Can Tamoxifen Prevent Breast Cancer?

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Family Practice Recertification, May 2015, Volume 33, Issue 5

The IBIS-I randomized control trial included women of ages 35-70 from 37 health centers in eight countries from April, 1992, until March, 2001 that were deemed to be at increased risk of developing breast cancer (by virtue of family history of breast cancer or abnormal benign breast disease), and randomized to treatment with oral tamoxifen or placebo for 5 years.

Review

Cuzick J, Sestak I, Cawthorn S, Hamed H, Holli K, Howell A, Forbes JF7; IBIS-I Investigators. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015 Jan;16(1):67-75.

Study Methods

The IBIS-I randomized control trial included women of ages 35-70 from 37 health centers in eight countries from April, 1992, until March, 2001 that were deemed to be at increased risk of developing breast cancer (by virtue of family history of breast cancer or abnormal benign breast disease), and randomized to treatment with oral tamoxifen or placebo for 5 years.

Eligible women had risk factors for breast cancer indicating at least a twofold relative risk for ages 45—70 years, a four-fold relative risk for ages 40–44 years, and a roughly ten-fold relative risk for ages 35–39 years. [1] Women were excluded if they had a history of any invasive cancer (except non-melanoma skin cancer), deep vein thrombosis, pulmonary embolism, current use of anti-coagulents, a life expectancy judged to be less than 10 years, or who were pregnant or wanted to become pregnant. [1]

The purpose of the study was to compare the occurrence of any type of breast cancer in the two groups. Secondary endpoints included the occurrence of invasive estrogen receptor-positive breast cancer, all-cause mortality, and major adverse events (death, other cancers, thromboembolic events and cardiovascular events).

Results and Outcomes

7154 women in the trial (3579 in the tamoxifen group and 3575 in the placebo group) were included in the data analysis. Median follow-up for this analysis was 16.0 years (IQR 14.1—17.6). Other characteristics of the study population include a median age at study entry of 49.9 years (IQR 46.0–55.0), with 3858 (54%) of 7154 women were postmenopausal. 4002 (56%) of 7154 had a body-mass index (BMI) higher than 25 kg/cm., and 2876 (40%) of 7154 used menopausal hormone therapy at some point during the active treatment phase of the trial. Use of this treatment during the trial was slightly, but not significantly, higher in women assigned to tamoxifen.

A total of 601 breast cancers were reported (251 [7.0%] in 3579 women in the tamoxifen group vs 350 [9.8%] of 3575 in the placebo group). The authors found a significant reduction in the occurrence of all breast cancers in the tamoxifen group compared to the placebo group (HR 0.71 [95% CI 0.60—0.83], p<0.0001). After 20 years of follow-up, the estimated risk of developing all types of breast cancer was 12.3% (95% CI 10.1–14.5) in the placebo group compared with 7.8% (95% CI 6.9–9.0) in the tamoxifen group, indicating that the number needed to treat for 5 years of tamoxifen was 22 to prevent one breast cancer over the next 20 years (95% CI 19–26).

With regard to invasive estrogen receptor-positive breast cancers, the tamoxifen group also had better outcomes, with the number needed to treat of 29 (95% CI 26—34). Interestingly, there were more estrogen receptor-negative breast cancers in the tamoxifen group after 10 years of follow up, and women who had menopausal hormone therapy during the 5 years of active treatment had significantly less benefit from tamoxifen than those who did not (p=0.04).

With regard to the study’s secondary endpoints, there was no statistically significant difference between the tamoxifen and placebo groups in terms of other types of cancers. Additionally, they found:

· During the 5 year treatment period, there were a higher absolute number of endometrial cancers in the tamoxifen group, however this did not reach statistical significance.

· Significantly fewer gastrointestinal cancers occurred in women receiving tamoxifen than in those receiving placebo (42 in the tamoxifen group vs 63 in the placebo group; OR 0.66 [95% CI 0.44—0.99], p=0.038).

· Non-melanoma skin cancers were significantly increased in the tamoxifen group, whereas there was a similar incidence of melanoma skin cancers between the two treatment groups.

· More cases of lung cancer were reported with tamoxifen (32 cases) than with placebo (24 cases), although this difference was not significant and was only observed in the first 10 years of follow-up

· A significantly higher incidence of deep vein thrombosis in women receiving tamoxifen than those receiving placebo (50 [1.4%] of 3579 women receiving tamoxifen vs 29 [0.8%] of 3575 women receiving placebo; OR 1.73 [95% CI 1.07—2.85], p=0.02). This only remained of statistical significance during the first 10 years of follow-up. (Number needed to harm = 167)

There were no significant differences between treatment groups with regard to major cardiovascular events or cerebrovascular accidents.

There were no significant difference in mortality between groups (OR 1.10 [95% CI 0.88—1.37], p=0.4), nor in breast cancer deaths (18 tamoxifen vs nine placebo; OR 2.00 [0.85–5.06], p=0.08) independent of the use of hormone replacement therapy. There were also no significant differences in other cancers or causes of death, however the authors do note a larger absolute number of deaths from endometrial cancers (p=0.06) and in respiratory deaths (p=0.1) in the tamoxifen group compared to the placebo group.

Conclusion

The results show that tamoxifen continues to protect against the development of all breast cancers versus placebo over the entire 20-year follow-up period of this study. The authors argue that given the longevity of this protection, the benefit-to-harm ratio of the drug for breast cancer prevention is substantially improved.

Commentary

This well done and ambitious study challenges medical providers to believe in the power of statistical analysis when helping patients to choose an intervention that has both benefit and harm. In high risk women, tamoxifen helped lower the risk of all breast cancers (NNT=22) and estrogen sensitive breast cancers (NNT=29), yet the drug increases the risk of some adverse events (deep vein thrombosis (NNH=167) while having no impact on all cause or cancer specific mortality.

How do we incorporate these findings? Was tamoxifen beneficial? Might tamoxifen mainly decreases the incidence of cancers with a very favorable prognosis, increases cancers with unfavorable outcomes, or both? And, is this data hampered by the significant changes over the last 20 years regarding diagnosing and treating the variety of breast tumor types, etc. that may influence survival and outcomes. [2]

Most would agree that an NNT of 22 provides a very strong argument supporting its use. What patients will likely want to know when weighing the risks and benefits of this therapy is will the decreased incidence in breast cancer translate into a longer life. Unfortunately, this study did not find an improved survival benefit, likely due to the small number of deaths which occurred. [4]

To begin patient counseling on whether tamoxifen is an option, first calculate the woman’s risk (http://www.cancer.gov/bcrisktool/). Only consider use if the patient meets the age and increased risk criteria (ages 45—70 years, double baseline risk, ages 40–44 years, 4 fold increase in risk, and ages 35–39 years, a 10 fold increase over baseline.) If she meets criteria, then explain the pros and cons of tamoxifen preventative treatment, and help gauge her anxiety and potential benefit.

In the future, the advent of individual genome mapping will likely be able to differentiate between the women that will definitely benefit from tamoxifen therapy versus not. Until then,,tamoxifen is an option providers have to offer to women who are at increased risk and want to do more than self breast exams and regular imaging.

References

1. Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 2002; 360: 817—24.

2. Chlebowski RT. IBIS-I tamoxifen update: maturity brings questions. Lancet Oncol. 2015 Jan;16(1):7-9. doi: 10.1016/S1470-2045(14)71184-2. Epub 2014 Dec 11.

3. Ebrahim S, Smith GD. The 'number need to treat': does it help clinical decision making? J Hum Hypertens. 1999 Nov;13(11):721-4.

4. Vogel VG. Ongoing data from the breast cancer prevention trials: opportunity for breast cancer risk reduction. BMC Med. 2015 Mar 26;13:63.