SAN ANTONIO, Texas — It's a gift that just keeps on giving: five years of tamoxifen continues to prevent breast cancer from developing in women at high risk for the disease, more than 15 years after they stopped taking it.
Median 16-year follow-up results from the IBIS-I (International Breast Cancer Intervention-I) trial, reported here at the San Antonio Breast Cancer Symposium, show a 29% lower risk for developing breast cancer among women who had been randomly assigned to five years of tamoxifen than for women assigned to five years of placebo.
"I think we have to recognize that breast cancer is truly the epidemic of our century," said principal investigator Jack Cuzick, PhD, professor of epidemiology at Wolfson Institute of Preventive Medicine at Queen Mary University of London, United Kingdom.
"Treatment is really not enough. We have to really get the incidence of this disease down," he said.
Yet while tamoxifen is one highly effective way of achieving that goal, getting at-risk women to take the drug is another matter, Dr Cuzick and breast cancer specialists who spoke with Medscape Medical News agree.
The current analysis of IBIS-I, published simultaneously in The Lancet Oncology (doi:10.1016/S1470-2045(14)71171-4), shows that the protective effect of tamoxifen therapy has not dwindled over time, Dr Cuzick said.
The IBIS-I study, which began recruitment in 1992, enrolled 7154 pre- and post-menopausal women aged from 35 to 70 years at high risk for breast cancer primarily because of a family history. They were randomly assigned to receive either tamoxifen 20 mg daily for five years (3579) or placebo (3575). Hormone replacement therapy was allowed during the trial and was used by 49.5% in the placebo group, and approximately 35% of women in each group had had a hysterectomy. The median age at enrollment was 50.8 years in each group.
At a median of 16 years of follow-up (longest follow-up 22 years), there were 601 breast cancers reported, 251 (7.0%) occurring in women who took tamoxifen, and 351 (9.8%) in women who took placebo.
The hazard ratio (HR) for breast cancer with tamoxifen was 0.71 (P <.0001).
In subanalysis, the most pronounced reductions in risk were seen for invasive estrogen-receptor-positive (ER+) breast cancer (HR: 0.66; P < .0001) and ductal carcinoma in situ (HR: 0.65; P = .05). However, tamoxifen did not significantly reduce the risk for invasive estrogen-receptor-negative (ER-) breast cancer (HR: 1.05; P = .8).
"There is some concern that estrogen-receptor-negative cancers were becoming more common in the longer follow-up," Dr Cuzick said at a media briefing on the morning of his presentation, and he hypothesized that these may be ER+ cancers that were being kept in check by tamoxifen but then transformed into ER- tumors.
Dr Cuzick also noted that "hormone replacement therapy turned out to be important. We found the effect was really only clearly demonstrated in women who did not use hormone replacement therapy during the treatment period. This was seen both in the first 5 years, and subsequently afterward. That was a significant difference: women who did not use hormone replacement therapy had a much bigger benefit from tamoxifen than those who did."
An earlier analysis showed that at 10 years of follow-up the number of women who needed to take tamoxifen to prevent one incident of breast cancer (the number needed to treat [NNT]) was 59. Now, in the latest analysis with longer follow-up, the NNT had fallen to 22.
Endometrial cancer, a known risk of tamoxifen therapy, was seen in 20 women in the placebo group and in 29 in the tamoxifen group. The cases all occurred during the active treatment period. The difference between the groups was not significant, however.
"A somewhat unexpected event is that in fact we did see a large increase in non-melanoma skin cancer, but a very low risk for mortality cancers and that's where most of the differences were, so it raises the question of were there any mechanisms [by which] tamoxifen might be causing these cancers, something important but that we don't fully understand," Dr Cuzick said.
In contrast, the risk of colorectal cancer, previously thought to be of concern with tamoxifen therapy, was lower among patients on the active drug, he added.
Although there were fewer breast cancer cases among women on tamoxifen, there were five more breast cancer deaths in this group (31 vs 26).
"It's actually probably too early to make any pronouncements, favorable or unfavorable, about breast cancer death. That's going to actually take another 10 years of follow-up," Dr Cuzick said.
In an editorial accompanying the study in The Lancet Oncology, Rowan T. Chlebowski, MD, from the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, California, suggests that "discordance between tamoxifen's effects on breast cancer incidence and outcome noted in the IBIS-I update could merely represent the effects of chance alone, or alternatively might indicate that tamoxifen mainly decreases the incidence of cancers with a very favourable prognosis, increases cancers with unfavourable outcomes, or both."
Many At-Risk Women Don't Get Tamoxifen
Despite the evident benefits of tamoxifen, many women with a family history or genetic background that put them at risk for cancer but are otherwise healthy don't take the drug, a persistent problem that troubles investigators and clinicians alike.
"It's a major issue. Cardiologists have been very effective in terms of identifying things like high blood pressure, high cholesterol, as diseases which need treatment. We have to find a way, I think, to make it very clear that women with breast cancer [risk] should be offered treatment. I think much of the problem is still in the education of the medical profession," Dr Cuzick said in reply to a question from Medscape Medical News.
"The important finding in this study is that there were fewer breast cancers overall, although primarily in the ER-positive over time. When we're looking at with 16 years of median follow-up and still seeing fewer breast cancers, I think that's significant," said Anees B. Chagpar MD, MSc, director of the Breast Center at Smilow Cancer Hospital at Yale-New Haven Hospital in Connecticut. She was not involved in the study, and was approached for comment.
"A lot of women are offered chemoprevention, but not many opt to take it," Dr Chagpar commented in an interview. "I think part of that is the fear of the side effects, and the fact that many of them will start tamoxifen or particularly an aromatase inhibitor, and find side effects that they find troubling, and so will stop."
She said that she tries to convince at-risk women of the benefits of tamoxifen by reviewing the data with them and explaining that there is a significant risk reduction associated with endocrine therapy.
"One of the difficult problems in this area is the fact that clinicians and patients have not been educated as to the fact that in pre-menopausal women, tamoxifen does not lead to an increased risk of endometrial cancer or either deep venous thromboembolism or pulmonary embolism," said Matthew Goetz, MD, a breast cancer oncologist at the Mayo Clinic in Rochester, Minnesota.
In an interview, Dr Goetz noted that data from various studies suggest that below age 55 the risk for endometrial cancer with tamoxifen is no higher than for the general population.
"I think the issue here is that when women think about the drug tamoxifen, they go on the internet and read about blood clots and endometrial cancer, and I think appropriately in that situation they say 'no thanks.' But if I think women are properly counseled and told that at least in the pre-menopausal setting that this drug could reduce the risk of cancer by almost 50%, I think they'd realize that it's a good option for pre-menopausal patients," he said.
The study was supported by Cancer Research UK and the National Health and Medical Research Council of Australia. Dr Cuzick disclosed that he is on the speakers bureau for AstraZeneca and that his institution receives research support from AstraZeneca, Sanofi-Aventis, and Cancer Research UK. Dr Chlebowski disclosed consulting fees or honoraria from Novartis, Amgen, and Genomic Health.
San Antonio Breast Cancer Symposium (SABCS) 2014: Abstract S3-07, presented December 11, 2014.
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Cite this: Tamoxifen Continues to Shine for Breast Cancer Prevention - Medscape - Dec 11, 2014.