Two European studies published yesterday cast doubt on the idea that the drug tamoxifen prevents breast cancer, as American researchers found in April.
But a number of cancer specialists said yesterday that there is still reason to believe the American findings are solid and that women at high risk of breast cancer who take tamoxifen to lower their risk should not stop doing so on the basis of the new studies, nor should women at lower risk start. Tamoxifen can raise the risk of uterine cancer and cause potentially dangerous blood clots.
The American study – which was about twice as big as the other two studies combined – followed women for four years on average. An Italian study followed women for almost four years, and a British study for almost six years.
After an analysis of all three studies, the American findings “seem robust,” wrote Dr. Kathleen I. Pritchard, head of clinical trials and epidemiology at the University of Toronto, in a commentary published with the new findings in the current issue of the British journal Lancet.
But the failure of the European studies to confirm the American findings does cast doubt “on the wisdom of the rush, at least in some places, to prescribe tamoxifen widely for prevention,” she noted.
In April, a team of American researchers led by Dr. Bernard Fisher of Pittsburgh, head of the Breast Cancer Prevention Trial, stopped its study of more than 13,000 women at high risk of breast cancer early because it became obvious that tamoxifen was linked with a 45 percent reduction in new cancer cases.
The chance of a finding this dramatic being a statistical fluke is less than 1 in 10,000, the National Cancer Institute noted.
But even the American study leaves in doubt one key question, said Dr. Irene Kuter, a medical oncologist at Massachusetts General Hospital.
“We know that in women taking tamoxifen for a few years there is a decreased incidence of breast cancer,” Kuter said. “The question is, is that just slowing down the appearance of cancers that are already there, or is it truly preventing new cancers?”
The new studies, one of 2,471 women in the United Kingdom and the other of 5,408 women in Italy, “just don’t have the statistical power” to reach as firm conclusions, said Fisher in a telephone interview. The new findings “don’t shake any of our confidence in the findings of the US study.”
Both European studies found that tamoxifen was not linked to a statistically significant difference in the number of new breast cancer cases between women taking the drug and those taking a placebo.
But the Italian study involved only women who had had a hysterectomy, many of whom had not only the uterus but also the ovaries removed. Women who have had their ovaries removed are considered at lower risk of breast cancer because without ovaries, a woman produces drastically reduced levels of the hormone estrogen, which drives many breast tumors.
Since the Italian study was both smaller than the American study and involved women at low or average risk of breast cancer, it is less likely that any protective effect of tamoxifen would show up.
The British study did include women at high risk of breast cancer by virtue of having a strong family history of the disease but did not include women with other risk factors such as early age at first menstrual period, late age at first childbirth, and biopsies of the breasts for suspicious lumps.
This means that since the American women may have been at higher overall risk, a protective effective of tamoxifen would be more likely to show up in the American data, said Dr. Barry Kramer, deputy director of the division of cancer prevention at the National Cancer Institute.
The American women were also older than the European women, and because breast cancer risk rises with age, this, too, means that a protective effect of tamoxifen would be more likely to show up in the American study.
Another confounding factor was that women in the European studies were allowed to take hormone replacement therapy – including estrogen – even if they were also taking tamoxifen, an estrogen blocker. The American women were not.
In the British study, about 41 percent of the women were taking hormone replacement therapy and in the Italian study, about 15 percent, said Kramer of NCI. “So the question is, could you be blunting the effect of tamoxifen” with estrogen?
The Italian study also showed a trend toward a statistically significant protective effect of tamoxifen in women who took the drug for more than one year; however, many of the Italian women dropped out in the first year of the study.