Debate Swirls Over Breast Cancer Drug : Health: Tamoxifen is used to treat the disease, but some scientists believe that it may cause cancer. The Wilson Administration has delayed putting it on the state's carcinogen list while its effects are further studied.

By PAUL JACOBS

Nov. 8, 1995 12 AM PT

TIMES STAFF WRITER

SACRAMENTO — Quietly last spring, a panel of state-appointed scientists unanimously concluded that one of the world’s most widely prescribed anti-cancer drugs, tamoxifen, can itself cause cancer.

This finding would normally mean that tamoxifen, which has been prescribed worldwide to about 3 million women with breast cancer, would be added to the governor’s list of 404 chemicals “known to the state to cause cancer.”

But the drug has not been listed. Instead, under pressure from the drug maker and the National Cancer Institute and after personal intervention by the governor, the Wilson Administration has delayed a decision indefinitely.

The listing by the state could have major economic consequences for the drug manufacturer and possibly a psychological impact on women taking the drug as well.

It also comes at a time when a National Cancer Institute study is under way to see if the drug is helpful not just in treating breast cancer but in preventing it. For that, investigators need to enroll healthy women, and some scientists believe that they would be scared away if the drug were declared a carcinogen.

Wilson intervened in the case just days before the July 1 deadline to add chemicals to the list.

Wilson became involved in the issue after he “was contacted by breast cancer patients, who informed him that this [scientific] advisory committee had made the recommendation,” said Paul Kranhold, the governor’s press secretary. The patients told Wilson that the scientists--along with the staff of the agency that reviewed the drug--had failed to consult with the NCI. “And it turned out they had not,” Kranhold said.

The governor did not decide to delay the listing and call the added hearings, Kranhold said. That decision was left to the Office of Environmental Health Hazard Assessment, which does the staff work on suspect chemicals.

The office delayed a final decision, called for two days of additional hearings that were held Oct. 10-11, and unleashed a passionate debate that has split the scientific community and raised questions about the wisdom of the state publicly listing any prescription drug as a carcinogen.

A spokesman for Zeneca, the sole manufacturer of the drug in the United States, credits Wilson with the delay.

“We had to get more aggressive to get a hearing,” said Zeneca’s Steve Lampert. “The governor was quite gracious making sure there was a public hearing and not just listing.”

Proponents of listing the drug say it is vital to alert women to the risks--particularly the healthy women enrolled in the nationwide trial to see if tamoxifen can prevent breast cancer. They also say that such a listing is required under Proposition 65, the anti-toxics initiative approved by voters in 1986.

Opponents argue that proof that the drug causes cancer is not clear-cut, that the drug is never issued without complete warnings about possible effects and that the listing is unnecessarily alarmist.

“What proportion of the women in the general population are sufficiently sophisticated to understand benefit versus risk, when all they’re told by the state is risk?” asked Dr. Sydney Salmon of the Arizona Cancer Center, one of a long list of scientists who testified against listing tamoxifen as a carcinogen.

The eight scientists on the state’s Carcinogen Identification Committee based their May vote largely on a string of scientific reports linking tamoxifen to a small but troubling increase in uterine cancer.

In almost every case, the decisions of the scientists have been followed and the substances added to the governor’s list of cancer-causing chemicals required under Proposition 65.

California’s listing of the drug could jeopardize the NCI-sponsored breast cancer prevention trial, said Dr. Phillip Bretz, director of the Breast Institute in Rancho Mirage. The trial hopes to enroll 16,000 women, half of whom will be given tamoxifen and the other half a placebo.

But the study was briefly suspended last year amid allegations that investigators had not fully informed patients about uterine cancer risks.

“Any further bad publicity, especially coming out of an important state as California, may sound the death [knell] for this trial and with it the hopes of Zeneca that tamoxifen will be the biggest selling drug in history,” Bretz said.

As those remarks show, the delay in the state’s decision whether to list tamoxifen as a carcinogen has kicked off a maelstrom of scientific, political and ethical debate. Among the developments:

* The chairman of the Carcinogen Identification Committee and six other members threatened to resign if their decision on tamoxifen is arbitrarily overturned by the Wilson Administration.

* Zeneca Pharmaceuticals launched an extensive campaign to keep the drug off the cancer list, circulating petitions among physicians, scientists and breast cancer activists to prevent the listing. The company reports $550 million a year in sales of the drug, which it markets under the brand name Nolvadex.

* Encouraged by the company, physicians and scientists from around the world--including some of the nation’s most respected cancer researchers--showed up at the special hearing last month to voice their often passionate objections to listing the drug.

* Officials of the National Cancer Institute, which is funding the breast cancer prevention trial, have weighed in, arguing that the decision was “premature.”

The director of the state Office of Environmental Health Hazard Assessment, James W. Stratton, made the decision to delay the listing.

David Roe, a staff attorney with the Environmental Defense Fund and one of the authors of Proposition 65, blames the delay in the decision on bureaucratic cowardice--an indirect consequence of Wilson’s unsuccessful campaign for the presidency.

“This is the chronic pattern since Pete Wilson decided to go off and run for President,” Roe said. “The standstill option trumps everything. . . . Lobbyists make noise and everything grinds to a halt.”

In May, the chairman of the state’s scientific committee, epidemiologist Thomas Mack of USC, told his colleagues that the evidence connecting use of the drug and an increase in the number of uterine or endometrial cancers “is about as solid as it can get in humans.”

A paper published by Swedish researchers just days before concluded that women taking relatively high doses of tamoxifen were 40% less likely than untreated women to get a new cancer in the opposite breast. But the study found a sixfold increase in uterine cancer in a long-term follow-up.

The package insert for Nolvadex contains the warning: “An increased incidence . . . of endometrial cancer has been reported in association with Nolvadex treatment.”

Said Zeneca spokesman Lampert: “We’ve been diligent as a company alerting [the Food and Drug Administration] as new data comes forward. . . . As you can see from the labeling, there may be reported potential associations with endometrial cancer, but as yet no causal relationship in humans.”

Scientists invited by Zeneca to speak at the October hearing said the increase in uterine cancer could be explained in other ways--such as a greater likelihood that uterine cancer would be detected in patients taking tamoxifen.

But Mack in a recent interview defended the committee’s vote to list the drug, saying that the only question posed to the scientists under Proposition 65 was whether the evidence supported the conclusion that tamoxifen causes endometrial cancer.

“The role of the committee is not to make cost-benefit judgments,” Mack said, “but simply to assess at the time of the decision, the weight of the evidence that there are cancers of any kind after use of tamoxifen that would not have occurred in the absence of that use.”

Mack complained that Zeneca had “pulled out all the stops in trying to stop the listing of tamoxifen.”

He also confirmed that he and six other scientists on the committee had threatened to resign if Stratton, as head of the Office of Environmental Health Hazard Assessment, succumbed to the lobbying and refused to list the drug without new information.

Stratton could not be reached for comment. But his chief deputy, Charles M. Shulock, said the delay in the decision was nothing more than an attempt to gather additional information.

The new information will be presented to Mack’s committee, Shulock said, and the panel will be given a chance to reconsider its May decision.

But Shulock also noted that the International Agency Research on Cancer, in Lyon, France, is scheduled to review in February whether tamoxifen causes cancer. If that agency, as an authoritative scientific body, decides to list the drug as a carcinogen, tamoxifen will automatically be added to the state list under Proposition 65.