CHICAGO – A second study shows that 10 years of adjuvant tamoxifen is superior to the standard five years in women with estrogen receptor-positive early breast cancer.
Among nearly 7,000 women randomized in the aTTom (Adjuvant Tamoxifen Treatment Offers More) study, extended tamoxifen significantly reduced the risk of recurrence from 32% to 28% in the 10 years or more after diagnosis (P = .003).
This translated into a borderline significant difference in breast cancer mortality, reducing it from 24% to 21% (P = .06), Richard Gray, M.Sc., reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.
Just 6 months ago, Prof. Gray reported that recurrences were down 25% and breast cancer deaths down 29% in years 10-14 after diagnosis in women on tamoxifen for 10 years in the companion ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial.
The benefits came at a cost, however. Extended exposure to tamoxifen in aTTom more than doubled the number of endometrial cancers (102 vs. 45 cases; rate ratio, 2.20; P less than .0001) and significantly increased the risk of dying from it (37 vs. 20 deaths; RR, 1.83; P = .02).
On a population basis, the benefits in reduced breast cancer mortality outweigh the risks, according to Prof. Gray, professor of medical statistics at the University of Oxford (U.K.).
Monitoring with ultrasound for endometrial changes could improve early detection and reduce the impact of this known toxicity, Dr. Hope S. Rugo, director of the breast oncology clinical trials program at the University of California, San Francisco, said in an interview. This risk is also known to vary considerably by age.
"The dramatic findings presented in the aTTom study today will clearly have a significant impact on clinical practice on Monday and are arguably some of the most important data for the treatment of women with early-stage, hormone receptor–positive breast cancer," she said.
Dr. Hope S. Rugo
The decision to continue tamoxifen beyond the recommended 5 years should be based on the extent of residual risk of recurrence, and must be balanced against tolerability and alternative options, Dr. Rugo said. Extended-duration tamoxifen is a particularly important option for women at risk for late relapse, who are not candidates for aromatase inhibitors because of menopausal status or tolerability.
Great option for premenopausal women
For women who remain premenopausal on tamoxifen, "extended tamoxifen is a great option where there has been no prior standard," said Dr. Ann H. Partridge, who founded the young women with breast cancer program at Boston’s Dana-Farber Cancer Institute and who was invited to discuss the study during the plenary session. These women have a higher risk of disease, and therefore potentially have the greatest risk reduction and lowest risk of serious toxicity, including an almost negligible risk of endometrial cancer.
She went on to say that the personal cost, however, in this population may be the greatest, referring to fertility. Interestingly, ATLAS also reported a significant increase in pulmonary embolism, but it was coupled with a decrease in ischemic heart disease (Lancet 2012 ;805-16 [doi:10.1016/s0140-6736(12)61963-1]). Cardiovascular events have not been reported for aTTOM.
Adherence, which is a challenge in the real world, quality of life, and symptoms such as vasomotor symptoms, alterations in mood, sexual functioning, and musculoskeletal problems also must be considered, Dr. Partridge said.
"We all know that minor side effects can become deeply troubling over time in this setting," she said.
ASCO spokesperson Dr. Sylvia Adams, a breast cancer specialist at New York University Langone Medical Center said in a statement that the results are practice changing for premenopausal women with hormone receptor–positive breast cancer, and especially relevant for women at high risk of recurrence.
A retrospective analysis of combined data from aTTom, ATLAS, and three smaller trials is planned to determine whether certain subgroups of women are most likely to benefit from longer tamoxifen treatment, according to Prof. Gray.
Tamoxifen compliance was about 75%
The aTTom study randomly assigned 6,953 women with estrogen receptor–positive (40%) or ER-untested invasive breast cancer (80% estimated to be ER+) who had been taking tamoxifen for 5 years to continue tamoxifen for another 5 years or stop immediately. Tamoxifen compliance in the continuation arm was about 75%.
Breast cancer recurred in 580 women allocated to continue tamoxifen and 672 randomized to stop (RR, 0.85; P = .003). There was no benefit in years 5-6 after diagnosis (odds ratio, 1.17), but began to emerge later on, in years 7-9 (OR, 0.99), years 10-14 (OR, 0.79) and 15 years or later (0.75), Prof. Gray said.