Drugs to Fight Breast Cancer Near Approval

By Gina Kolata and Lawrence M. Fisher
Copyright 1998 New York Times
September 3, 1998

An advisory committee to the Food and Drug Administration voted unanimously Wednesday to approve the use of a drug, tamoxifen, to reduce women's risk of developing breast cancer.

If the drug, which is already on the market, is approved for this purpose, it will be a milestone in efforts to prevent cancer, some experts said. Although it is intended only for women at high risk of breast cancer, it would nonetheless be the first drug that could prevent cancer in healthy people.

"As far as I know, this is the first drug approved for the prevention of cancer," said Dr. Leslie Ford, the associate director for early detection and community oncology at the cancer institute.

Wednesday evening, the advisory panel unanimously recommended approval for a new drug for women with advanced breast cancer. Officials say that the drug, Herceptin, made by Genentech, is intended for use by the estimated 30 percent of breast cancer patients who have a defective gene called HER2/neu that makes their cancer spread aggressively through the body.

Herceptin is not a cure, but has been shown in clinical trials, either alone or with chemotherapy, to delay the progression of the disease.

The agency typically follows its advisers' recommendations.

Tamoxifen is already on the market as a treatment to prevent recurrences of breast cancer in women who have had the disease. Since doctors can prescribe drugs for other than their approved uses, they could give tamoxifen to healthy women even without the FDA's approval. But approval of tamoxifen as a drug to reduce cancer risk would allow the company to advertise and market it widely for this purpose and would mean that health insurance companies would be more likely to pay for it for women who have never had cancer.

Supporters expressed delight that women would have a new avenue to prevent one of the diseases they dread the most. "We're very pleased," said Susan Braun, the president and chief executive of the Susan G. Komen Foundation, an advocacy group for women with breast cancer.

But tamoxifen is not a panacea, experts warn, and the 11-member advisory panel said it did not yet have enough information to determine which women are at high enough risk of breast cancer to make the drug's hazards, including potentially fatal blood clots as well as cancer of the uterine lining, worth its benefits.

Critics say they fear that the drug will be overpromoted and that more women may be harmed than helped.

"The message we try to get across is that not everyone is at high enough risk to make this worthwhile," said Cindy Pearson, executive director of the National Women's Health Network. "It isn't like putting iodine in your salt or chlorine in your drinking water. Women have already died taking this drug," she said, adding that it was still not clear that, in the long term, it would save lives.

Alan Milbauer, who is vice president for external affairs at Zeneca Pharmaceuticals, the Wilmington, Del., firm that makes tamoxifen, said the company plans to advertise the drug directly to women in 1999, after first educating general practitioners about its use. Milbauer said tamoxifen costs $80 to $100 a month.

Dr. Robert Justice, who is acting director of the division of oncology drug products at the FDA, said "potentially tens of millions of women" could be candidates for tamoxifen. He said Zeneca applied to market the drug for the prevention of breast cancer at the behest of the agency and the National Cancer Institute and called the advisory committee's decision to recommend that the drug be approved for this purpose "courageous."

Already demand for tamoxifen is starting to build. Dr. Barbara Weber, who directs the breast cancer program at the University of Pennsylvania, said that "more and more women are calling me," asking about the drug and that other doctors have had the same experience.

Cancer experts had long hoped that tamoxifen might prevent breast cancer. Its biochemistry was promising, since it prevents the hormone estrogen from stimulating breast tissue. "It's holding up across the board -- in any setting where you get reduced exposure to estrogen, you get less breast cancer," Dr. Weber said.

For example, women who start menstruating late or who reach menopause early are less likely to develop breast cancer. But the notion of testing tamoxifen as a breast cancer preventative in healthy women was controversial because it would mean exposing women to the known risks of the drug to provide a possibly elusive benefit.

Nonetheless, the cancer institute went ahead, with a large study involving 13,388 women who had at least double the average risk of breast cancer. Half took tamoxifen and the others took a placebo. The institute ended the trial abruptly in April, six years after it began, announcing that it was unethical to continue because the data had become so clear that women who took the drug were less likely to develop breast cancer. Eighty-five women taking tamoxifen had gotten breast cancer as compared to 154 women taking a placebo, a 45 percent reduction.

But 33 women taking tamoxifen developed cancer of the uterine lining, as opposed to 14 of women taking the placebo; 17 women in the tamoxifen group had blood clots in their lungs, as against 6 taking the placebo.

And the tamoxifen picture soon became muddied. While the cancer institute's study still awaits publication in a medical journal, two European groups published results from their own studies in the journal Lancet in July, and the data were not so encouraging. A British study of 2,471 women and an Italian study of 5,408 women found no reduction in breast cancer risk in women who took tamoxifen.

Perhaps, many said, the European studies were too small to see tamoxifen's benefit. In addition, noted Dr. Ford, who directed the tamoxifen trial for the cancer institute, the women in the European trials were at lower risk of developing breast cancer.

But, wrote Dr. Kathleen Pritchard of the University of Toronto in an accompanying editorial, "The failure of these trials to confirm the results of the U.S. study, however, casts doubt on the wisdom of the rush, at least in some places, to prescribe tamoxifen widely for prevention."

By that time, momentum was already building for the approval of tamoxifen for healthy women at increased risk of breast cancer. In April, shortly after the U.S. tamoxifen study ended, officials from the FDA, the cancer institute, and the U.S. tamoxifen study met and decided that the agency should consider allowing Zeneca to market tamoxifen as a breast cancer preventative, Justice of the FDA said. "They were encouraged to submit an application to us as soon as possible," he added. Wednesday's meeting was the result.

The expert panel, headed by Dr. Janice Dutcher, a professor of medicine at Montefiore Medical Center in the Bronx, was unhappy with the wording of the agency's questions, which asked if tamoxifen should be approved as a way to "prevent" breast cancer. That had not been demonstrated, the group said, noting that it remained possible that the drug merely staved off cancers that would eventually occur. So it changed the works to "reduce the risk" of breast cancer and voted unanimously to recommend approval for that purpose.

Dr. Ford said that the cancer institute and its tamoxifen researchers have been preparing for this day, developing a computer disk that will be available to women and doctors and that can calculate a woman's risk of developing breast cancer as well as compare her risk to that of the women in the large tamoxifen study. Those who want the disk can order it through the cancer institute's clinical trials Web site, Dr. Ford said.

If Herceptin is approved, it will be the first genetically engineered drug for the treatment of advanced breast cancer.

Herceptin has not yet been tested in earlier-stage breast cancer, but some specialists said they believed it could also prevent or delay the spread of the disease.

Although Herceptin potentially delays tumor progression in less than one-third of patients whose breast cancer has spread, or metastasized, cancer specialists said it represents an important step toward a new method of treatment. Unlike chemotherapy, which kills fast multiplying cells, healthy as well as cancerous, Herceptin targets a specific genetic alteration linked to the cancer. Thus Herceptin has relatively few side effects.

Dr. Debu Trepathy, director of clinical trials at the breast care center of the University of California at San Francisco and a principal investigator of the drug, called the drug a breakthrough. "There is no doubt in my mind that this is the beginning of a whole new wave of biological drugs that modulate the causes of cancer," he said.

Herceptin is a genetically engineered copy of an immune system protein known as a monoclonal antibody. It was developed by Genentech Inc., based in South San Francisco, Calif., which is 67 percent owned by Roche Holdings Ltd., of Basel, Switzerland. Shares in Genentech closed Wednesday at 66 3/4, up 1 3/4, on the New York Stock Exchange.

Herceptin was recommended for the treatment of patients with advanced metastatic breast cancer whose tumors produce excessive amounts of a gene known as HER2, for human epithelial growth factor receptor-2. When several copies of a HER2 gene exist in a cancer cell, excessive amounts of a protein are produced on the surface of cells.

About 25 to 30 percent of metastic breast cancer patients produce too much HER2. In turn, too much HER2 often means the patient's cancer will spread faster and kill sooner than in patients producing smaller amounts of HER2. Patients in clinical trials of Herceptin were screened using laboratory tests to determine who produced large amounts of HER2.

"The ability to ask functional questions about cells, and about what causes a normal cell to become malignant, and then to intervene to fix what is broken, that has been the promise," of molecular biology in cancer, said Dennis Slamon, director of the Revlon UCLA Women's Cancer Research Program in Los Angeles. "HER2 and Herceptin, in that context, represent to my mind the first real-world realization of that hope," he said. Slamon was a principal investigator of Herceptin.

In clinical trials of patients with metastatic disease who had not received chemotherapy, those treated with Herceptin and chemotherapy experienced tumor progression later than those treated with chemotherapy alone. The median time to disease progression increased from 4.6 to 7.6 months, or about 65 percent. About 28 percent of women treated with Herceptin and chemotherapy did not show tumor progression at one year, compared with 14 percent who were treated with chemotherapy alone.

A second trial, of women who were not helped by chemotherapy, showed that Herceptin alone delayed tumor progression to some extent in a fifth of the patients.

For most patients, the main side effect of Herceptin was a fever, treatable with Tylenol. In a minority, however, who received Herceptin along with a class of chemotherapy drugs called anthracyclines, the combination caused cardiac problems, such as congestive heart failure. These effects typically ceased when the drug was withdrawn.

"It's a very big advance," said Larry Norton, medical director of the breast center at New York's Memorial Sloan-Kettering Cancer Center. "All by itself, it's definitely going to help a lot of people, and it dramatically augments the Taxol effect," he said, referring to a chemotherapy drug that has been particularly effective in breast cancer.

"The key issue is not the efficacy, although that's very exciting," he said. "The key issue is that this is the beginning of the whole new approach in the treatment of cancer."

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