Six Years of Anastrozole After Adjuvant Tamoxifen Not Better Than 3 Years

Article

First results from the phase III DATA study show no advantage to extending anastrozole therapy from 3 years to 6 for the primary endpoint of 5-year adapted disease-free survival.

Vivianne Tjan-Heijnen, MD, PhD

The use of extended adjuvant aromatase inhibitor (AI) therapy after 5 years of sequential endocrine therapy in all postmenopausal women with hormone receptor-positive early breast cancer is not supported by the results of a phase III randomized study. First results from the DATA study show no advantage to extended anastrozole on the primary endpoint of 5-year adapted disease-free survival (DFS), reported Vivianne Tjan-Heijnen, MD, PhD, at the 2016 San Antonio Breast Cancer Symposium.

In a subgroup analysis that was not prespecified, extended anastrozole did show a significant effect on adapted DFS in women who were estrogen receptor (ER)-positive and progesterone receptor (PR)-positive, HER2-negative, node-negative, and who received neoadjuvant chemotherapy. Adapted DFS was defined as the DFS starting as of 3 years after randomization. “This was an unplanned analysis, but I think this is very useful for daily clinical practice,” said Tjan-Heijnen, professor in the division of medical oncology in the department of Internal Medicine at Maastricht University Medical Center, Maastricht, The Netherlands.

In the overall analysis, 5-year adapted DFS was 83.1% in the group randomized to 6 years of anastrozole, compared with 79.4% in those randomized to only 3 years of anastrozole after 2 to 3 years of adjuvant tamoxifen, for a hazard ratio of 0.79, which was not significant (P = .07).

In DATA, 1,912 women with M0 breast cancer who were postmenopausal and ER- and/or PR-positive with no sign of disease recurrence and who received 2 to 3 years of adjuvant tamoxifen were randomized to 3 years (n = 833) or 6 years (n = 827) of 1 mg anastrozole per day. Minimum follow-up was at least 6 years after randomization. Patients were stratified by nodal status, RR/PR status, HER2 status, and duration of tamoxifen.

“It’s very important to know that for the first 3 years after randomization, all patients received the same treatment, so we decided to have the adaptive DFS as the primary endpoint…which [means] that we account for events starting beyond a year after randomization,” said Tjan-Heijnen.

The adapted DFS endpoint events included breast cancer recurrence (local, regional, or distant); a second primary cancer, including contralateral breast cancer and cancers other than basal-cell or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix; and death from any cause.

Most patients had larger tumors or had nodal positive disease. About 54% in each arm had pathologic stage II tumors, pathologic stage III/IV tumors, and about two thirds in each arm had pathologic nodal status of stage I or stage II/III. Three fourths of the patients had both ER-positive and ER-positive disease, and 90% had HER2-negative disease. “So it seems to be a hormone-sensitive population,” Tjan-Heijnen said.

Although the 5-year adapted DFS of 83.1% in the 6-year anastrozole group, and 79.4% in the 3-year group did not achieve significance, there were several subgroups that did show significant benefit to extended anastrozole. The HR in favor of 6 years of anastrozole for patients with larger (pathologic tumor stage II or pathologic tumor stage III/IV) tumors was 0.72 (95% CI, 0.51- 0.98) and the difference in adapted 5-year DFS was about 6%, “which I think is also clinically meaningful,” she said.

The same advantage to 6 years of anastrozole was observed in the node-positive group (HR 0.72; 95% CI, 0.52-1.00), patients with both ER- and PR-positive disease (HR 0.70; 95% CI, 0.53-0.92), patients with HER2-negative status (HR 0.79; 95% CI, 0.61-1.03), and those who received neoadjuvant chemotherapy (HR 0.68; 85% CI, 0.49-0.92).

The 5-year adapted DFS for patients who were ER-positive, PR-positive, HER2-negative, node-negative and who received neoadjuvant chemotherapy was 86.0% in those randomized to 6 years compared to 75.9% in those randomized to 3 years of anastrozole (HR 0.58; P = .01).

There was no difference in 5-year adapted overall survival: 90.8% compared to 90.4% in the 6-year and 3-year groups, respectively, but the median adapted follow-up was only 4.1 years at the time of presentation.

The 6-year anastrozole group had a slightly higher rate of predefined adverse events compared to the 3-year group, such as arthralgia/myalgia (57.6% vs 51.9%), bone fracture (9.8% vs 7.4%), osteopenia/osteoporosis (20.9% vs 16.5%), and cardiovascular events including arrhythmia (13.4% vs 12.9%).

About 80% of patients in the 3-year arm were able to complete treatment, compared with 60% in the 6-year arm. Occurrence of adverse events was the reason for early termination in 23% of the 6-year am and 14.4% in the 3-year arm.

A follow-up analysis will be performed when all patients have reached a minimum adapted follow-up of 9 years.

Tjan-Heijnen VC, Van Hellemond IE, Peer PG, et al. First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10; San Antonio, TX. Abstract S1-03.

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View more from the 2016 San Antonio Breast Cancer Symposium

The rationale for DATA at the time of its design in 2006 is the elevated risk of breast cancer recurrence (2% to 4% per year for up to 15 years), despite the use of 5 years of endocrine therapy. Extended use of an AI after 5 years of adjuvant tamoxifen led to an improvement in DFS in the MA17, NSABP-833, and ABCSG6a clinical trials, but no studies have examined the use of extended AI in patents with 5 years of sequential endocrine therapy (tamoxifen followed by an AI).

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