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Tamoxifen conferred long-term breast cancer prevention benefit
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SAN ANTONIO — Women who underwent 5 years of tamoxifen treatment for breast cancer prevention derived “strong and unabated” long-term benefit, according to extended follow-up results of the IBIS-I trial presented at the San Antonio Breast Cancer Symposium.
“It’s very striking that the reduction in incidence has been maintained, with no loss right out to 20 years,” Jack Cuzick, PhD, John Snow professor of epidemiology at Wolfson Institute of Preventive Medicine at Queen Mary University of London, told HemOnc Today.
Jack Cuzick
About 1.6 million breast cancer cases are diagnosed each year worldwide, and rates are rising.
“We have to recognize that breast cancer is truly the epidemic of our century,” Cuzick said. “Treatment is not enough. We have to get incidence of this disease knocked down.”
The IBIS-I trial included 7,154 women at high risk for breast cancer primarily due to family history of the disease. Researchers randomly assigned 3,579 women to 5 years of treatment with tamoxifen (20 mg daily). The other 3,575 women received placebo.
Median age (50.8 years) was the same in both treatment groups. Other characteristics — including BMI, menopausal status, receipt of hormone therapy and receipt of hysterectomy — were comparable between cohorts.
Breast cancer incidence, including ductal carcinoma in situ, served as the primary endpoint. Secondary endpoints included Incidence of other cancers, breast cancer mortality, all-cause mortality and adverse events.
Previously released results, based on median 10 years of follow-up, showed tamoxifen was associated with reduced risk for all breast cancers (HR=0.72; 95% CI, 0.59-0.88) and invasive, ER-positive breast cancers (HR=0.68; 95% CI, 0.53-0.88). Those results indicated the number needed to treat to prevent one breast cancer case was 59.
In San Antonio, Cuzick presented new data based on a median 16 years of follow-up. Some patients had been followed for as long as 22 years.
At the time of the analysis, 251 women assigned tamoxifen and 350 assigned placebo developed breast cancer (7.8% vs. 12.3%; HR=0.71; 95% CI, 0.6-0.83). Incidence of invasive ER-positive disease also was lower in the tamoxifen arm (4.9% vs. 8.3%; HR=0.66; 95% CI, 0.54-0.81). Researchers observed no effect of tamoxifen on ER-negative breast cancers.
After the longer follow-up, the number needed to treat to prevent one breast cancer declined to 22, and the number needed to treat to prevent one invasive, ER-positive breast cancer was 29. The incidence curves between the two groups are continuing to separate, Cuzick said.
“This bodes well for the prospects that the prevention may be longer than 20 years, and potentially even lifetime,” he said.
Women who did not take hormone replacement therapy derived the greatest risk reduction benefit from tamoxifen (38% vs. 12%; P=.04).
Overall incidence of other non-breast cancers was slightly higher in the tamoxifen arm than the placebo arm (9.8% vs. 8.8%). Researchers reported higher incidence of endometrial cancer (29 cases vs. 20 cases; OR=1.45; 95% CI, 0.79-2.71) and non-melanoma skin cancers (116 cases vs. 84 cases; OR=1.39; 95% CI, 1.04-1.87) among those treated with tamoxifen.
“There are concerns related to endometrial cancer mortality and development of estrogen receptor-negative cancers, but they are statistically nonsignificant and could be chance observations,” Cuzick said. “Somewhat unexpected, we did see a large increase in non-melanoma skin cancer. That raises the question as to whether there is any mechanism of tamoxifen that may be causing these cancers. That is something that is important but we don’t fully understand.”
At the time of the analysis, 182 women (5.1%) in the tamoxifen arm and 166 (4.6%) in the placebo arm had died. Thirty-one women in the tamoxifen arm had died from breast cancer, compared with 26 in the placebo arm (HR=1.19; 0.68-2.1).
“The women entered the study around age 50 and, on average, they’re only about 66 now,” Cuzick told HemOnc Today. “Consequently, it’s too early to see any effect on breast cancer mortality. That will take further follow-up and is very important.”
Efforts also must intensify to better educate clinicians and patients about the benefits of tamoxifen, Cuzick said.
“Cardiologists have been very effective at identifying high blood pressure and high cholesterol as diseases that require treatment,” Cuzick said. “We have to find a way to make it very clear to women at high risk for breast cancer should be offered treatment much more often.
“There is still a misunderstanding about the side effects of tamoxifen,” he added. “Some women do get them but that’s no reason to not give it a try. If you have side effects, you can always stop and they’ll disappear. The benefits on risk for breast cancer will continue.”
For more information:
Cuzick J. Abstract #S3-07. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.
Disclosure: The researchers report speakers’ bureau roles with AstraZeneca. Their institutions received grant support from AstraZeneca, Cancer Research UK, Novartis and Sanofi-Aventis.
Perspective
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Erin Hofstatter, MD
This is one of the first studies reporting on 20-year follow-up of breast cancer chemoprevention with tamoxifen, and it is very important to have that kind of follow-up. It is very significant that taking a medication, such as tamoxifen, for 5 years can continue to protect women up to 20 years out. That’s a lot of bang for your buck, if you will.This brings us to a second important point about the side-effect profile of tamoxifen. Although it is a concern for many women in terms of blood-clots, endometrial cancer [and] stroke, it really was not borne out in long-term follow-up in a clinically meaningful way. This study can be reassuring to many women that the safety profile of tamoxifen is sound and that many more providers and patients should really be considering this for breast cancer prevention.
Another important point is that, with long-term follow-up, the number needed to treat to prevent one breast cancer has fallen to approximately 22. To put that in perspective, to prevent one important cardiovascular event with the use of a statin, you need to treat about 60 patients. I think many people are very comfortable taking something like [atorvastatin calcium (Lipitor, Pfizer)], whereas they hear about tamoxifen and they get concerned.
So, I think an important take-home message is that tamoxifen really should be a clinically relevant, actively discussed modality to prevent breast cancer. It is important to realize that this did not translate into a mortality benefit, meaning that this medication has not been proven to prevent breast cancer-related death. That said, I think the morbidity on quality of life is very important in treating breast cancer, so morbidity as well as mortality should be considered when counseling patients about these drugs.
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John Robertson, MD
It’s tremendous that we’re seeing 20-year data because, often, we get short-term results. Also, it is really striking that we see continued separation of the curves in terms of the incidences of breast cancer. In the second 10 years, we’re still seeing not just that the difference has been maintained, but that the curves are still separating. With 5 years of treatment, you’re seeing the effect 20 years later.One thing we need to pay attention to — and understand a bit more — is the fact that we haven’t seen a reduction in deaths from breast cancer. It is not clear whether this is purely about smaller numbers, as there is not a huge number of breast cancers in the population. But, if anything, the numbers do go slightly in the opposite direction. So, I think those are discussions to be had with patients. Yes, this drug does prevent breast cancers, but in the overall context, we will have to see what we are aiming for. We are trying to prevent breast cancer from happening, but we also want to be sure we are stopping women from dying from breast cancer. The IBIS-1 trial tells us we can do the former, but it does not tell us — yet — that we can do the second. But it certainly opens up the discussion, again, about prevention and shows this is a potential long-term goal with new drugs and other drugs being tested.
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