At this year’s San Antonio Breast Cancer Symposium, we see the first long-term results of a trial called ATLAS. In this clinical trial, between 6,000 and 7,000 women were randomly assigned to take the drug tamoxifen for the standard 5 years or for 10 years. What this study shows is a benefit for those patients who took it for 10 years, and the benefit extends beyond the 10 years of treatment out to the 14th year of follow-up.

This study looked at several endpoints. It shows a reduction in the risk of distant metastatic disease, which is — after all — the fatal complication of breast cancer. It also shows a reduction in fatalities. It shows an improvement in OS. Very reassuringly, it does not show any increase in deaths from other causes. This is something that everybody has been worried about with long-term use of tamoxifen, especially with regard to cancer of the uterus.

The group of patients who are completely reliant on tamoxifen these days are those who are premenopausal at diagnosis. Whether or not they receive chemotherapy, we routinely give them 5 years of tamoxifen. For those patients who are in an age range where they’d be expected to be premenopausal — or who clearly are premenopausal — even after 5 years of tamoxifen, treatment is over. The interesting thing about this study is, if it’s true that 10 years of tamoxifen really is better than 5, it has an immediate impact on them in terms of reducing the risk of recurrence. But it has a continuing or carryover effect into the third 5 years — the second half-decade — and probably beyond. Because those patients are young, this in fact has a tremendous potential impact on their long-term outcomes because they’re not yet old enough to have significant competing causes of death.

So it’s possible for the small but important subset of young patients who receive tamoxifen, this could make a difference in their long-term outcomes.

Right now, there is a difference between premenopausal and postmenopausal women. In premenopausal women, tamoxifen is the primary hormonal therapy. For those patients, aromatase inhibitors don't work. In postmenopausal, aromatase inhibitors have been superior to tamoxifen. The results of ATLAS are most relevant to younger women. For women who are approaching 5 years of therapy, up to this point we have been telling them they are going to be stopping tamoxifen. Now we can tell them that 10 years is superior to 5 years. I'm going to be comfortable doing that.

Endometrial cancer risk was a risk, but it is very low in premenopausal women. It is so low that it is hard to tell if the risk is increased in premenopausal women.

There will be a major immediate impact to this trial.

One thing that is profoundly important about it is that with the biology of this disease, some women are fated to have late relapses but there are some drugs that block this late relapse. Now we can treat these women with hormonal therapy beyond 5 years and have benefit.

It is always important to weigh risks and benefits. High-risk women with positive nodes and bigger tumors will definitely be candidates for longer therapy. Another patient with a low risk may rationally decide that she doesn't want to take tamoxifen beyond 5 years. If there are other adverse events associated, they may not want to induce these risks.

The study by Davies and colleagues challenges the current standard practice of limiting duration of tamoxifen treatment to 5 years in the adjuvant treatment of breast cancer. In this large randomized study, women with ER-positive early-stage breast cancer who had completed 5 years of adjuvant tamoxifen and remained free of recurrence were randomly assigned to continuation of tamoxifen for an additional 5 years or discontinuation of therapy. The group that received a total of 10 years of tamoxifen experienced a reduction in breast cancer recurrence, breast cancer mortality and risk of death from any cause compared with those who had received the standard 5 years of therapy alone.

Interestingly, the differences between the two groups did not emerge until more than 5 years from randomization, such that the majority of the added benefit occurred after the 5 additional years of treatment were complete. Although there was some increase in toxicity — including a higher risk of uterine cancer with longer duration of treatment — that was more than offset by the advantage in breast cancer mortality reduction. In addition, the increase in uterine cancer risk was not observed in premenopausal women for whom these findings are most relevant, given that postmenopausal women are likely to receive aromatase inhibitors in either the adjuvant or extended adjuvant setting.