Aromatase Inhibitors: Updates from Major Trials

By Christin Melton
Published: Thursday, May 20, 2010
In 2009, we covered several long-term studies investigating the use of aromatase inhibitors (AIs) alone or sequenced with tamoxifen. This includes the Intergroup Exemestane Study (IES), the TEAM trial, and the BIG 1-98 trial, all of which presented new or updated data at the 2009 SABCS in December.

Update from Intergroup Exemestane Study (IES)

Postmenopausal women with hormone receptor–positive (HR+) breast cancer who switch to the AI exemestane (Aromasin) after taking tamoxifen for 2 to 3 years have superior outcomes compared with women who stay on tamoxifen for 5 years, according to an updated analysis of IES . “These women [who switched to exemestane] have real improvements that persist at least 9 years, which is 11 years from the time of diagnosis,” stated Judith Bliss, MD, The Institute of Cancer Research, Sutton, United Kingdom. “They have a modest but persistent improvement in overall survival [OS ] and a modest reduction in distant recurrence,” she added.

The study included 4724 patients recruited from 366 sites in 37 countries from 1998 to 2003. Slightly less than 50% of patients (44.2%) had nodepositive disease; one-third had received adjuvant chemotherapy. The mean age of the women was 64 years. The analysis presented at SABCS was completed after 91 months of follow-up.

The 4599 women with estrogen receptor–positive and estrogen receptor–unknown status who switched to exemestane had superior OS compared with women who had 5 years of tamoxifen therapy. The absolute difference in OS favoring exemestane was 1.4% at 5 years and 2.4% at 8 years (P = .04). Diseasefree survival (DFS ) was highly statistically significant in favor of exemestane: at 5 years, the absolute difference in DFS was 3%, and at 8 years, it was 4.4% (P = .0009). The annual DFS event rate (including breast cancer recurrence, new primary cancer, or death) was 4% per year. “There is no evidence that the event rate diminishes more than 10 years from diagnosis,” Bliss told the audience.

The risk for local recurrence was .5% per year and the risk of distant recurrence was 2.5% per year. Inter-current deaths are rare, she explained, and as they become more common over time, they can blunt the difference between treatment groups.

“Breast cancer–free survival is a more sensitive estimate of differences,” Bliss said. At 5 years, the absolute difference in breast cancer–free survival favoring exemestane was 2.8%, and at 8 years, it was 4.1% (P = .001). While on treatment, the women who switched to exemestane had a 40% reduction in the risk of a breast cancer event. In the post-treatment follow-up phase, the risk of a breast cancer event was reduced 16% for exemestane users.

All subgroup analyses for the breast cancer–free survival endpoint favored exemestane. Looking at time to distant recurrence, which is strongly associated with breast cancer mortality, exemestane was significantly superior to tamoxifen (P = .01). There were 319 distant recurrences in the group that switched to exemestane versus 370 in the tamoxifen group.

In an exploratory analysis of sites of first reported distant recurrence, exemestane appeared to correlate with a reduction in the risk of bone metastases. Bone-only metastases occurred in 75 patients in the exemestane group compared with 109 in the tamoxifen group. In addition, the exemestane group had 147 distant recurrences that involved bone versus 192 in the tamoxifen group. Bliss said this purported benefit of exemestane was “wildly speculative” and hypothesis generating.

Another surprising finding was an increase in the number of nonbreast primary cancers in the tamoxifen group compared with the exemestane cohort: 159 versus 106, respectively. “Exemestane has an unexpected lower number of reported nonbreast second primary cancers,” Bliss noted. Looking at age at randomization, the evidence for nonbreast primary cancers suggests that these are true second primary cancers and not recurrences, she added. T he findings regarding the metastases involving the bone and the smaller number of nonbreast second primary cancers require further validation, Bliss said.

TEAM trial reports final data

One of the most provocative questions regarding endocrine therapy for HR+ breast cancer is which strategy is superior: a sequential strategy that involves giving tamoxifen up front followed by an AI for a total of 5 years or giving only an AI for 5 years. The final results from the TEAM trial failed to resolve this issue; with both strategies in a dead heat as far as DFS, time to recurrence (TTR), and OS endpoints.

“TEAM was the first trial prospectively powered to detect superiority of 5 years of an AI [in this case, exemestane] versus sequential therapy with tamoxifen followed by AI. This large study showed that either strategy is an appropriate therapeutic option. Translational research may be able to identify subsets of patients who can benefit from each of these strategies,” said Daniel Rea, MD, University of Birmingham, United Kingdom.

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