Tamoxifen for Prevention of Breast Cancer: Extended Long-Term Follow-Up of the IBIS-I Breast Cancer Prevention Trial

The longest randomized controlled trial to date on breast cancer chemoprevention with tamoxifen (a synthetic drug that blocks the effects of estrogen), IBIS-I, recently reported, after 16 years of follow-up, a 29 percent reduction in breast cancer (invasive and noninvasive types) for ‘high-risk’ women taking the drug for 5 years. The reduction in breast cancer risk occurred only in estrogen-receptor positive (ER+) breast cancer cases.

IBIS-I included 7,154 women aged 35 to 70 years from 37 centers in eight countries. Defining “high risk,” most women (97%) had a family history of breast cancer, and 8 percent had a benign (noncancerous) breast lesion associated with increased risk. To be eligible for the study, women aged 45–70 years had to have risk factors indicating at least a twofold increased risk for breast cancer whereas for women under age 45, this risk needed to be higher than two times average risk. According to the American Cancer Society, having one first-degree relative (mother, sister, or daughter) with breast cancer approximately doubles a woman’s breast cancer risk and having two first-degree relatives triples the risk. Importantly, less than 15 percent of women with breast cancer have a family member with the disease.

The study’s “primary endpoint” (e.g., the result measured at the end of a study) was incidence (the occurrence of invasive breast cancer or ductal carcinoma in situ, DCIS) not mortality (dying from breast cancer or other causes. In other words, the study measured Tamoxifen’s effect on reducing the frequency of breast cancers, not its effect on lowering the number of deaths.

The difference between incidence and mortality is crucial: after 16 years, there was almost a 30 percent reduction in incidence of breast cancer, but no statistically significant reduction in deaths. No documented survival benefit. If the primary endpoint were mortality, the study would have been powered to examine statistically significant (e.g., a calculation predicting that a result did not likely occur due to chance) effects of tamoxifen on deaths. The results showed, after 16 years following women who received 5 years of tamoxifen, an excess of 5 deaths from breast cancer and another 5 from endometrial cancer, compared to the placebo without tamoxifen.

Risk for deep vein thrombosis, a well-known life-threatening tamoxifen outcome, also increased by 75 percent (but this figure was not discussed in the article abstract and was downplayed in the discussion.)

Interpretations and Implications

A report by Jack Cuzick for IBIS-I investigators that updated IBIS-I in 2014 found that high-risk women who took tamoxifen for five years had about a 30 percent benefit (reduction in breast cancer) 16 years after stopping treatment. [0.71 CI .60-.83]. The data also showed a 3.8-fold (380%) increase in endometrial cancer risk, along with 5 additional deaths from endometrial cancer in the tamoxifen group compared to the placebo, all during the five years of treatment.

In addition, a comment in the same issue of Lancet Oncology from Rowan T. Chlebowski about IBIS-I highlights the worrisome, though not statistically significant, finding of increased deaths in the tamoxifen group despite the reduction in breast cancer incidence. Results that are not statistically significant does not necessarily mean that there was no impact. After ten years of follow-up, there were twice as many deaths (18) in the tamoxifen group as in the placebo (9).

“The discordance between tamoxifen’s effects on breast cancer incidence and outcome noted in the IBIS-I update could merely represent the effects of chance alone, or alternatively might indicate that tamoxifen mainly decreases the incidence of cancers with a very favorable prognosis, increases cancers with unfavorable outcomes, or both.”

This pattern of more deaths over time from breast cancer is consistent with other major tamoxifen studies, thus can be called a “trend.” A study from twenty years ago showed a 50 percent protective effect of tamoxifen on high risk women, but deaths from blood clots. The IBIS-I study is larger, better designed, and longer in follow-up. In addition, the IBIS-I trial was started before it was possible to identify HER2 breast cancers and endocrine therapy is less effective in HER2-positive advanced breast cancer.

With no survival benefit, treating healthy women with tamoxifen, to “chemoprevent” breast cancer exposes them to major harms, including deep vein clots, endometrial cancer, and possibly death from breast and endometrial cancers. The IBIS-I update highlighted risk reduction in getting breast cancer, but downplayed the data showing no survival benefit as well as the trend toward increased deaths from breast and endometrial cancers.

Source: Jack Cuzick et al. for IBIS-I Investigators. 2015. “Tamoxifen for prevention of breast cancer: Extended long-term follow-up of the IBIS-I breast cancer prevention trial,” Lancet Oncology [16:67-75]. http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2971171-4/fulltext

See also: Rowan T. Chlebowski, “Comment: IBIS-I tamoxifen update: maturity brings questions,” Lancet Oncology, Dec.11,2014. http://dx.doi.org/10.1016/S1470-2045(14)71184-2.

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