Tamoxifen's Preventive Benefits Sustained but Drug Still Underutilized in Practice

Photo Courtesy © SABCS/Scott Morgan 2014

Jack Cuzick, PhD

Five years of tamoxifen continues to offer protection against breast cancer, reducing the risk of breast cancer by 29% in otherwise healthy women at high risk of the disease who have been followed now for 16 to 22 years.

The benefit was even more pronounced for preventing invasive estrogen receptor (ER)-positive disease, as well as for women who did not use hormone replacement therapy (HRT) during their 5 years of tamoxifen therapy, according to new findings from the IBIS-I study reported at the 2014 San Antonio Breast Cancer Symposium.

Although this study offers yet more evidence in support of tamoxifen’s prophylactic benefit to high-risk women—one these results suggest may extend even longer than 20 years, said lead investigator Jack Cuzick, PhD—tamoxifen’s use in practice for this purpose continues to be underwhelming worldwide.

“It’s a major issue. I think cardiologists have been very effective in terms of identifying things like high blood pressure and high cholesterol as diseases that need treatment. We have to find a way to make it very clear that women at high risk of breast cancer should be offered treatment much more often,” said Cuzick, the John Snow professor of Epidemiology at the Wolfson Institute of Preventive Medicine at Queen Mary University of London.

In addition to a need for more education in the medical profession, Cuzick attributed much of this problem to a misunderstanding about the side effects of tamoxifen. “Some women do get them, but that’s no reason to not give it a try,” he said.

Benefit Grows Over Time

The ongoing IBIS-I study, known formally as the International Breast Cancer Intervention Study-I, recruited 7154 women at breast care and genetics clinics in eight countries between 1992 and 2001 and randomized them evenly to receive 20 mg of daily tamoxifen for 5 years (n = 3579) or matching placebo (n = 3575).

The median age of participants across both cohorts was 50.8 years; slightly more than 50% were postmenopausal, and the mean body mass index was 27. Women with an increased risk of breast cancer, largely due to a family history of the disease, were eligible for the study regardless of whether they were using HRT before the trial, during it, or had not used HRT, or whether they had undergone a hysterectomy. These characteristics were also balanced across the two arms.

At 10 years of follow-up, substantial differences between the two groups were observed confirming previously reported analyses, noted Cuzick. He said 163 breast cancers were reported in the tamoxifen arm (4.6%), versus 226 (6.3%) with placebo (HR = 0.72; 95% CI, 0.59-0.88). For invasive ER-positive disease specifically, 100 breast cancers were reported in the treatment arm versus 145 in controls (HR = 0.68; 95% CI, 0.53-0.88). For all breast cancer, the number needed to treat (NNT) for 5 years to prevent one breast cancer was 59.

“What’s new is that with an additional 10 years of follow-up, we now have substantially larger differences,” said Cuzick, including a reduction in the NNT to 22. Although the reduced risk remains about 30% overall, “the differences between the two arms is now substantially larger, with 12.3% of women in the placebo arm developing breast cancer compared with 7.8% in the tamoxifen arm.”

A total of 601 breast cancers were reported before data cutoff May 1, 2014. In the tamoxifen cohort, breast cancer was reported in 251 women versus 350 in the placebo arm (HR = 0.71; 95% CI, 0.60-0.83; P <.0001). For invasive ER-positive breast cancer, risk was reduced by 35%; 160 cases were reported in the treatment arm versus 238 with placebo (HR = 0.66; 95% CI, 0.54-0.81; P = .0001).

Although tamoxifen was associated with a significant reduction in ductal carcinoma in situ (DCIS), this impact was only observed at 10 years of follow-up. As observed in earlier analyses, the drug did not impact the incidence of ER-negative breast cancer, said Cuzick, but researchers are concerned about the fact that ER-negative cancers became more common with longer follow-up.

“I don’t think these cancers are caused by tamoxifen. My explanation, and this is still hypothetical, is that there are some cancers that would appear as ER-positive if untreated. Tamoxifen will hold them at bay for some years, but when they escape tamoxifen control, they escape as ER-negative tumors. This has been seen in the adjuvant treatment setting, and I think this is very likely to be the case here,” said Cuzick.

Additional IBIS-I Findings

The benefits of tamoxifen were greater for women who did not use HRT during the trial, and again, the effect was even greater in preventing ER-positive disease. Women who did not use HRT during their 5 years of treatment had a 45% reduction in the risk of developing ER-positive breast cancer; for noncurrent HRT users, the risk for all breast cancers was reduced by 38%.

“That was a significant difference. Women who did not use hormone replacement therapy have a much bigger benefit from tamoxifen,” said Cuzick.

Not surprisingly given tamoxifen’s adverse event profile, the incidence of endometrial cancer was higher in the tamoxifen arm versus controls (29 vs 20). However, the large increase in the incidence of non—melanoma skin cancer in the tamoxifen arm (116 vs 84) was unexpected, said Cuzick. “This raises the question as to whether there is any mechanism that tamoxifen might be causing these cancers, something important but which we don’t fully understand.”

In this study, tamoxifen continues to have no impact on breast cancer mortality, with no significant difference seen between the two groups, said Cuzick. There were 31 deaths in the tamoxifen arm versus 26 with placebo. Among women who took tamoxifen, there was a nonsignificant increase in all-cause mortality, but this was smaller than in the 8-year follow-up report, he added. Five deaths from endometrial cancer were reported, versus none in the control groups. Death from all cancers was higher in the tamoxifen arm (83 vs 78).

“After 20 years of follow-up, these results show a clear, long-standing benefit of 5 years of tamoxifen for preventing breast cancer,” Cuzick concluded.

And, since the average age of the participants who have survived thus far is 66 years, “there is a substantial amount of follow-up still to be done,” Cuzick said.

References

• Cuzick J, Sestak I, Cawthorn S, et al. Extended long-term follow up of the IBIS-I breast cancer prevention trial. Paper presented at: San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S3-07.
• Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial [published online December 11, 2014]. Lancet Oncol. http://dx.doi.org/10.1016/S1470-2045(14)71171-4.