IBIS-II: Anastrozole and Tamoxifen Similar on Recurrence, but Toxicity Profiles Differ

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Breast cancer recurrence was similar whether postmenopausal women with ductal carcinoma in situ received anastrozole or tamoxifen for 5 years following local excision in the IBIS-II trial.

Jack Cuzick, PhD

Breast cancer recurrence was similar whether postmenopausal women with ductal carcinoma in situ (DCIS) received anastrozole or tamoxifen for 5 years following local excision in the IBIS-II trial.

Although adherence was nearly identical between the two treatments, the side effect profiles were distinctly different, said Jack Cuzick, PhD, at the 2015 San Antonio Breast Cancer Symposium. Women taking anastrozole had an increase in fracture and joint-related symptoms, whereas those taking tamoxifen had more vasomotor/gynecologic symptoms, except vaginal dryness, and an expected increase in thromboembolic events.

“We feel that anastrozole is now another agent that can be considered for ER-positive DCIS,” said Cuzick, professor and director of Wolfson Institute of Preventive Medicine, Queen Mary University of London. “For women who can’t take tamoxifen, for example because of prior deep vein thrombosis, it’s very attractive, but if there are concerns about fractures, then tamoxifen might be better.”

IBIS II was a study of 2980 postmenopausal women with locally excised ER-positive DCIS who were evenly randomized to1 mg anastrozole or 20 mg tamoxifen daily for 5 years. The study was conducted in 236 centers in 14 countries. The primary endpoint was all breast cancer recurrence, including DCIS, at a median follow-up of 7.2 years.

Women randomized to anastrozole had an 11% lower rate of recurrence of DCIS or invasive cancer than those randomized tamoxifen (6.6% vs. 7.4%), but the difference was not significant (P = .49).

On subgroup analysis, women in the anastrozole arm were found to be less likely to have HER2-negative invasive cancer recurrence (HR, 0.48; 95% CI, 0.26-0.84) and more likely to have HER2-positive invasive cancer recurrences (HR, 1.62; 95% CI 0.53-4.96). In a post hoc evaluation of recurrence of invasive ER-positive/HER2-negative cancers, “we saw a striking effect in that particular group of almost two thirds reduction of recurrence [with anastrozole],” Cuzick said.

Although the overall difference in efficacy was small, “we did see dramatic differences in the side effect profiles, in particular, other cancers, where, overall, there was not a significant difference, but the types of cancers were dramatically different,” said Cuzack.

There were 17 gynecologic cancers, including 11 endometrial cancers, in the tamoxifen arm and only one in the anastrozole arm. “That’s probably a combination of two effects,” he said. “We do know that tamoxifen increases endometrial cancer by two- to three-fold; there is emerging evidence that the anti-estrogenic properties of anastrozole actually reduce endometrial cancer.”

A somewhat newer finding was the increase in the incidence of ovarian cancer with tamoxifen compared with anastrozole (5 vs 0). The incidence of nonmelanoma skin cancers was reduced with anastrozole (odds ratio [OR]: 0.43, P = .04). The incidence of colorectal cancer was greater in the anastrozole arm (10 vs 5).

The OR for fracture was increased significantly with anastrozole (1.36; P = .03).

As observed previously, thromboembolic events were more common with tamoxifen compared with anastrozole (24 vs 7; P = .003).

The incidence of cardiovascular events was not significantly different between the two arms, but the anastrozole group compared with tamoxifen suffered more cerebrovascular accidents (13 vs 4; P = .025) and more transient ischemic attacks (13 vs 5; P = .05). An increased risk of cerebrovascular events and TIAs had not been seen previously with anastrozole, Cuzack indicated.

Sixty-four percent of patients in the anastrozole arm experienced musculoskeletal events compared with 54% of the tamoxifen arm (P < .001). Muscle spasm, however, was four times more likely with tamoxifen (106 vs 25; P <.001).

Vasomotor/gynecologic symptoms were much more common with tamoxifen compared with anastrozole (69.2% vs 60.7%: P <.001). Vaginal dryness, however, was more common with anastrozole (189 vs 159 events; P = .047).

Overall, side effects led to virtually identical adherence, at about 67% in each group.

At first glance, the finding from IBIS-II appears to contradict those from the NSABP B-35 trial, a similar study to IBIS-II that found a significant 27% reduction (P = .03) in recurrence with anastrazole compared with tamoxifen. In a meta-analysis of the two trials, a 21% relative reduction in recurrence favors anastrozole over tamoxifen, and the difference is significant (95% CI, 0.64-0.97), said Cuzack. “The similarities between the two trials are greater than the differences,” he told OncLive. “The only difference in design is that NSABP 35 required radiotherapy for everybody, and we left it as an option. We had about 70% getting radiotherapy. But we saw no differences in the treatment effects. Probably the truth is the meta-analysis, which is the effect is about a 20% recurrence reduction with anastrozole.”

The IBIS-II study was published simultaneously December 11 in the Lancet.

Cuzick J, Sestak I, Howell A, et al. Anastrozole versus tamoxifen for the prevention of loco-regional and contralateral recurrence in postmenopausal women with ductal carcinoma in-situ (IBIS-II DCIS). Presented at the 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S6-03.

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