors, missing 10. Using both methods, 11 of 13 tumors would have been detected.

“These images are quite striking,” Ms. Hruska said. “You can see how the cancers would be hidden on the mammograms.”

Mammograms gave false alarms — leading doctors to conclude that cancer was present when it was not — in about 9 percent of patients, compared with 7 percent for M.B.I. The M.B.I. tests led to more biopsies than mammograms did, but they more often revealed cancer.

The Susan G. Komen for the Cure foundation and Bristol-Myers Squibb, which makes the imaging agent used in the study, paid for the work.

The next test will be to see how M.B.I. stacks up against M.R.I. The federal government is paying for a new study Mayo is leading that compares the two in 120 high-risk women with dense breasts.

M.R.I. is often used now for women with dense breasts, but it gives many false alarms that lead to unnecessary biopsies. Doctors hope the new test . will prove more accurate and cost less — under $500, compared with more than $1,000 for an M.R.I.

“We all know that mammography is, in and of itself, an imperfect tool, and we clearly need to do better in the future,” said Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston, a spokesman for the oncology group. “It is fair to say that M.R.I. will not solve all problems either.”

One drawback of M.B.I.: It uses about 8 to 10 times the radiation of mammograms, a dose that engineers like Ms. Hruska are trying to lower with newer technology. Other medical centers also are testing M.B.I.

“We’re just beginning to see what this technology can do,” she said.

New York Times, April 10, 2008

Sharper Digital Breast Exams Can Add Anxiety

By DENISE GRADY

It is a phone call that women dread. Something is not quite right on the mammogram: come back for another one. But don't worry, the script goes, most repeat tests wind up normal.

Still, most women know someone who has breast cancer, and even the calmest, most rational minds may think the worst when summoned back to the clinic.

At many centers, these nerve-racking calls are on the rise, at least temporarily -- the price of progress as more and more radiologists switch from traditional X-ray film to digital mammograms, in which the X-ray images are displayed on a computer monitor.

Problems can arise during the transition period, while doctors learn to interpret digital mammograms and compare them to patients' previous X-ray films. Comparing past and present to look for changes is an essential part of reading mammograms. But the digital and film versions can sometimes be hard to reconcile, and radiologists who are retraining their eyes and minds may be more likely to play it safe by requesting additional X-rays -- and sometimes ultrasound exams and even biopsies -- in women who turn out not to have breast cancer.

Digital is growing fast. In the United States, 32 percent of mammography clinics now have at least one digital machine, up from only 10 percent two years ago. Eventually, film will be phased out.

The rush to digital is occurring in part because for certain women -- younger ones and others with dense breast tissue -- it is better than film at finding tumors. Digital is especially good at picking up tiny calcium deposits, or calcifications, which are sometimes -- but by no means always -- a sign of cancer. In the long run, radiologists say, digital technology will make mammograms more accurate for many women.

There have been no studies yet to measure what happens during the transition period, but many radiologists say they do find themselves calling more women back. About 35.8 million mammograms a year are done in the United States, including those for screening and follow-ups for problems. The National Cancer Institute recommends mammograms every year or two for most women over 40 (women at high risk may be advised to start earlier). Mammography is not perfect -- it can miss tumors -- but even its critics say it has helped to lower death rates from breast cancer, which is the second leading cause of cancer deaths in women, after lung cancer.

There are about 178,000 new cases of breast cancer each year in the United States, and 40,000 deaths.

Of 10 radiologists interviewed for this article, eight said that during the transition from film to digital, recall rates went up in women who were ultimately found to have nothing wrong. Normally a recall rate of 10 percent or less is considered desirable. But during the transition period at their clinics, the doctors estimated that callbacks of women who turned out to be healthy increased by a few percentage points to as many as 10. Only one radiologist reported no problems: Dr. Etta D. Pisano, a professor of radiology and biomedical engineering at the University of North Carolina.

''I don't believe it,'' Dr. Pisano said. ''I question that there's a problem with the transition.''

But Dr. Mary Mahoney, a professor of radiology and the director of breast imaging at the University of Cincinnati Medical Center, said, ''I am living through the pain of this transition period on a daily basis.''

Dr. Mahoney's center recently opened an entirely digital clinic for breast cancer screening.

''Our whole group is kind of pulling our hair out some days,'' she said. ''You struggle and you struggle. It's just so much harder. These are really experienced, qualified radiologists who are wringing their hands. It's where the increase in callbacks and biopsies is coming into play. It happens every day. Many times we're able to bring the woman back, do additional views and feel comfortable we can follow that area.''

Regarding the higher callback rates, Dr. Mahoney said: ''I know it's not a small thing, the anxiety. Patients are practically in tears because they're so worried. But I think in the long run it's going to be to everybody's benefit.''

Dr. Margarita Zuley, the director of breast imaging at Magee-Women's Hospital at the University of Pittsburgh Medical Center, said it could take six months to a year to learn to interpret the new images.

Lecturing in Manhattan recently about the transition to digital, Dr. Zuley told an audience of radiologists: ''When you first start out, you may feel a little anxious and recall more patients because everything looks like a cancer to you. It's O.K. Just bring the patients back. It's part of the learning curve.''

Regarding higher recall rates during the transition, Dr. Zuley said: ''Everybody sort of knows it, but it's anecdotal. There are no numbers.''

Meanwhile, patients or their insurers are paying for the extra tests. Fees for mammograms vary around the country. A clinic in Manhattan recently billed an insurer $387 for a digital mammogram and then $336 for extra images of one breast -- needed because of confusion between the old films and the new digital pictures -- and was paid about half of those fees. Fees for film-based mammograms are usually $45 to $120 less.

Nancy Liber, a radiologic technologist at Dr. Mahoney's center, was called back by her own colleagues at the center after her mammogram last month.

''I thought exactly what every woman does,'' Ms. Liber said. ''Immediately you panic and think, 'Oh my gosh, what if something is really wrong?' ''

She found herself worrying about what would happen if she became ill and unable to take care of her children. She did not even tell her husband what had happened until after the second test, which turned out normal. The concerns were due entirely to the difference between film and digital images. Despite the stressful experience, Ms. Liber said that from what she had seen in her work, digital mammograms were the way to go.

''The inconvenience it may cause is worth it,'' she said. But, she added, ''I definitely know what these women are going through.''

Radiologists say one of digital's advantages is that it lets them adjust features like contrast and magnification, and see things that were blurry or maybe even invisible on film. In the long run, doctors say, the increased clarity of digital mammograms may lead to fewer callbacks of healthy women -- but it takes time to learn the ropes.

Dr. Constance D. Lehman, the director of breast imaging and a professor of radiology at the University of Washington, said she was not sure whether more women were called back during the transition. But describing the two technologies, she said, ''In some areas it's like comparing apples and oranges.''

When looking at a woman's first digital image, Dr. Lehman said, radiologists must ask themselves whether a seeming change in the breast is truly new, or was it there all along but just not visible with earlier techniques.

Once a woman has had enough digital mammograms, the comparisons should be easier, radiologists say. But the first few may raise questions because when radiologists compare, they often go back to images from two or three years before. And in some clinics that have a mixture of film and digital machines, if a woman is switched between the two types from year to year, ambiguities may crop up again and again.

Many women do not know the difference between film and digital, or notice which is being used, and clinics may or may not inform them of potential problems during the changeover.

Digital mammography got a boost from a large study in 2005 that showed it was better than film at finding tumors in women under 50, or women of any age who had dense breasts, meaning a lot of glandular and connective tissue in proportion to fat.

A buzz grew around digital after the study. Some radiologists use the technology as a selling point, and others feel they must follow suit. Now there is such a demand for digital machines that there is a six-month wait for certain types, Dr. Zuley said, even though they cost $350,000 to $600,000, about three to five times as much as units that use film.

Dr. Leonard M. Glassman, who practices at Washington Radiology Associates, said that his practice in the Washington, D.C., area, which performs 85,000 mammograms a year, converted to digital about two years ago.

''There's an increase in the rate of things you think are abnormal for about three months, and then you get used to it,'' Dr. Glassman said. ''You take more extra pictures, of things that six months later you would dismiss. It happened probably 5 to 10 percent of the time right at the beginning, so it's a significant amount, and then it tails off.''

When questions first arise, Dr. Glassman said, he does not warn women that the imaging may be the culprit because he cannot be sure what the problem is until he sees the second set of X-rays.

''At the end I tell patients, 'You were a victim of technology,' '' he said. ''They give me a blank stare. I say: 'Your last one was film; this one was digital. They look different, and we just didn't know that.' ''

New York Times, December 11, 2007

Vital Signs - In the Lab: Gene Study Helps Explain Link to Breast Cancer

By NICHOLAS BAKALAR

More than 10 years ago, scientists discovered that mutations in a gene called BRCA1 lead to a particularly deadly type of breast cancer. Now an international group of researchers has found at least one reason why. BRCA1 inactivates a tumor suppressor gene known as PTEN.

Mutations occur spontaneously, but most organisms have mechanisms that can prevent the damage they might cause. PTEN has instructions to produce a protein that stops the uncontrolled cell growth of cancer. BRCA1, the scientists reported online Sunday in Nature Genetics, prevents PTEN from doing its work.

The researchers found that inactivating the PTEN gene in mice led to the formation of the malignant tumor associated with BRCA1 mutations. Then they examined PTEN in nonhereditary breast tumors from 297 patients and tumors from 34 women who had inherited the BRCA1 mutation. In most cases, the protein that PTEN produces was undetectable in tumor cells, but clearly present in nearby normal cells.

PTEN might be a target for chemotherapy. “I am cautiously optimistic,” said Dr. Ramon E. Parsons, the lead researcher and a professor of pathology at Columbia, “that within the next five years we’ll be using drugs that are effective on the PTEN pathway.”

Women with BRCA1 mutations are at very high risk for breast cancer at an early age. Those who know they carry the mutation sometimes choose preventive mastectomies.

New York Times,December 4, 2007

F.D.A. Sees Problems in New Use for Cancer Drug

By ANDREW POLLACK

Genentech's drug Avastin did not help women with breast cancer live meaningfully longer, and it caused significant side effects, including a few deaths, the Food and Drug Administration said yesterday in a review of the drug.

The analysis by the agency's staff appeared to dim the prospects that Avastin would win a approval as a treatment for breast cancer. Genentech's stock fell $2.75, or 3.6 percent, yesterday, closing at $73.50.

An advisory committee to the F.D.A. will meet tomorrow to discuss whether Avastin, already a blockbuster drug for colon and lung cancer, will win an additional approval for breast cancer. The drug had $1.7 billion in United States sales in the first nine months of the year. Roche Holding, which owns a majority of Genentech, sells it overseas.

The agency's staff did not take a position on whether Avastin should be approved for breast cancer. The staff noted Avastin's positive effect in delaying the period before cancer worsens, though the drug did not extend overall survival time. But that benefit must be weighed ''against the increased toxicity, including deaths'' associated with use of the drug, the F.D.A. staff said.

Advisory panels, which are made up largely of practicing doctors, sometimes look more kindly on a drug than the F.D.A., whose analysis is to some extent intended to note flaws in the data.

Moreover, it was already known that Avastin, like many cancer drugs, can cause serious side effects like cardiovascular problems and bowel perforations and even some deaths. The issue in this case is whether such risks outweigh the benefits.

''At the end of the day, oncologists are very familiar with the incremental improvements required to move cancer treatment forward,'' Michael Aberman, an analyst at Credit Suisse, said in a note. He said that while the meeting would not be ''a walk in the park,'' he expected the panel to recommend approval.

Some doctors on their own already use Avastin to treat breast cancer, in a so-called off-label use of the drug. But F.D.A. approval for that purpose would enable Genentech to advertise and promote the drug as a breast cancer treatment and probably make insurers more willing to pay for it.

At one point Avastin, also called bevacizumab, seemed a shoo-in to be approved for breast cancer. A clinical trial found that adding Avastin to the drug paclitaxel nearly doubled the time before tumors worsened.

The results were so strong that they were announced in April 2005 before the trial was finished. The trial, involving 722 patients, was run by a group of academics sponsored by the National Cancer Institute.

Women with metastatic or recurring breast cancer who received Avastin plus paclitaxel went a median of 11.3 months before either their cancer worsened or they died, a measure known as progression-free survival. That compared to 5.8 months for the women who got only paclitaxel, a generic drug also sold as the branded treatment Taxol.

But the F.D.A. staff rebuffed Genentech's efforts to win breast-cancer approval in 2006, making the company submit new analyses. The agency questioned whether an improvement in progression-free survival was a sufficient basis for approval.

The agency favors overall survival as a more meaningful indicator of a drug's value, but in some cases it can take years before patients die. Progression-free survival allows for quicker results and therefore quicker approvals. But it can be tricky to measure and might not correlate with how long patients live.

Genentech, in its briefing document, argues that progression-free survival has been used by the F.D.A. to approve other breast cancer drugs in the past. Both its document and the F.D.A. analysis were posted yesterday on the F.D.A. Web site.

In this case, the substantial delay in the worsening of cancer did not seem to translate into longer life. The women who got Avastin and paclitaxel lived a median of 26.5 months, compared with 24.8 months for the women who got paclitaxel alone. That difference is not statistically significant.

In addition, the F.D.A. said that 71 percent of the women who got Avastin suffered a serious side effect, compared with 51 percent of the women who got paclitaxel alone. Among those side effects were the deaths of at least five patients that the F.D.A. said were probably or definitely because of the treatment itself, representing 1.4 percent of the women getting Avastin. There were no deaths from the treatment itself among women getting only paclitaxel.

The trial investigators and Genentech initially said no deaths were attributed to Avastin, but the F.D.A. took issue with that. One case it cited was that of a 64-year-old woman who had suffered a bowel perforation, a known side effect of Avastin, and a serious infection. Genentech and the trial investigators had classified the woman's death as being from her cancer, according to the F.D.A. review.

But Genentech's new briefing document acknowledged that at least five deaths might have been caused by Avastin.

The F.D.A. did agree with Genentech's assessment that some of the increased side effects were caused by paclitaxel. Treatment was supposed to stop once the tumor started worsening. Since women getting Avastin went twice as long before their tumors worsened, they got twice as much paclitaxel, allowing its toxic effects to accumulate.

New York Times,September 16, 2007

The DNA Age Cancer Free at 33, but Weighing a Mastectomy

By AMY HARMON

CHICAGO — Her latest mammogram was clean. But Deborah Lindner, 33, was tired of constantly looking for the lump.

Ever since a DNA test had revealed her unusually high chance of developing breast cancer, Ms. Lindner had agonized over whether to have a mastectomy, a procedure that would reduce her risk by 90 percent.

She had stared at herself in the mirror, imagining the loss of her familiar shape. She had wondered, unable to ask, how the man she had just started dating would feel about breasts that were surgically reconstructed, incapable of feeling his touch or nursing his children.

But she was sure that her own mother, who had had chemotherapy and a mastectomy after a bout with the cancer that had ravaged generations of her family, would agree it was necessary.

“It could be growing inside of me right now,” she told her mother on the phone in February, pacing in her living room here. “We could find it any time.”

Waiting for an endorsement, she added, “I could schedule the surgery before the summer.”

But no approval came.

“Oh, sweetheart,” her mother said. “Let’s not rush into this.”

Joan Lindner, 63, is a cancer survivor. Her daughter, by contrast, is one of a growing number of young women who call themselves previvors because they have learned early that they are genetically prone to breast cancer, and have the chance to act before it strikes.

As they seek to avoid the potentially lethal consequences of a mutant gene, many of them turn to relatives who share its burden. But at a moment when a genetic test has made family ties even more tangible, they are often at their most strained.

Parents who have fought cancer typically have no experience with the choices that confront their children, and guilt over being the biological source of the problem can color their advice. Siblings and cousins who carry the risk gene evangelize their own approach to managing it, while those who dodged its inheritance seem unqualified to judge.

Even as she searched for her own answer in the year after her DNA test, Deborah Lindner, medical resident, found herself navigating her family’s strong and divergent opinions on the imperfect options that lay before her.

Her father, who once feared he would lose his wife to cancer, encouraged the surgery. Her sister reminded her that cancer might be cured in a few years if she could wait.

Her aunt said she hated to see her niece embrace a course of action akin to “leechings of the Dark Ages.” A cousin declined even to take the DNA test.

But it was her mother’s blessing that Deborah most eagerly sought.

Mrs. Lindner, who had passed her defective gene to her daughter, wanted to will her more time. When she had her own breasts removed she had been married for 27 years and had raised two daughters. Now Mrs. Lindner couldn’t shake the fear that her daughter might trade too much in her quest for a cancer-free future. What if taking such a radical step made it harder for Deborah to find someone special and become a mother herself?

“I have this amazing gift of knowing my risk,” her daughter told her over the phone that winter night, gazing out over the frozen city from her apartment on the 38th floor. “How can I not do anything about that?”

The Lindners share a defective copy of a gene known as BRCA1 (for breast cancer gene 1) that raises their risk of developing breast cancer sometime in their lives to between 60 and 90 percent. Only 30,000 of more than 250,000 American women estimated to carry a mutation in BRCA1 or a related gene, BRCA2, have so far been tested. But their numbers have doubled in the last two years, and with a sharp increase in genetic testing, are expected to double again in the coming one.

About a third opt for preventive mastectomies that remove the tissue where the breast cancer develops. A majority have their ovaries removed, halving their breast cancer odds while decreasing the risk of highly lethal ovarian cancer, to which they are also prone. Some take drugs that ward off breast cancer. Others hope that frequent checkups will catch the cancer early, or that they will beat the odds.

Their decisions, which require weighing an inborn risk against other life priorities, are highly individual. But with DNA forecasts of many other conditions on their way, BRCA carriers offer the first clues for how to reckon with a serious disease that may never arise — and with the family turmoil that nearly always does.

A 50-50 Chance

Deborah Lindner’s sister, Lori French, got her results first.

Long ago, before she knew about the DNA test, Ms. French, 37, had resolved to have her breasts and ovaries removed by age 40 to avoid the family cancer. Nor did she want reconstructive surgery, having seen her mother struggle with the pain and cosmetic disappointment of hers.

“Plan on it,” she had told her husband before they got married a decade earlier. “I’m going to get old and have big hips and no breasts.”

The envelope with the test results that Ms. French opened with shaking hands in the summer of 2005 offered a reprieve. She and her husband sobbed, hugging each other in the knowledge that she was free of the genetic defect. While she still had the 12 percent chance any woman has of developing breast cancer, she could not have passed on the steep BRCA risk to either her daughter or son.

“It’s done!” Ms. French told her family. “In our line, it’s ended.”

For years, the sisters had united in a common dread. Now it was Deborah’s alone.

“I’m so sorry you have to be the one,” Ms. French said when her sister called a week later with the news that she had tested positive for the mutation.

“I’m so glad it’s not you,” Deborah replied.

It could have been either, neither or both of them — each sister, she knew, had had a 50 percent chance of inheriting the defective gene from their mother, dictated solely by a roll of the genetic dice. But if it was going to be one of them, Deborah thought she was in a better position to handle it. Her sister taught at a missionary school in the Philippines, where she lived with her family, while Deborah was single and in the second year of her medical residency program at Northwestern University, with ready access to quality health care.

Yet in the weeks that followed, Deborah fought off pangs of jealousy and the fantasy that fate could somehow be rearranged.

“She already has a husband, she already has kids,” Deborah thought on morning runs along Lake Michigan.

She enrolled in a stepped-up surveillance program that required alternating mammograms and sonograms with M.R.I.’s every six months. But on the mornings of her appointments, and at unpredictable moments in between, she was overwhelmed with fear. Often, she would examine her breasts every other day.

“It’s taking over my mind,” she told Erin King, a close friend and fellow resident in the obstetrics and gynecology program.

Ms. King, 33, who had had breast implants for cosmetic reasons, and another resident friend were proponents of pre-emptive surgery.

“Get them off and get new ones,” they told her. “They’ll be awesome and perky and cute.”

But they sympathized with her distress at the appearance of traditional reconstruction, with skin grafts molded into a fake nipple that can never quite match the texture of a real one and the areola simulated by a tattoo.

“They just don’t look normal,” Deborah sighed as they debated the question over the barbecue grill at Ms. King’s apartment one night.

Accustomed to seeking her mother’s counsel, Deborah kept her distance in those months, not wanting to worry her. Instead, she pestered breast specialists. How many cancers do you actually catch? How many in an early stage? The answers were vague. Still, they discouraged her from surgery. Most women who had a preventive mastectomy, a breast surgeon told her, already had a family.

A Frightening Pattern

In the fall of 2006, Deborah turned her residency research requirement into a personal quest for better information, analyzing the records of BRCA mutation carriers who had been counseled at Northwestern.

One file told of a woman who had developed cancer and chosen a lumpectomy, a procedure that leaves the breast mostly intact. The cancer came back — while she was pregnant. When she had an early Caesarean section so she could get chemotherapy without harming the baby, doctors discovered an ovarian tumor that had already spread to her abdomen.

The pattern was not uncommon. BRCA-related breast cancer usually strikes early, before age 50, and is more likely to recur in the other breast. Ovarian cancer, which strikes about 50 percent of BRCA1 carriers, compared with 2 percent of the general population, is rarely detected early and is fatal three-quarters of the time.

“It’s like I’m reading this book and I know what’s coming,” Deborah told her fellow residents. “I see the note, ‘Patient opts for surveillance,’ and I’m like, ‘No, don’t do it, don’t do it!’ ”

Several times during her oncology rotation that term, she slipped out of an ovarian cancer patient’s room to cry in the stairwell. To eliminate her risk of ovarian cancer, doctors had recommended that she have her own ovaries removed by age 40, or as soon as she had children. Removing her ovaries would halve her breast cancer risk as well, but the hormones that are generally used to treat the harsh menopausal symptoms brought on by the procedure, Deborah learned, would then raise the risk again — unless she had her breasts removed first.

Unspoken Questions

Over Thanksgiving at her parents’ winter home in Florida, Deborah ran through her risk analysis. Her father, Philip Lindner, listened and nodded. Mammograms and ultrasounds, she noted, may miss more than half of cancers in younger women with denser breasts. Magnetic resonance imaging tests are more reliable but produce more false positives, which can lead to unnecessary biopsies and worry. And it is not yet clear that early detection improves survival rates in women with BRCA mutations.

“You can’t argue with statistics,” said Mr. Lindner, a financial executive. “You don’t want to get cancer and then say, ‘I wish I would have done thus and so.’ ”

Deborah’s mother agreed it was important to know the risks. But not knowing them could be a luxury, too. Had she had the same options as her daughter, would she have found a man and had a family? It might have altered her whole life.

“I know the joy that my girls have brought to me,” she confided to a friend. “If Deb misses it, she won’t know what she missed. But having experienced it, I would never have wanted to miss it.”

Tentatively, she broached the subject of breast-feeding with her daughter. “That was something very special to me,” Mrs. Lindner said.

“Wouldn’t it be more special,” Deborah shot back with uncharacteristic edge, “if I was around to have children in the first place?”

But if her mother worried that surgery would make her less attractive to men, Deborah shared those concerns.

“Do fake boobs freak you out?” she often imagined asking Jeff Zehr, the man she had begun dating a few months before.

Mr. Zehr, a fellow marathon runner who attended her church, had told her she was special to him, and she felt similarly. But she didn’t want to scare him away or, worse, put pressure on the relationship to proceed faster than it otherwise would.

As Deborah felt increasingly torn between life events that couldn’t be rushed, and surgeries that shouldn’t wait, there was one more piece of information she thought would sway her mother.

“Will you do something for me?” she asked. “Look through the family tree and find out how old everyone was when they got their cancer.”

The answers were chilling. One of her first cousins, Mrs. Lindner learned, had breast cancer at age 33. Now the cancer had returned, and she was losing the fight.

Another first cousin got her breast cancer diagnosis at 34; she died. Her daughter, at 33, had recently learned she had the disease.

Mrs. Lindner called her daughter. “Have the surgery as soon as possible,” she said.

But a few days later, Mrs. Lindner called back. Her mother’s ovarian cancer, she remembered, had not surfaced until she was in her 70s — and she had survived. Joan Lindner had been 48 when the doctors detected her breast cancer, and she had survived too.

“We were really on the far side of the bell curve,” she said.

Memories of Chemotherapy

Deborah remembered her mother’s cancer diagnosis, which came just before her graduation from high school. Her school choir had been selected to sing at Carnegie Hall, and her parents had planned to come as chaperones. Instead, she went alone while her father accompanied Mrs. Lindner to chemotherapy appointments. During that summer, her mother’s bedroom door, always open, stayed closed.

Now Deborah reminded her what she had always said about her chemotherapy. Her eyelashes, once long and curly, had been rendered short and stubby. Food tasted different. It had, in so many subtle ways, aged her.

“I don’t want that for myself,” Deborah said. “I don’t want to treat cancer. I just never want to get it.”

She began to seek support elsewhere. A genetic counselor gave her a brochure for Bright Pink, a group of young women who have tested positive for the BRCA genes. Lindsay Avner, its 24-year-old founder, lived in Chicago, and their meeting over coffee in the hospital lounge one evening in March lasted four hours. Ms. Avner had had a prophylactic mastectomy last year.

“You’ve got to see my breasts,” she told Deborah, escorting her into the bathroom.

Ms. Avner’s surgeon at Memorial Sloan-Kettering Cancer Center in Manhattan had used a technique that preserved the breast skin and nipples, leaving a scar only under the breast.

Deborah, still in her scrubs, said, “Wow.”

Mr. Zehr drove her to an appointment with Geoffrey Fenner, the chief of plastic surgery at Evanston Memorial Hospital one evening in mid-April. If she could find a surgeon to perform the mastectomy, Dr. Fenner said he would perform the reconstruction.

The nipple-sparing technique, the doctor explained, is not popular in the United States; a decade-old study suggested that leaving the nipple increased the risk of cancer. But more recent research indicated that the risk was perhaps only 1 percent greater than with traditional reconstruction.

“I can live with that,” Deborah said.

Mr. Zehr, a corporate insurance underwriter, waited outside. On the car ride home, Deborah lobbed her question into the darkness.

“Does the thought of plastic surgery bother you?” she asked.

A moment passed.

“It would if I thought the person I was with was doing it because they didn’t like the way they looked,” he said. “But that isn’t this situation.”

He looked at her. “So, no, it doesn’t bother me.”

Deborah announced her intention to have surgery in a long e-mail message to family members at the end of April.

“I want to share with you what I feel is the right answer for me,” she wrote.

Like anyone who carried the defective gene, she might never get cancer, she acknowledged. Or she might only get it when she was old. “But I’m not a gambler,” she wrote.

Her aunt, Gloria Spurlock, a music teacher in Louisville, Ky., immediately called Mrs. Lindner, her sister, at her home in Des Moines.

“How could you let her dismember her body?” she demanded. “You have to talk her out of it.”

Stung, Mrs. Lindner tried to defend her daughter. But Mrs. Spurlock was voicing some of her own worst fears.

“Gloria,” she replied. “This is Deb’s decision.”

It was the first of several heated phone calls between the sisters. Mrs. Spurlock had considered getting tested after Mrs. Lindner found out she had a BRCA mutation. The sisters knew the gene must have come from their mother, who had had ovarian cancer a decade earlier, and whose own mother had died of the same disease. But Mrs. Spurlock concentrated instead on a healthy diet, rest and positive thinking.

The medical profession, she had long believed, was far too eager to administer drugs and remove body parts that could be healed.

Mrs. Spurlock’s daughter, Lisa Spurlock, 24, also expressed dismay.

“I’m sorry you have to be so scared of this disease,” Ms. Spurlock wrote to her cousin.

The reactions gave Deborah pause. Then they made her angry.

“Why are they saying things like this to me?” she demanded of her mother.

From the Philippines, her sister suggested that Deborah was exposed to the worst-case scenarios as a doctor. Can’t breast cancer often be cured?

“You’re right, it can often be cured,” Deborah wrote back. “The problem is that the cure involves cancer, surgery, chemotherapy, sometimes radiation and the possibility of metastasis and death.”

When a second surgeon in Chicago gave the idea of the preventive mastectomy a lukewarm reception because of her age, Deborah flew to New York for a consultation with the doctor who had performed Ms. Avner’s surgery. She invited her mother to come with her.

On the plane, Deborah showed her mother a PowerPoint presentation she had created, making the case for preventive surgery. Mrs. Lindner listened. But mostly she watched the relief in her daughter’s face as she talked about escaping her genetic prognosis.

It was there again the next day in Dr. Patrick I. Borgen’s office on Park Avenue, when the doctor supplied the first unconditional medical affirmation of Deborah’s view.

“Maybe your grandchildren will have better options,” said Dr. Borgen, director of the Brooklyn Breast Cancer Project at the Maimonides Cancer Center. “But right now a draconian operation is the best thing we can do for you.”

Back home in Iowa, Mrs. Lindner asked her husband: “What would we have done? What if we had known when we were dating?”

“We would have done the same thing,” he said. “We would have wanted you to live.”

At Dr. Borgen’s recommendation, Deborah scheduled the double mastectomy with Dr. D. J. Winchester at Evanston Northwestern hospital for the last weekend in June, three days after her medical board exam. Her insurance agreed to pay after requesting a letter of support from her surgeons. There would be just enough time to recover before she began practicing in the fall.

A Glance in the Mirror

But with the date fixed, Deborah, for the first time in months, began to doubt her decision.

Glancing in the mirror on her way out for a run, she looked herself over.

“I was like, all right, there’s me, those are my breasts,” she told a friend. “That is what I see.”

It did not help that Mr. Zehr did not seem to quite understand what the surgery entailed. “I won’t be able to breast-feed,” she reminded him.

“I thought you were having reconstruction,” he said, puzzled.

“Yes,” she said, “but they’ll be silicone.”

With three days to go, Deborah met with a nurse to go over the details of the procedure she had discussed with the surgeon. She wanted to be sure about where the incisions would be, and the size of the implants.

“We had talked about the scars on the side,” she told the nurse, “and not touching the nipple.”

“Oh, you may have incisions everywhere,” the nurse said. “There may be one up the front and underneath and up the nipple.”

Deborah burst into tears.

“Am I doing the right thing?” she asked her mother from her cellphone after she left the office.

Mrs. Lindner, packing for the drive to Chicago to be with her daughter during her hospital stay, knew she was not just asking about the scars. And she had the answer.

“Yes,” Mrs. Lindner said. “You are doing what is right for you.”

On the morning of the surgery, Mr. Zehr was there, holding Deborah’s hand. “You look cute in your gown,” he told her.

In the lounge, Mrs. Lindner waited. The surgery and reconstruction took seven and a half hours, twice as long as the doctors had expected. The incisions were small, Dr. Winchester explained when he came out, and hidden under the breast, so it had taken a long time to scrape out all the breast tissue.

Then Mrs. Lindner rode up in the elevator with her daughter, still unconscious from the anesthesia. As they arrived at their floor, Deborah opened her eyes.

“Mom,” she said, and managed a small smile.

New York Times, August 21, 2007

VITAL SIGNS At Risk: Isolating the Factors Involved in Breast Cancer

By NICHOLAS BAKALAR

Breast density and high levels of circulating sex hormones are independent risk factors for breast cancer in postmenopausal women, a new study finds.

It is known that women who have denser breasts, breasts that have more connective tissue than fat, are at higher risk for breast cancer. It is also known that higher levels of circulating sex hormones put women at increased risk. But because the two often occur together, it has been unclear whether each is a risk by itself.

Researchers studied 253 women who had breast cancer, comparing their breast density and levels of sex hormones with 520 women without the disease. After controlling for other factors, they found that when breast density was not considered, women in the highest quarter in circulating sex hormones had twice the risk of developing breast cancer as those in the lowest one-quarter.

They also found that women in the highest one-quarter in density had four times the risk of those in the lowest quarter, without considering levels of sex hormones.

Women with both the highest hormones and densest breasts had up to six times the risk.

“Having dense breasts or high hormone levels doesn’t mean you’re going to get breast cancer,” said Celia Byrne, a co-author of the study and an assistant professor of epidemiology at Georgetown. “But screening is important, and maintaining lower weight can help keep hormone levels lower.”

The report, in the Aug. 1 issue of The Journal of the National Cancer Institute, is based on a nine-year prospective study.

New York Times, July 18, 2007

No Cancer Shield Found in Fruit and Vegetable Diet

By THE ASSOCIATED PRESS

Hopes that a diet low in fat and full of fruits and vegetables could prevent the return of breast cancer were dashed Tuesday by a large seven-year experiment in more than 3,000 women.

The government study found no benefit from a diet that included far more than the recommended servings of five fruits and vegetables a day.

The study appears in Wednesday's Journal of the American Medical Association.

''It sends us back to the drawing board,'' said Susan M. Gapstur of the Feinberg School of Medicine at Northwestern University, who was not involved in the new study but was a writer of an accompanying editorial in The Journal.

''Should we really have focused on dietary components like fruits, vegetables and fat?'' Dr. Gapstur asked. ''Or should we be focusing, in addition to diet, on lifestyle factors including physical activity and weight?''

For now, the message for the 2.4 million breast cancer survivors in the United States is that they do not need to go overboard on vegetables, researchers said.

Earlier research on whether a healthy diet prevents breast cancer has shown mixed results. The new study was designed to be more rigorous.

In this experiment, all the women had been successfully treated for early stage breast cancer. Their average age was 53 when the study began.

A group of 1,537 women were randomly assigned to a daily diet that included five vegetable servings, three fruit servings, 16 ounces of vegetable juice and 30 grams of fiber. In most cases, a serving equaled a half cup. French fries and iceberg lettuce could not be counted as vegetables.

The women were allowed to eat meat, but were told to get no more than 15 percent to 20 percent of their calories from fat.

As a comparison, an additional 1,551 women were assigned to get educational materials about the importance of eating five servings of fruits and vegetables a day.

During the next seven years, the cancer returned in about the same proportion of women in both groups. About 10 percent of both groups died during that time, most of them from breast cancer.

New York Times, July 11, 2007

Researchers Find Distinctive Patterns of Cancer in 5 Groups of Asian-Americans

By DENISE GRADY

Asian-Americans, both those born here and new immigrants, have distinctive patterns of cancer incidence that doctors should consider when treating them, researchers have found.

A report appearing today in the journal CA is ''one of the most comprehensive summaries of cancer among Asian-Americans,'' according to the American Cancer Society, which publishes the journal.

The report is based on information on cancer cases collected by California from 2000 to 2002, and focuses on five ethnic groups: Chinese, Filipino, Vietnamese, Korean and Japanese. The state has a large Asian population, 3.7 million, and carefully sorts its cancer data by ethnic group.

When all cancers are combined, Asian-Americans actually have lower rates than other groups in the United States. But cancer is still a major cause of death for Asians, killing more of them than heart disease. Different groups appear prone to different types of cancer.

Groups that have been in this country the longest are likely to develop cancers that are most common here, like breast and colorectal cancer, though their rates are still significantly below those of non-Hispanic whites. The risk of those cancers may be increased by obesity, inactivity, high alcohol intake and diets rich in fat and low in fruits and vegetables, and the rates in Asians seem to rise gradually as they adopt more and more American habits.

Recent immigrants, by contrast, tend to suffer from the same types of cancer that are predominant in their native countries, like stomach and liver cancer. In developing countries, those cancers are often caused by chronic infections with certain bacteria and viruses that are routinely treated or prevented in the United States.

''I was surprised to see the diversity in cancer among the ethnic groups,'' said Melissa McCracken, an epidemiologist with the cancer society and the first author of the report. ''The group is not homogeneous. Clinicians need to be aware of that and to really extend their scope of attention to cancer due to infectious agents, not just typical chronic conditions.''

Among the more striking findings are that Vietnamese men have incidence and death rates from liver cancer that are seven times the rate in non-Hispanic white men, and Korean men and women are five to seven times as likely as whites to develop stomach cancer. Other Asians are also prone to these cancers, but their rates are generally not as high.

The hepatitis B virus is endemic in Asia, Ms. McCracken said, and chronic infection is a major cause of liver cancer there and in recent immigrants. A study last year found high rates of infection in East Asian immigrants in New York.

Worldwide, the cancer society report says, 80 percent of liver cancer cases occur in developing countries, with 55 percent of the total in China. Pregnant women can transmit hepatitis B to the fetus, so the disease can persist in the population, along with the cancers that appear later.

Doctors should be aware of the problem, Ms. McCracken said, because there are treatments that can lower the risk of transmission from mother to baby. In others, antiviral drugs can fight the infection and lower the odds of cancer. Vaccination prevents the disease and has become routine for infants in the United States, but doctors may have to make a special effort to inform immigrants about it.

The high rates of stomach cancer are thought to have two causes. One is chronic infection with Helicobacter pylori bacteria, which is common in developing countries, and treatable with antibiotics. Stomach cancer rates in this country plummeted as refrigeration came into use. In Koreans, diet is also blamed, specifically foods that are preserved with nitrates and nitrites.
Stomach cancer is also a problem in Japan, and screening programs there have lowered death rates. But screening is not performed here, so doctors should be on the lookout for symptoms in Asian patients, Ms. McCracken said.

Genetic differences among ethnic groups may play some role in determining susceptibility to various cancers, said Dr. Regina M. Santella, a professor of environmental health science at the Mailman School of Public Health at Columbia University. Dr. Santella was not involved in the study.

For example, she said, not all smokers get lung cancer, but research has shown that smokers who lack a certain gene--about 50 percent of the population lacks it--have a slightly increased risk of developing the disease.

''But there may also be exposure differences,'' Dr. Santella said.

Compared with other Asians, Chinese women have high incidence and death rates from lung cancer, the report notes. The reason is not known, since their smoking rates are low. But they do have high exposures to secondhand smoke at home and at work, and to cooking-oil vapors from high-temperature frying.

Vietnamese women pose the same puzzle, with even higher lung cancer rates and lower smoking rates.

Among Filipinos, men have higher rates of prostate cancer than other Asians, and women have the highest death rate from breast cancer. Risk factors for prostate cancer are not well understood, but breast cancer is linked to obesity, and 33.5 percent of Filipino women are overweight, more than in other Asian groups. Japanese Americans have high rates of colorectal, stomach, prostate and breast cancer compared with other groups, the researchers found. Obesity may play a role, they said, noting that 52.5 percent of Japanese men and 28.3 percent of women are overweight, and many say they are relatively inactive. Colorectal cancer rates have risen in Japan and are higher than in other Asian countries, maybe because eating habits have become more like those in the West.

Another concern raised in the report is that Vietnamese and Korean women have higher rates of cervical cancer than other groups, and lower rates of Pap test screening for it.

Several of the groups also had low rates of screening for breast and colorectal cancer. Language barriers, lack of insurance and cultural attitudes about the tests may all play a role, especially in newer immigrants, the report said, and it urged that doctors make an extra effort to convince those patients of the value of prevention and early detection.

The report is on the Internet at http://CAonline.AmCancerSoc.org.

New York Times, June 20, 2007

Study Tracks a Little-Explored Genetic Path of Breast Cancer

By THE ASSOCIATED PRESS

CHICAGO, June 19 (AP) — A deadly gene’s path can hide in a family tree when a woman has few aunts and older sisters, making it appear that her breast cancer struck out of nowhere when it really came from her father.

A new study suggests thousands of young women with breast cancer — an estimated 8,000 a year in the United States — are not offered testing to identify faulty genes and clarify their medical decisions.

Guidelines used by insurance companies to decide coverage for genetic testing should change to reflect the findings, said an author of the study, Dr. Jeffrey N. Weitzel of City of Hope Comprehensive Cancer Center in Duarte, Calif. Testing can cost more than $3,000.

“Interestingly, it’s about dad,” Dr. Weitzel said. Half of genetic breast cancers are inherited from a woman’s father, not her mother. But unless the father has female relatives with breast cancer, the faulty gene may have been passed down silently, without causing cancer. (Men can get genetic breast cancer, too, but it is not common.)

Dr. Weitzel said doctors often overlooked the genetic risk from the father’s side of the family.

The study, appearing in Wednesday’s Journal of the American Medical Association, looked at the genetic test results from 306 women whose breast cancer was diagnosed before age 50. None of the cancer patients in the study had a family history of breast or ovarian cancer.

Among the women with plenty of female relatives, about 5 percent had BRCA gene mutations. But among those with few sisters and aunts older than 45 (when breast cancer would be likely to appear), almost 14 percent had mutations of the genes BRCA1 or BRCA2. That suggests that these cancer patients were unaware of their genetic mutations because there were so few women in the family to signal a cancer risk.

The researchers defined few female relatives as fewer than two on either the father’s or mother’s side of the family.
Women who were adopted and do not know their family medical history should be aware of the findings, Dr. Weitzel said. Women whose female relatives died young before breast cancer had time to show up are also affected.

When such a woman gets breast cancer before age 50, she should get a genetic test, said Dr. Noah D. Kauff, a cancer geneticist at Memorial Sloan-Kettering Cancer Center in New York. That would help her decide whether to have the unaffected breast or her ovaries removed to prevent more cancer. Dr. Kauff was not involved in the research, but wrote an accompanying editorial.

“The study allows physicians and patients to make an argument to insurance carriers that, although there’s not a family history of breast cancer, it’s still reasonable to test and it should be a covered benefit,” Dr. Kauff said.

Genetic testing helps a woman choose her next medical steps. A woman with breast cancer who has a BRCA gene mutation has a four times greater risk of developing cancer in the other breast and a 10 times greater risk of ovarian cancer than does a woman with breast cancer who has no BRCA gene mutation.

Some women with a family history of breast cancer choose to have a BRCA genetic test so they can decide whether to reduce their cancer risk by removing their ovaries and breasts before cancer appears. Drug therapy and monitoring with annual M.R.I. tests offer alternatives.

Testing the genes of more women would cost more money, but Dr. Weitzel said it would not add significantly to health care costs and would prevent cancer in some of the women.

The study also showed that three commonly used predictive models did not accurately estimate the genetic breast cancer risk for women without a family history of cancer. The American Cancer Society recently based its recommendation for annual M.R.I.s on risk assessments from the predictive models.

New York Times, April 24 , 2007

Breast Cancer Not Linked To Abortion, Study Says

By NICHOLAS BAKALAR

There is no association between abortion and an increased risk for breast cancer, scientists reported yesterday in a large study.

There has been considerable debate over whether abortion, induced or spontaneous, is linked to breast cancer -- a debate that may intensify with last week's 5-4 Supreme Court ruling, which suggested that an abortion procedure could be banned if it posed a risk to a woman's health.

The possibility of such a link has been suggested by some retrospective studies -- that is, studies that looked for a history of abortion in women who had already been given a diagnosis of breast cancer.

But such studies are subject to error caused by inaccurate reporting. Because of personal sensitivities and the stigma associated with the operation, healthy women may be reluctant to reveal that they have had an abortion, while those with breast cancer, seeking a cause for their illness, are more likely to report one.

This study, published in The Archives of Internal Medicine, tracked women prospectively to see if those who reported having abortions were more likely to develop breast cancer in the future. They were not.

''There are still some states that require women to be informed about the risk of breast cancer if they get an abortion,'' said Karin Michels, the lead author and an associate professor of epidemiology at Harvard. ''I think that may not be justified based on the current evidence.''

Researchers studied 105,716 women enrolled in a study designed to examine associations between lifestyle and disease. The women were 29 to 46 years old at the beginning of the study in 1993, and 93 percent were premenopausal.

Initially, the women responded to a questionnaire about abortion, with 16,118 saying that they had had one or more induced abortions and 21,753 reporting one or more spontaneous abortions. The researchers collected data on breast cancer risk factors beginning in 1989, updating them every other year through 2003. There were 1,458 newly diagnosed cases of breast cancer during the study period.

The scientists found no difference in breast cancer incidence between the women who had had spontaneous or induced abortions and those who had not. Breast cancer incidence did not differ among women who had had an induced or spontaneous abortion before or after their first birth, or who had had no abortion at all.

At the same time, the authors write, it is well established that a full-term pregnancy before age 35 does reduce the long-term risk for breast cancer. So it might be said that a pregnant woman who aborts increases her risk for breast cancer compared with what it would be if she carried the pregnancy to full term.

Joel Brind, a professor of biology and endocrinology at Baruch College in Manhattan, found fault with the ways in which the study reported the data. Rather than reporting all of the abortions, he said, the researchers should have analyzed only those that occurred earliest in the study, allowing enough time after the abortion for breast cancer to develop.

''I see no reason why this study would change my opinion that having an abortion increases the risk about 30 percent over not having gotten pregnant in the first place,'' Dr. Brind said. ''I believe also that this particular study, were the data properly handled and reported, would have come up with a result in agreement with that.''

Dr. Michels said that most of the abortions occurred more than 10 years before the breast cancer diagnosis, and that analyzing only the earliest abortions made no difference in the results. But she acknowledged that Dr. Brind raised a crucial issue.

''In analyzing data,'' she said, ''we have to be careful what we are comparing and take account of whether a woman who has had an induced abortion misses out on the potential benefit she would have had if she had a full-term pregnancy.

''We did analyze the data keeping this issue in mind,'' Dr. Michels said, ''and we did not find that an incomplete pregnancy deprives a woman of the protection a full-term pregnancy would have conferred.''

New York Times, March 28, 2007

Call to Increase M.R.I. Use for Breast Exam
Two reports being published today call for greatly expanded use of M.R.I. scans in women who have breast cancer or are at high risk for it.

By DENISE GRADY

The recommendations do not apply to most healthy women, who have only an average risk of developing the disease.

Even so, the new advice could add a million or more women a year to those who need breast magnetic resonance imaging - a demand that radiologists are not yet equipped to meet, researchers say. The scans require special equipment, software and trained radiologists to read the results, and may not be available outside big cities.

Breast M.R.I. costs $1,000 to $2,000, and sometimes more - 10 times the cost of mammography - so a million more scans a year would cost at least $1 billion. It is sometimes covered by insurance and Medicare, sometimes not.

One report is a set of new guidelines for using M.R.I. in women at high risk for breast cancer, and the other is a study in The New England Journal of Medicine showing that in women who have newly diagnosed cancer in one breast, M.R.I. can find tumors in the other breast that mammograms miss.

M.R.I. has drawbacks. It is so sensitive - much more so than mammography - that it reveals all sorts of suspicious growths in the breast, leading to many repeat scans and biopsies for things that turn out to be benign. For women who are likely to have hidden tumors, the prospect of such false-positive findings may be acceptable. But the risk of needless biopsies and additional scans is not considered reasonable for women with just an average risk of breast cancer, and is the main reason M.R.I. is not recommended for them.

The new guidelines, from the American Cancer Society, are being published in the society's journal CA: A Cancer Journal for Clinicians. They recommend scans and mammograms once a year starting at age 30 for high-risk women.

High risk is defined as a 20 percent to 25 percent or higher chance of developing breast cancer over the course of a lifetime. (The average lifetime risk for women in the United States is 12 percent to 13 percent.)

The high-risk group includes women who are prone to breast cancer because they have certain genetic mutations, BRCA1 or BRCA2, or those whose mothers, sisters or daughters carry those mutations, even if the woman herself has not been tested. These mutations are not common - they cause less than 10 percent of all breast cancers - but they greatly increase a woman's risk, to 36 percent to 85 percent.

Women with even rarer mutations, in genes called TP53 or PTEN, are also advised to be screened, as are women who had radiation treatment to the chest between ages 10 and 30, for disorders like Hodgkin's disease.

Others at high risk include women from families in which breast cancer is common, especially in their close relatives, even if no genetic mutation has been identified. Women and their doctors can estimate their odds by using one of several online risk calculators that factor in the medical history of both the woman and her family. A simple calculator is available at http://www.cancer.gov/bcrisktool/.

But different calculators can give quite different results, and women may need help from their doctors to interpret the results, said Dr. Elizabeth Morris, a member of the expert panel that drew up the guidelines and director of Breast M.R.I. at Memorial Sloan-Kettering Cancer Center in Manhattan.

"Just to figure out who should have it will be the hardest thing," Dr. Morris said. "A lot of that onus is put on the referring physician. A lot of women are going to think they're high risk, and they're not."

The cancer society said that for women with certain conditions, there was not enough information to recommend for or against M.R.I. screening. The uncertain group includes women with very dense breast tissue on mammograms, and women who had breast cancer in the past, or growths called carcinoma in situ or atypical hyperplasia.

Dr. Robert Smith, the cancer society's director for screening, estimated that the new guidelines would add one million to two million women a year to the number who should have breast M.R.I.

Increased demand for such scans could easily outstrip the capacity, even though the number of centers offering them has increased markedly in the last five years, said Dr. Constance Lehman, another member of the panel that wrote the guidelines and a professor of radiology at the University of Washington. She said professional societies in radiology were scrambling to provide training and accreditation for the scans.

Insurers will probably cover the scans because the new guidelines are based on good evidence and promoted by a respected medical group, said Peter V. Lee, president of the Pacific Business Group on Health, a nonprofit coalition of large buyers of health care that cover about five million people. Huge amounts of money are now wasted on unnecessary M.R.I., Mr. Lee said, adding: "Here we have a case where there's evidence. Hallelujah! Let's use it."

Not every imaging center is qualified to perform such scans, but some that are not up to par may offer it anyway, so patients must beware.

Special equipment is needed: a powerful, "high-field" magnet and a special breast coil to generate a magnetic field around the breast. The scan is done with the woman lying on her stomach on a special table with openings that let the breasts rest in wells surrounded by the coil.

"And you have to make sure they're doing enough, not one a week, and make sure they have biopsy capability," Dr. Morris said.

If the breast scan is done at a center that cannot perform biopsies, a woman with a suspicious finding may have to start all over again at another clinic.

The second new report describes a study showing that in women who had cancer in one breast, an M.R.I. scan of the other breast found tumors that mammograms had missed in 3 percent of the women. Researchers say M.R.I. can help women who already have one cancer by detecting a hidden tumor in the other breast, enabling them to have both cancers treated at once instead of having to go through treatment all over again when the second tumor is finally detected.

Research has shown that 10 percent of women who have cancer in one breast will eventually develop it in the other as well.

"This study supports the recommendation that women who are diagnosed with breast cancer consider the benefits of a breast M.R.," said Dr. Lehman, the senior author of the study. "What we think is most important is that we understand the full extent of a woman's breast cancer before her therapy is initiated."

The scans are recommended in newly diagnosed cases, but not for most women who had breast cancer treated in the past.

Currently, women with newly diagnosed cancer in one breast are given mammograms of the other, but only a minority are offered M.R.I., Dr. Lehman said. This year, about 180,000 new cases of breast cancer are expected in the United States.

Some surgeons think every woman with a new diagnosis of breast cancer should have an M.R.I. of the other breast, and some think no one should, Dr. Morris said. She said the scans were most likely to be useful in younger women with breast cancer and dense tissue that hides tumors from mammograms. In older women with small, early tumors and clear mammograms, she said, such scanning is less important.

The study findings will make it harder for insurance companies to refuse to pay for such scans of the second breast in women with breast cancer, said Dr. Etta D. Pisano, another author of the study and a professor of radiology at the University of North Carolina.

The study, conducted at 25 medical centers, included 969 women with recently diagnosed cancer in one breast and a normal mammogram on the other. All were given M.R.I. scans, which discovered cancers in the supposedly healthy breast in 30 women, 3.1 percent of the group. Nearly all the cancers were at an early stage, and were treated at the same time as the ones originally discovered.

Without the scans, Dr. Lehman said, the tumors would not have been found until later, and then the women would have had to go through surgery, and perhaps radiation and chemotherapy as well, all over again. "We know cancers diagnosed later in these women don't do as well as cancers diagnosed initially," she said.

But to find 30 cancers, 121 women had biopsies, which were ordered because of abnormalities on M.R.I. That means 91 false-positive scans and biopsies of healthy tissue, and a false-positive rate of about 10 percent. Dr. Lehman said most cancer patients were willing to accept the risk of a false-positive and a biopsy in order to find out whether there was anything to worry about in the other breast.

The study was paid for by the National Cancer Institute.

New York Times, February 7, 2007

Test to Predict Breast Cancer Relapse Risk Is Approved

By ANDREW POLLACK

A new genetic test that tries to predict whether a woman with breast cancer will have a relapse won approval yesterday from the Food and Drug Administration, marking a step toward an era in which medical treatments are personalized for each patient.

The approval was the first ever of such a complex genetic test, not only the first for breast cancer relapse.

While other breast cancer recurrence predictive tests are being sold or developed, the new one, called MammaPrint, is the first to go through the formal F.D.A. approval process. The agency has signaled its intention to oversee more closely a profusion of sophisticated diagnostic tests that until now have often been marketed without its blessing.

The test is not totally accurate. ''You can't go all the way to the bank with this information,'' said Dr. Steven Gutman, the F.D.A. official in charge of diagnostic tests, in a conference call with reporters. Still, he said, ''I think it's a fabulous tool and one that needs further study.''

MammaPrint, developed by scientists in the Netherlands, examines the pattern of activity of 70 specific genes in a breast tumor after it is removed by surgery.

Dr. Gutman said that 23 percent of women deemed by this genetic signature to be at high risk actually had a recurrence of cancer somewhere in the body within five years. Only about 5 percent of those with a favorable genetic signature had a return of cancer in that time, he said.

Agendia, a company based in Amsterdam that already offers the test in its own country and some others, is considering how to make the test available to Americans, its chief executive, Bernhard Sixt, said in an interview. He would not say how much the test would cost.

MammaPrint and other tests like it seek to help guide the treatment of roughly 100,000 American women each year who have early stage breast cancer that has not spread to lymph nodes.

After their tumors are removed, many of these women undergo chemotherapy to lower the chances that the cancer will return. But studies have shown that most of them would not have a recurrence even without chemotherapy. The new tests could help doctors and patients decide whether some women might avoid chemotherapy and its side effects.

''Everyone is looking for ways to figure out who needs and who doesn't need chemotherapy,'' said Dr. Clifford A. Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York. ''This allows us to use the tumor to tailor therapy for individual patients.''

Dr. Hudis is an adviser to Genomic Health, a California company that sells a similar test called Oncotype DX. Genomic Health operates under federal rules that allow tests developed by and performed in a single laboratory -- as opposed to test kits that are widely sold to hospital labs and doctors' offices -- to be offered without F.D.A. approval. These tests are called ''home brew'' tests.

But the F.D.A. said in September that it intended to require approval for certain particularly complex home brew tests -- those that examine multiple genes or proteins and use an algorithm to compute a result. It has sent letters to certain companies, including Genomic Health, saying they may need F.D.A. approval.

The agency will hold a public hearing tomorrow about its proposals. Some test developers and clinical laboratories say they are concerned stricter regulation could slow the development or improvement of tests.

The labs are now regulated by the federal Medicare agency under the Clinical Laboratory Improvement Amendments of 1988.

But Dr. Sixt, of Agendia, said that gaining the F.D.A. imprimatur could help the tests establish credibility. ''I believe the industry in total will gain a lot of speed and clinical acceptance for such tests,'' he said.

The Agendia test could provide some competition to Oncotype DX, the Genomic Health test. The Oncotype test, which costs about $3,500, has been used for more than 21,000 patients over the last three years. Last year, the company performed more than 14,500 tests, double the level in 2005. Big insurers are starting to pay for the test.

Randy Scott, chief executive of Genomic Health, said yesterday that he was encouraged by the approval of Agendia's test because it removed some uncertainty over the F.D.A.'s stance. ''Through this approval they've indicated this is a field they'll be broadly supportive of,'' Mr. Scott said. He would not discuss his company's progress with the agency.

Scientists at the University of North Carolina and the Netherlands Cancer Institute tested 295 tumor samples using both the Genomic Health and Agendia tests. Although the tests examine different genes, they were in accordance about the risk of recurrence about 80 percent of the time, the scientists reported in August in The New England Journal of Medicine.

New York Times, December 18, 2006

Breast Cancer News Brings a Range of Reactions

By GINA KOLATA; CAROLYN MARSHALL CONTRIBUTED REPORTING.

Diane Raymond of Columbia, S.C., was just 45 when she started taking Prempro, the most popular hormone therapy for menopause. Ms. Raymond had not yet entered menopause, but her doctor encouraged her to take the drug anyway. His words, she recalls, were, ''We'll keep the wolves from the door, so when you do go into menopause, the transition will be much smoother.''

Four and a half years later, she developed breast cancer, and her doctor told her to stop the Prempro. Immediately.
Since then, Ms. Raymond, now 60, has closely followed the developing news about Prempro and breast cancer.
In 2002 when a large study, the Women's Health Initiative, concluded that Prempro could slightly increase the risk of breast cancer, she decided that maybe it was too soon to start thinking, ''What if I'd never taken Prempro?''
But the news last Friday was different, so vivid and immediate that it hit home.

Researchers reported that breast cancer rates, which had been inching up since 1945, suddenly took a sharp turn downward in 2003, the most recent year for which national data was available. They declined 7 percent over all, and by more than twice that rate -- 15 percent -- in the 7 in 10 women whose tumors were fed by estrogen.

The researchers said the most likely reason for the sudden decline was that the 2002 study prompted many women to stop taking hormones or never to start them.

''If that's all the time it takes for H.R.T. to do that kind of damage,'' Ms. Raymond said, using the abbreviation for hormone replacement therapy, ''someone ought to sit up and take note.''

She wishes she had never taken the drugs. It may be that they had nothing to do with her cancer. But what if they caused it?

Across the country, reactions to the new report varied from fury to disbelief to a kind of complacency, a feeling of ''what else is new?'' Some women say they are glad they never took the drugs; others are saying that they cannot do without them and will just have to accept the risk.

Kathy Boston, a 53-year-old dental assistant who lives in Oakland, Calif., said she was relieved that she refused to take hormones because of concerns about the side effects. Even though her doctor offered her free samples of hormones about a year ago, they have been sitting in a drawer ever since, she said.

''When I get hot flashes, I open the window,'' Ms. Boston said.

Betty Young, who is 60 and lives in Oakland, said she did not take the drugs, but added that she had no confidence in studies like these.

''I get so disgusted,'' Ms. Young said. ''This month they say it's bad for you; next month they say it's good for you. If you're going to get breast cancer, you get it.''

Some women are undaunted by the new findings, said Dr. Mary Jacobson, an obstetrician-gynecologist at Stanford.
''The patients with whom I spoke on hormonal therapy were pretty defiant about staying on it,'' she said, adding that as for the breast cancer link, those patients ''think it does not apply to them.''

The new study on the falling breast cancer rates was reported Thursday at a breast cancer conference in San Antonio.
The investigators, led by Donald A. Berry, a statistician at the M. D. Anderson Cancer Center in Houston, calculated that there were 14,000 fewer diagnoses of breast cancer when women stopped taking the drugs after July 2002. Prescriptions for Prempro, the most popular of the drugs, fell by half.

A similar report, by Christina Clarke and colleagues at the Northern California Cancer Center, which looked at California data, found that the trend continued into 2004.

Wyeth, the maker of Prempro, said in a statement yesterday that ''the potential impact of hormone therapy on breast cancer has long been warned in product labels.'' But the new data analysis, the company said, does not prove cause and effects. There were other possible reasons for the decline, Wyeth added. For now, the company said, ''caution and further examination over a longer period of time is advised before these data can be fully understood.''

But researchers say the good news about breast cancer rates is a vindication of the Women's Health Initiative, a large study that was attacked from the start as being too big, too expensive, unnecessary because everyone knew hormone therapy promoted health, and even unethical, because some women would have to take placebos for comparison.
Now, investigators say, the news that breast cancer rates are going down for the first time makes sense because hormones are among the only known factors that can affect cancer so immediately.

Something similar happened a few decades ago when researchers realized that the popular hormone therapy of the time, estrogen alone without progestins, was causing cancer of the endometrium, the lining of the uterus. When the link became known, women who had not had hysterectomies to remove their uterus began taking estrogen with progestins, which lowered the cancer risk.

Dr. Barnett Kramer, associate director of the office of disease prevention at the National Institutes of Health, said there was a sharp drop in prescriptions for estrogen alone, followed ''by a very rapid decline'' in endometrial cancer.
Nor did the shift in prescriptions simply delay the onset of endometrial cancers. ''They never showed up at all,'' Dr. Kramer said.

It is not yet certain whether estrogen alone raises the breast cancer risk. The Women's Health Initiative did not find such a link, but other studies found a very small risk.

Barbara Balaban, 77, of Somers, N.Y., said she was furious when she read the news Friday about the fall in breast cancer rates. Not so long ago, she said, doctors were all too eager to put every woman on the drugs, starting at menopause and continuing indefinitely.

''Going through menopause was not an illness,'' she said. ''There was no reason to take it, but they told me I should. They said it would be so wonderful. My gynecologist, my internist, my endocrinologist, they were all pushing it.''

At one point, she said, a doctor finally wore her down and she ended up taking the drugs for a year.

''I hope that doctor sitting out there reads the report and remembers all the people he pushed this on,'' Ms. Balaban said.
Yet some women, well aware of the risks of hormones, say it is not so easy for them to simply throw the drugs away.
Nancy Richardson, 60, of Wayland, Mass., said she resisted taking Prempro. When she entered menopause at age 52, she tried waiting for the drenching night sweats to go away, she tried what she called ''useless homeopathic things,'' and then she gave up and tried Prempro.

She has been unable go off it despite repeated efforts to taper down her dose. Every time she got down to no drug at all, her disabling menopause symptoms came roaring back.

She is trying again now, with the help of Dr. Marcie Richardson (no relation), a menopause specialist at Harvard Vanguard Medical Associates, a group practice in Boston. And if it does not work, she said, she has made her peace with the drug.

''No one in my family has ever had breast cancer,'' Ms. Richardson said. ''Is it quality of life or quantity of life? Truthfully, if my destiny is to feel great now and maybe shorten my future, I'd rather feel well now.''

New York Times, December 15, 2006

Reversing Trend, Big Drop is Seen in Breasst Cancer

By GINA KOLATA
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.