"Practice-changing" is the term several physicians and researchers used when asked by the media to describe the results of a study showing that extending tamoxifen therapy from 5 to 10 years for women with estrogen receptor (ER)-positive breast cancer further reduced recurrence and mortality. Results of the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) study, reported at the 2012 San Antonio Breast Cancer Symposium and published simultaneously in The Lancet,1,2 received extensive coverage by the major media and medical press.
“It’s going to be practice-changing, in my view, immediately for premenopausal women with breast cancer,” said Eric Winer, MD, Chief of Women’s Cancers at Dana-Farber Cancer Institute in Boston, who was quoted in the Boston Globe Daily Dose blog.3
“Certainly, the advice to stop in 5 years should not stand,” the study’s senior author, Sir Richard Peto, FRS, of Oxford University, commented in The New York Times.4
In the ATLAS study, led since its inception in 1995 by Christina Davies, MBChB, of Oxford University, 6,846 women with ER-positive breast cancer who had been taking tamoxifen for 5 years were randomly assigned to continue treatment for another 5 years or stop immediately. This treatment allocation had little effect on recurrence or mortality rates from 5 to 9 years after diagnosis, but in the second decade following diagnosis, women who had continued tamoxifen treatment beyond 5 years had a 25% lower recurrence rate and a 29% lower breast cancer mortality rate. Details of the study were reported in the January 15 issue of The ASCO Post.5
Saved a Lot of Lives
Over the years, tamoxifen has “saved a lot of women’s lives. That is the important thing,” V. Craig Jordan, OBE, PhD, DSc, told The ASCO Post. Scientific Director at the Lombardi Comprehensive Cancer Center, Georgetown University, in Washington, DC, Dr. Jordan has been a leader in the development of tamoxifen and other selective estrogen receptor modulators (SERMs), but was not directly involved in the ATLAS study. “This has been my life’s work for 40 years. I don’t know anybody else who has been that lucky,” Dr. Jordan said.
“I think it is fair to say that tamoxifen has really gone further than our furthest dreams could possibly imagine,” Dr. Jordan continued. “Cancer is so clever” that drug resistance might have been expected after 5 or 10 years, “but we’ve been very lucky because this is a unique agent, so you couldn’t really predict that this was going to happen. The laboratory research with animal models in the 1970s indicated that longer therapy was going to be better, and maybe even that lifetime therapy would be optimal. This was at a time when the only other alternatives were chemotherapies—very aggressive chemotherapies.”
During the 1980s and 1990s, concern arose about balancing gains vs side effects, but the use of tamoxifen for 1 year, 2 years, and 5 years showed continued benefits “and then long-term benefits even after you stop the tamoxifen”—the carry-over effect, Dr. Jordan said. “This really provided enthusiasm for going longer than 5 years with a very safe, very cheap drug, in very large populations, to find the real answer. That is what we have with ATLAS and will soon have that with aTTom,” he continued. The aTTom (adjuvant Tamoxifen—To offer more?) trial randomly allocated 7,000 women, most with unknown ER status, to continue tamoxifen for 10 years or to stop at 5 years. Results are expected later this year.
“This next year or two is going to be critical,” Dr. Jordan said, as physicians and researchers review the results of ATLAS and aTTom and “compare and contrast” treatment with tamoxifen and aromatase inhibitors for individual patients. “I think leadership from ASCO is absolutely essential here.”
‘The Good, the Bad, and the Ugly’
Like 5-year tamoxifen trial results, 10-year results showed an increased incidence of endometrial cancer among postmenopausal women. The cumulative risk of endometrial cancer at 5 to 14 years of follow-up was 3.1% for women who continued tamoxifen beyond 5 years vs 1.6% for those who stopped; and the corresponding mortality rates were 0.4% vs 0.2%.
“What we have is a conversation between the laboratory and the clinic to be able to get an understanding of what I’ve always called ‘the good, the bad, and the ugly’ of tamoxifen,” Dr. Jordan said. “Our laboratory studies showing that tamoxifen could encourage the growth of endometrial cancer very quickly got confirmed in clinic. This presaged the prevention trial, where the definitive study showed, yes, you get a threefold increase in endometrial cancer in postmenopausal women, but the drug is safe in that respect in premenopausal women. What is very, very clear from ATLAS is, irrespective of this side effect in postmenopausal women, the benefits in survivorship far outweigh the risks of dying from endometrial cancer.”
The ATLAS study reported that “tamoxifen produces favorable lipid changes” and suggested tamoxifen could provide some protection against ischemic heart disease. Animal studies had shown “that tamoxifen will lower the ‘bad’ cholesterol—the LDL cholesterol—and have no impact on the HDL cholesterol,” Dr. Jordan reported. A Scottish trial found that women who had 5 years of tamoxifen had a decrease in coronary heart disease, but this finding was not replicated in any of the overview analyses, he said.
As SERMs became more widely used in clinical practice, Dr. Jordan remained interested in seeing whether lowering LDL would be a positive side effect. “What basically we found is raloxifene [Evista] has an effect an effect on LDL but does not protect from coronary heart disease. At this point, I don’t think we can make a definitive decision about what tamoxifen does with regard to lipid changes. Sir Richard Peto’s data demonstrate that at up to 5 years, there is no positive effect, but he is finding a positive effect for between 5 and 10 years.”
Taking tamoxifen may now be a more favorable option for premenopausal women who should not take aromatase inhibitors or postmenopausal women who cannot tolerate the side effects of aromatase inhibitors. “I think the key lesson here is, you have to take the drug to get the effect,” Dr. Jordan said. For women who stop taking aromatase inhibitors after 1 or 2 years because of the side effects, “tamoxifen now becomes a very good option because 5 years of tamoxifen saves lives. Just 1 or 2 years of tamoxifen or any adjuvant endocrine therapy really doesn’t have a big impact. We have to pay attention to long-term therapies, have operational systems in place to get people to continue taking the drug. Without long-term therapy, you put yourself at risk for a recurrence. That’s the bottom line,” he emphasized.
Cost and Worldwide Impact
“Part of the reason for this trial,” Dr. Jordan said, is “Sir Richard Peto has a passion for improving health care on a global basis, and tamoxifen could be a key tool in that effort. If we can gain an enormous health-care benefit from such an inexpensive drug [less than $200 per year, according to the New York Times article4], we should go for it, because I think we understand the drug. We can keep mothers alive so they can see their children grow. In societies where the grandmother is integrated in part of the family group, caring for the grandchildren, let’s keep these women alive for 5, 10 years or longer.” He added that “worldwide, the aromatase inhibitors are probably going to stay on the pricey side, but tamoxifen will be used internationally before anything else.”
While immunohistochemistry has made it easier to determine the estrogen receptor status of patients, ER testing might not be feasible in economically challenged countries, and tamoxifen may be given to women with breast cancer whose ER status is unknown. This can still produce significant benefits, Dr. Jordan said.
“In the United Kingdom, there was a great reluctance in the 1980s to go with the idea that tamoxifen’s action was based on the estrogen receptor,” he continued. That and a lack of sophisticated ER labs “mandated that virtually everybody who received a diagnosis of breast cancer—because there was a thought that it might have some effect in ER-negative cancer—got tamoxifen. This had a dramatic effect,” Dr. Jordan said. “The control of breast cancer was staggering in the United Kingdom. It dropped like a stone with adjuvant tamoxifen being given to everybody.”
Longer-term follow-up of the ATLAS study is “almost mandatory” and deserving of government funding, Dr. Jordan stated. “This is a massively important public health issue,” he said. “Money has to be invested so we analyze our data over the next 20 or 30 years.” ■
Disclosure: Drs. Winer, Peto, and Jordan reported no potential conflicts of interest.
References
1. Davies C, Pan H, Godwin J, et al, for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. December 5, 2012 (early release online).
2. Davies C, Pan H, Godwin J, et al, for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group: ATLAS—10 v 5 years of adjuvant tamoxifen in ER+ disease: Effects on outcome in the first and in the second decade after diagnosis. 2012 San Antonio Breast Cancer Symposium. Abstract S1-2. Presented December 5, 2012.
3. Kotz D: Should breast cancer patients have a decade of tamoxifen? Boston Globe. December 5, 2012.
4. Pollack A: Bigger role seem for breast cancer drug. New York Times. December 5, 2012.
5. Goodman A: Adjuvant tamoxifen for women with ER-positive breast cancer: 10 years superior to 5 years. ASCO Post. January 15, 2013.
