SAN ANTONIO—Women at increased risk of breast cancer who were treated with five years of tamoxifen in the 1990s are still benefiting from that treatment 16 or more years later, researchers reported at the San Antonio Breast Cancer Symposium.
In the updated results of the International Breast Cancer Intervention Study-I (IBIS-I) Jack Cuzick, PhD, Director of the Wolfson Institute of Preventive Medicine at Queen Mary University in London, reported: “We have observed a 30 percent reduction in breast cancer, and that reduction has been sustained out to 20 years, after five years of use of tamoxifen.”
The researchers had previously reported that the benefit extends to 10 years. “We are now reporting that with a median of 16 years—and a maximum follow-up of 22 years—to our delight, the benefits are sustained and there was a continued reduction of incidents out to 20 years,” Cuzick said in an interview.
“Survival of breast cancer is quite good right now, so the real benefit is in preventing cancers,” he said. “That is a real benefit because women do not have to go through the procedures of having breast cancer.”
After 16 years, the number of breast cancer cases in this trial overall is 601, and the number of deaths is about 350. “The number of deaths from breast cancer is only 56—that means that the mortality from breast cancer in this trial is less than 10 percent of the number of breast cancers diagnosed,” he said.
“We would have liked to have shown a mortality benefit, and people were disappointed that we could not, but any way one looks at the data, they are just not mature enough. This has been a 20-year trial, and the data are still not mature enough. This is what happens when you do prevention.”
The results of the trial were also published simultaneously in Lancet Oncology (2015;16:67-75).
In an accompanying editorial (Lancet Oncology 2015;16:7-9), Rowan Chlebowski, MD, Director of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, suggested that there may be a darker undercurrent in the study, and that the 20-year findings may contain more questions than answers, especially concerning the mortality benefit—or lack of it.
“There is an unusual twist to the findings, which I am sure will have people running to their prevention study datasets,” Chlebowski said in an interview. “There were 350 breast cancers in the placebo group and 251 in the tamoxifen group, so there were 99 fewer cancers, but five more breast cancer deaths in the tamoxifen group. So how do you get 99 less breast cancers and five more breast cancer deaths?
“It might be that tamoxifen is only inhibiting cancers that aren't so bad for you or it is stimulating a few cancers that are bad for you such as the negative receptor cancers,” he continued. “Having said that, though, there is still benefit in having prevented 99 breast cancers. The question is what is going to happen as we continue to follow these women. This will raise a lot of scientific interest in the characteristics of the cancers that are prevented by tamoxifen.”
Cuzick said that five years of tamoxifen appears to be sufficient in attempting to prevent cancer in woman at high risk. “We think that for prevention, five years is enough. We could see no reduction in the benefit right out to 20 years, so the benefit after stopping was just as good as while on active treatment. The question remains: Will this be a lifetime benefit, or will there be some loss of effect after 20 to 25 years?”
‘Still a Lot More to Learn’
The median age of the women on the trial is now 65 and 90 percent are alive, he said. “There is still a lot more to learn. Prevention is a very long-term game—even more so than treatment. So one has to be patient about waiting a long time to get the clear picture. We do not yet have evidence for a mortality reduction. That is probably going to take even longer.”
Cuzick said the aromatase inhibitors, now standard of care for post-menopausal women, are a better preventive agent than tamoxifen—but tamoxifen can be used to prevent breast cancer in pre-menopausal and post-menopausal women.
For the study, researchers enrolled 7,154 pre-menopausal and post-menopausal women. A total of 3,579 women were assigned to receive tamoxifen (20 mg daily); and the other 3,475 were randomly assigned to placebo. The median age of the women was 50, with a range of 35 to 70. During 16 years of follow-up, 351 women in the tamoxifen group developed a breast cancer compared with 350 women on placebo—a 29 percent reduction.
As noted, a reduction in breast cancer-specific deaths following tamoxifen treatment has not yet been seen. There were 31 breast cancer deaths in the tamoxifen patients compared with 26 deaths in the women taking placebo. In addition, five women receiving tamoxifen died from endometrial cancer compared with none in the placebo group. Deaths from other causes were very similar in both groups—146 among women on tamoxifen versus 140 among women on placebo.
The extended analysis of the IBIS-I trial is announced a year after the first results of the IBIS-II trial were released, which found that taking the breast cancer drug anastrozole for five years reduced the chances of post-menopausal, high-risk women developing the disease by 53 percent compared with women who took a placebo.
AstraZeneca, the maker of tamoxifen, supplied the drug and matching placebo for the trial.