Tamoxifen Continues to Prevent Breast Cancer for Years After Therapy Is Stopped

Zosia Chustecka

December 18, 2006

December 18, 2006 (San Antonio) (updated December 29, 2006) — Long-term data from a large study of tamoxifen for breast cancer prevention show that the protective effect continues for years after treatment is stopped. The benefit after 10 years — which includes 5 years on the drug and then 5 years without it — is “just as good as, if not even better than, what we saw after 5 years of therapy, whereas the side effects stop as soon as patients stop taking the drug,” lead investigator Jack Cuzick, MD, from the Wolfson Institute of Preventive Medicine, in London, United Kingdom, told attendees at the 29th Annual San Antonio Breast Cancer (SABC) Symposium.

“This means that the risk/benefit ratio improves long-term and is much more favorable than we thought,” Dr. Cuzick told Medscape. This should encourage use of tamoxifen for breast cancer prevention, he said, as concern over side effects is one of the reasons that both physicians and patients cite as putting them off this therapeutic strategy.

“The risk/benefit is reduced substantially,” agreed Powell Brown, MD, PhD, from the Baylor College of Medicine, in Houston, Texas, comoderator of the session at which the data were presented. “Women continue to benefit even after stopping the drug, while the side effects are seen only while they are taking the drug.”

“These are critically important long-term data,” Dr. Brown told Medscape. “It’s amazing that an even greater effect was seen after 5 years of stopping therapy than after 5 years of taking the therapy.”

Benefit Even Greater Years After Therapy

The data come from the IBIS-1 study, a placebo-controlled trial coordinated by Cancer Research UK and conducted in 7145 healthy women at high risk for breast cancer. Results after 5 years of therapy, released in 2002, showed that tamoxifen reduced breast cancer by about a third.

Now the results at 10 years, including 5 years after therapy was stopped, show a 29% reduction in all cases of breast cancer (142 cases in the tamoxifen group vs 195 cases in the placebo group; P = .002) and a 34% reduction in estrogen-receptor positive (ER+) tumors (87 with tamoxifen vs 129 placebo).

The effect on the overall rate of breast cancer “is just as big at 10 years as it was at 5 years,” Dr. Cuzick commented, but “the effect specifically on ER+ tumors is even bigger at 10 years than it was at 5 years.” He presented the data in terms of a percentage decrease in incidence, as shown in the tables.

Incidence of all breast cancer

Time
Placebo (%)
Tamoxifen (%)
Decrease Due to Tamoxifen (%)
5 y
3.3
2.2
1.1
10 y
6.4
4.7
1.7

Incidence of ER+ breast cancer
Time
Placebo (%)
Tamoxifen (%)
Decrease Due to Tamoxifen (%)
5 y
2.0
1.5
0.5
10 y
4.3
2.9
1.4


“The effect of tamoxifen on breast cancer prevention is very long-term,” Dr. Cuzick commented. “It continues even after therapy is stopped; in fact, the effect is even stronger in the follow-up period.” When asked as to why that may be the case, Dr. Cuzick speculated that tamoxifen might be turning precancerous cells back into normal cells.

In a separate presentation at the meeting, 20-year follow-up data from another trial also showed a sustained effect of tamoxifen on breast cancer prevention. Trevor Powles, MD, from the Royal Marsden Hospital, in London, United Kingdom, presented results from a long-term follow-up of a study in which 2494 women took tamoxifen or placebo for a period of 8 years. At that point, the difference between the 2 groups was not significant, but it has become so during the posttreatment period, he told the meeting. The fact that most of the benefit occurred in the later follow-up period supports a true preventive action rather than a treatment effect on established occult disease, Dr. Powles commented.

Little Protective Effect in Women Taking HRT

In the IBIS-1 study, women were allowed to take hormone replacement therapy (HRT) for symptoms of menopause, and about 40% did so. The protective effect against breast cancer was much smaller in this subgroup of women, Dr. Cuzick commented.

Women who had never used HRT or who had used it before enrolling in the trial showed a significant reduction in ER+ breast cancer (37 cases with tamoxifen vs 77 with placebo, a 52% reduction). In contrast, women who were taking HRT during the trial showed no clear benefit from the drug, either for ER+ tumors or for all cases of breast cancer, Dr. Cuzick noted.

Noting that there has been a suggestion that tamoxifen could be used to protect against the breast cancer induced by HRT, Dr. Cuzick stated: “These data are not supportive of that approach.”

This is very important, says another of the IBIS-1 coordinators, John Forbes, MD, from the University of Newcastle, Australia. Commenting in a news release, he pointed out that previous research has suggested that women taking HRT together with tamoxifen have a lower risk of breast cancer compared with those not taking tamoxifen, and as a result some clinicians are using these therapies in tandem. “The IBIS-1 results are therefore very important, and we must continue to examine these, because they suggest the opposite,” he said.

Side Effects Stop Once Drug Is Stopped

The 3-fold increase in thromboembolic events seen during the 5-year treatment period “virtually disappeared” once therapy was stopped, Dr. Cuzick told the meeting. The typical gynecological and vasomotor symptoms also stopped once therapy was halted, and no increase in endometrial cancer in the tamoxifen group was seen in the posttreatment period, although there had been a 4-fold increase during therapy, which is “somewhat surprising,” he commented. No cataracts were seen during the treatment period, but they did develop in the 5 years afterward.

This falloff in side effects while the protective effect continues means that the risk/benefit ratio is “least twice as good,” and it continues to increase with follow-up, Dr. Cuzick concluded.

“This is the first time that concrete evidence is available on the benefits and side effects of tamoxifen after treatment is stopped,” commented Tony Howell, MD, professor of cancer prevention at South Manchester University Hospitals Trust, United Kingdom, in a news release. “These results suggest that the overall risk/benefit ratio will improve over a longer follow-up period.”

But Higher Mortality in Tamoxifen Group 
 
However, overall the mortality was higher in the group of women who took tamoxifen for 10 years than those who took placebo, although the difference was not statistically significant. In total, there were 65 deaths with tamoxifen vs 55 with placebo (P = .36), with cause of mortality outlined in the table.

Death and Cause of Death in Tamoxifen Study


Placebo
Tamoxifen
Total deaths
55
65
Breast cancer
13
11
Endometrial cancer
0
1
Other cancer
21
24
Myocardial infarction
1
4
Other cardiac causes
1
2
Stroke or cerebrovascular accident
1
1
Deep vein thrombosis or pulmonary embolism
2
3
Other
16
19


In an email to Medscape, Thomas Bachelot, MD, from the Leon Bernard Centre, in Lyon, France, says that the fact that more women died in the tamoxifen group is "disturbing, at least," especially in view of the fact that this was a prevention trial. "I think this point should be emphasized every time this study is presented," Dr Bachelot commented, adding: "We should work to know why this happened."

29th Annual SABC Symposium: Abstract 34. Presented December 16, 2006.

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