Virtual Meeting Clip
In women with early-stage breast cancer, extending the duration of adjuvant tamoxifen therapy from 5 to 10 years reduces the risk of recurrence and breast cancer mortality, according to updated results of the aTTom trial presented by Richard Gray, MD, MSc, of the University of Oxford, United Kingdom, in Sunday’s Plenary Session (Abstract 5).
Compared with 5 years of tamoxifen, 10 years of tamoxifen was associated with a significant 15% reduction in the risk of recurrence (relative risk [RR] 0.85, 95% CI [0.76, 0.95]; p = 0.003) and a significant 25% reduction in the risk of breast cancer mortality starting at year 10 (RR 0.75, 95% CI [0.63, 0.90]; p = 0.007) among the 6,953 women enrolled in the trial. These findings aligned closely with those from the recently published ATLAS trial.
A pooled analysis of the 17,477 patients enrolled in aTTom and ATLAS showed a 9% reduction in the risk of death after patients received 10 versus 5 years of tamoxifen for the entire follow-up period (RR 0.91, 95% CI [0.84, 0.97]; p = 0.008); the relative risk reduction increased to 16% starting at year 10 (RR 0.84, 95% CI [0.77, 0.93]; p = 0.0007).
Extending the duration of tamoxifen had little effect on non–breast cancer mortality. Dr. Gray noted that there was an increased risk of endometrial cancer with the use of extended tamoxifen, although the absolute hazard was low at 0.5%. Otherwise, there were no safety concerns with the extended use of tamoxifen as reported.
Discussant Ann H. Partridge, MD, MPH, of the Dana-Farber Cancer Institute, noted that late relapses have remained a major issue in hormone-positive breast cancer, even with the introduction of more effective early therapies. Extended tamoxifen does appear to reduce the risk of these late relapses. In the aTTom and ATLAS trials, extended tamoxifen primarily reduced the risk of recurrences starting after year 7.
It had previously been established that a 5-year regimen of adjuvant tamoxifen was associated with a significant reduction in the risk of recurrence and a 34% reduction in late breast cancer mortality. However, the relative benefit of longer durations of tamoxifen was previously unclear due to inadequate follow-up and insufficient numbers of patients.
Together, the results of the aTTom and ATLAS trials provide what Dr. Gray called “proof beyond reasonable doubt” that continuing tamoxifen beyond 5 years reduces the risk of late recurrence and reduces breast cancer mortality. In fact, the benefit of tamoxifen in the aTTom trial may be even greater than reported, as 60% of enrolled patients had an unknown estrogen receptor (ER) status. An estimated 15% of patients likely had ER-negative disease and did not benefit from tamoxifen.
However, there are many factors to consider when assessing the potential efficacy benefit of adjuvant therapy for individual patients, including their tumor burden, tumor biology, comorbidities, and age. There are also risks to consider, such as the potential for serious adverse events, like endometrial cancer, or less severe symptoms that can still adversely affect quality of life. “Minor side effects can become deeply troubling over time,” Dr. Partridge noted.
Another issue to consider is the role of aromatase inhibitor therapy. Dr. Partridge said that the optimal duration of extended aromatase inhibitor therapy remains an open question. Extended endocrine therapy options are largely driven by menopausal status and prior treatment.
Dr. Partridge suggested that most postmenopausal women should consider taking an aromatase inhibitor for the first 5 years. Women who have completed 5 years of an aromatase inhibitor could begin tamoxifen, and those who initially received tamoxifen instead of an aromatase inhibitor could continue tamoxifen.
For women who develop amenorrhea after 5 years of adjuvant tamoxifen, Dr. Partridge noted that switching to an aromatase inhibitor has previously demonstrated a significant benefit in this subgroup of patients and is likely an appropriate approach. If ovarian function resumed or continued, continuing tamoxifen would be an alternative.
The third category of women—those who remain premenopausal after 5 years of tamoxifen—may gain the greatest benefit from extended tamoxifen, noted Dr. Partridge, as these women tend to have higher-risk disease.
However, the absolute benefit with extended tamoxifen must be weighed against the feasibility of a 10-year regimen, with its associated effects on quality of life, particularly for younger patients. Effects on fertility and family planning will likely be a major concern for many younger women.
Adherence will likely also be a concern. Already, adherence to adjuvant tamoxifen is known to decrease in the first 4 years of therapy. It will likely continue to decline as therapy is extended beyond 5 years.
“For some women,” concluded Dr. Partridge, “these are very difficult decisions. We need ways to better support our patients to make these decisions not only at diagnosis, but also in long-term survivorship.”