As Preventive Agent, Tamoxifen Shows Long-Term Breast Cancer Reduction

LONDON, Feb. 22 -- The beneficial effects of five years of tamoxifen to healthy high-risk women in preventing breast cancer persist for at least 10 years, whereas most side effects fade, according to two major trials.

Both studies found a reduced occurrence rate from tamoxifen for estrogen receptor-positive disease after the end of the five-year treatment along with an appreciable tapering of adverse events, according to reports in the Feb. 21 issue of the Journal of the National Cancer Institute.

The first study was an eight-year update of the International Breast Cancer Intervention Study (IBIS-I). In that study, 7,145 high-risk women, ages 35 to 75, were randomly assigned to receive 20 mg a day of tamoxifen or a placebo for five years.

Early results reported in 2002, about four years into the trial, found that tamoxifen reduced the occurrence rate of invasive ER-positive breast cancers by 31% in high-risk women, although most of the follow-up was during the active treatment phase.

Updated results of this study, headed by Jack Cuzick, Ph.D., of the Wolfson Institute of Preventive Medicine here, and colleagues, found that tamoxifen reduced the occurrence rate of breast cancer by about 27% after a median follow-up of about eight years.

The occurrence rate reduction was for ER-positive breast cancer only. The benefits for ER-negative breast cancer rates were similar in both groups, the researchers reported.

Compared with placebo, this reduction amounted to an annual incidence of 4.97 cases versus 6.82 cases per 1,000 woman-years, respectively; risk ratio [RR] 0.73, 95% confidence interval, 0.58 to 0.91, P = .004).

One hundred and forty-two breast cancers were diagnosed in 3,579 women in the tamoxifen group and 195 in the 3,575 women in the placebo group, the researchers noted.

Furthermore, the rates of ER-positive invasive breast cancers in the tamoxifen group were 26% lower than those for the placebo group during the first four years and 44% lower during years five and beyond, the researchers reported.

The prophylactic effect of tamoxifen in ER-positive women was fairly constant from the earlier report to the current one, and no fall-off of the benefit was observed for up to 10 years after randomization, the researchers reported.

However, side effects in the tamoxifen group were much lower after completion of the active treatment period than during active treatment, the researchers reported.

For example, deep-vein thrombosis and pulmonary embolism were statistically significantly higher in the tamoxifen arm than in the placebo arm during active treatment (52 versus 23 cases, RR, 2.26, CI = 1.36 to 3.87). However, after tamoxifen was stopped, the rates fell (16 versus 14 cases, RR, 1.14, CI , 0.52 to 2.53). In addition, the increased frequency of vasomotor and gynecologic symptoms during active treatment with tamoxifen also disappeared.

The investigators also noted that slightly larger risk reductions were observed for premenopausal women who also had a lower rate of adverse events than postmenopausal women, suggesting that tamoxifen is a particularly attractive option for these women, they said.

Women with ER-negative tumors did not benefit from tamoxifen. The two arms did not differ in the risk for ER-negative invasive tumors (35 in each arm, RR = 1.00, CI = 0.61 to 1.65) across the entire follow-up period. Compared with ER-negative tumors, the risk of ER-positive invasive breast cancer was 34% lower in the tamoxifen arm (87 versus 132 cases, RR, 0.66, CI, 0.50 to 0.87), the researchers reported.

Study limitations, according to Dr. Cuzick's team, included the fact that information on side effects was obtained somewhat differently during the active and post-treatment phases.

In addition, women in the trial were allowed to take hormone replacement therapy, which could have confounded the results. However, hormone replacement therapy was not associated with the development of ER-negative breast cancers, either during the active treatment period or after.

Finally, the study authors concluded, even longer follow-up is necessary to determine the full extent of the risk reduction associated with tamoxifen prophylaxis.

In the second study, Trevor Powles, Ph.D., of the Royal Marsden Hospital here, and colleagues analyzed more than 13 years of data from 2,471 healthy women, ages 30 to 70, enrolled in a 20-year follow-up of a tamoxifen breast-cancer prevention clinical trial at their hospital. The women were at increased risk of breast cancer because of a family history.

In the Royal Marsden trial, started in 1986, women were randomized to oral tamoxifen (20 mg/day) or placebo for eight years. The first analysis in 1998 found no reduction in breast cancer when tamoxifen was compared with placebo.

In this, the second analysis, with a median follow-up of more than 13 years, the researchers again found a non-significant 22% reduction of breast cancer with tamoxifen.

However, when they looked specifically at ER-positive breast cancers, they found a statistically significant 39% reduction of ER-positive disease. The reduction occurred for the most part after the eight-year treatment period, the researchers reported.

Among the eligible participants (1,238 in the tamoxifen arm and 1,233 in the placebo arm), 186 developed invasive breast cancer (82 on tamoxifen and 104 on placebo; HR, 0.78, 95% confidence interval, 0.58 to 1.04; P = 0.1).

The risk of ER-positive breast cancer was not significantly lower in the tamoxifen arm than in the placebo arm during the eight-year treatment period (30 cancers in the tamoxifen arm and 39 in the placebo arm (HR, 0.77, CI = 0.48 to 1.23; P = .3), the researchers reported.

However, the benefit took time to appear. The lowered risk became statistically significant only in the post-treatment period (23 in the tamoxifen arm and 47 in the placebo arm (HR = 0.48, CI = 0.29 to 0.79; P = .004).

This statistically significant 52% reduced risk in the post-treatment period supports the long-term prevention of estrogen-dependent breast cancer by tamoxifen, the researchers said.

Fifty-four participants in each arm have died from any cause (HR = 0.99, CI = 0.68 to 1.44; P = .95). The adverse-event profiles for both arms, especially gynecologic toxicity, were similar to those previously reported and occurred predominantly during the treatment period.

Finally, the investigators said, reductions in post-treatment ER-positive risk were observed among pre- and postmenopausal women, among those who used or did not use hormone replacement, and among those with a family history of breast cancer.

Discussing the study's limitations, the researchers noted that the trial was a small, single-institution study and that participants were younger and had a stronger family history of breast cancer than those in other trials, specifically the American National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial. However, follow-up, they said, was longer than in other studies.

Tamoxifen treatment for eight years appears to have a long-term preventive effect against ER-positive breast cancer, Dr. Powles' team said. "This overall risk reduction for ER-positive cancers occurred for the most part after the treatment period, indicating a preventative rather than a treatment action by tamoxifen on estrogen-dependent disease," the researchers concluded.

In an accompanying editorial, significantly titled "Tamoxifen: An Enduring Star," Umberto Veronesi, M.D.,of the European Institute of Oncology in Milan, Italy, and colleagues wrote, The results of these trials illustrate "how an old and presumably superseded drug like tamoxifen . . . continues to spawn new insights and challenges for those scientists and clinicians subscribing to evidence-, rather than business-, based medicine."

Overall, Dr. Veronesi and colleagues said, tamoxifen was less active in reducing breast cancer risk, and also less toxic, in these two mostly European investigations compared with the American NSABP P-1 trial.

The results of both of these studies, the editorialists said, support previous evidence from meta-analysis of adjuvant trials and from follow-up data of the NSABP P-1 trial of a durable--and possibly permanent--preventive effect of tamoxifen on ER-positive breast cancer that extends well beyond treatment cessation.

Because both trials found that tamoxifen benefited only ER-positive cancers, it is important to identify specific risk factors for these cancers so that the drug's use can be appropriately guided, they said.

The results of these two trials and the findings of other studies "convincingly move tamoxifen beyond the proof-of-principle stage and underscore its worth as a viable standard option for preventing ER-positive breast cancer in high-risk women," they concluded.

They pointed out that "tamoxifen is a telling example of an effective agent with an unprecedented body of clinical evidence that has thus far had little appeal in the prevention setting mainly because of its poor commercial interest (the drug is

cheap and off patent)."

They concluded by urging "the community of scientists and clinicians to rethink its priorities and move toward choices driven more by public health concerns than by market interests."

Listing financial disclosures, Dr. Cuzick, John Forbes, M.D., and Anthony Howell, M.D., reported that they have served as occasional consultants to and advisory board members for AstraZeneca, Novartis, Pfizer, and Lilly. Drs. Forbes and Cuzick are principal investigators for trials for which their institutions (ANZ BCTG and Cancer Research UK, respectively) receive funding from AstraZeneca.