Praise for global study, but concern for subset

We have known for some time that endocrine-responsive patients should probably receive an AI, but studies presented at SABCS provided some answers to our questions: Should we start with tamoxifen and then switch to an AI or is the best approach to initiate treatment with an AI from the start?

The meta-analysis by Dr. Ingle confirmed that AIs are better. While the meta-analysis did not show an improvement in survival in this cohort, differences might have emerged with a larger population. It is not necessary to demonstrate this; it is sufficient to have a drug that reduces recurrences above and beyond tamoxifen, and is safe. In the analysis of the switching strategy, the AI arm performed better as well, and a small but significant survival benefit was demonstrated.

Two other studies offered a preliminary look at the question of sequencing tamoxifen and AIs, versus giving AIs all the way, which is the issue we are now most interested in. The TEAM study will eventually give us some answers, but preliminary findings were based on just 2.75 years’ follow-up. At this point, exemestane and tamoxifen were similar in DFS; however, in the adjusted analysis of patients who actually received treatment with the assigned study drug, exemestane was associated with a significant reduction in recurrences.

The BIG 1-98 trial also showed a trend favoring letrozole over tamoxifen as initial therapy (statistical significance was affected by crossover), and showed that five years of letrozole was comparable to switching from tamoxifen to letrozole. Altogether, these data inform clinicians who are accustomed to prescribing tamoxifen for five years that switching to an AI after two to three years is better. There is an early suggestion that it may be better to start treatment with an AI, though these results are not yet significant. They seem equivalent statistically, but there is a subtle emerging trend for AIs to perform better.

The other question is tolerability, and the drugs have different side effect profiles. In clinical trials, discontinuation rates are about the same for each, but in clinical practice patients may discontinue one drug more often. What may be even more important than choice of endocrine therapy is compliance, which speaks to the need to carefully query patients regarding compliance and to individualize therapy based on side effects.