Edited comments by Professor Dixon

Background of ATAC Trial: Anastrozole vs Tamoxifen vs Combination

I’ve been convinced for quite some time that the aromatase inhibitors would be superior to tamoxifen in the adjuvant setting, because in the neoadjuvant situation we noticed that the rapidity and extent of responses to aromatase inhibitors were greater than with tamoxifen. So, I’ve had a feeling that these neoadjuvant findings would result in benefits in the adjuvant setting, which was proven in the early data from ATAC.

Aromatase inhibitors cut off proliferation in the tumor within days of starting treatment. This can have a major biological effect on the tumor even between the time of diagnosis and surgery. We’ve seen tumor shrinkage within a few weeks of starting an aromotase inhibitor. In the past, we’ve rushed to get patients to the operating room, and this does disrupt their lives.

Now we know that they can start anastrozole and cut down proliferation within the tumor and elsewhere in the body. When a woman takes that first tablet, she’s on systemic treatment for breast cancer, and whether she has surgery in two days, two weeks or even two months is unlikely to have any impact on long-term outcome.

Toxicity profile of anastrozole versus tamoxifen

Tamoxifen has many more side effects than we sometimes appreciate. Anastrozole was superior to tamoxifen in most of the quality of life endpoints; therefore, it is not only more effective, but also it causes fewer side effects.

The biggest long-term concerns about anastrozole are bone density and lipids. The available lipid data look reassuring. I don’t see bone loss as a major long-term worry, because not only can we monitor this, but I also think that in the future we will be giving an aromatase inhibitor with a bisphosphonate. The other side effect we have observed with aromatase inhibitors is musculoskeletal symptoms — arthralgias, which are usually very mild but occasionally can be fairly severe.

ATAC showed a number of significant benefits to anastrozole versus tamoxifen. Vasomotor symptoms can be a problem in women taking tamoxifen, and the reduction in these symptoms with anastrozole was a pleasant surprise. Anastrozole also was associated with fewer thrombotic events and endometrial cancers. These are significant advantages over tamoxifen, in that these conditions can actually cause death.

Finally, it has always mystified clinicians that randomized trials of tamoxifen have not revealed weight gain, despite a large percentage of patients saying that it is associated with weight gain. Anastrozole caused less weight gain than tamoxifen in ATAC. This backs up the clinical impression that despite the trials, tamoxifen does affect weight.

We must attempt to prolong life, but we must also prolong good quality of life. We’ve now got another option in anastrozole.

Other aromatase inhibitors as adjuvant therapy

There are only adjuvant data for anastrozole and at the moment that is the drug we should use. All the aromatase inhibitors are slightly different, and there are slightly different effects on circulating estrogen levels. So, unless or until we obtain some data comparing the different drugs, then you’ve got to use the drug in this setting that has been tested, namely anastrozole. And of course, these agents currently are only for use in postmenopausal women.

Anastrozole in chemoprevention trials

The number of second breast cancers in the ATAC trial was significantly reduced with anastrozole, even beyond the nearly 50% reduction seen with tamoxifen. This is not surprising, because we know that estrogen is a carcinogen, which promotes the development of cancers. When you reduce estrogen, cells have less drive to proliferate and are much less likely to undergo carcinogenesis.

The next prevention study in the United Kingdom will compare placebo to tamoxifen to anastrozole in high-risk women. From the ATAC data we’ve seen already, we expect that anastrozole will dramatically decrease the number of breast cancers and should be superior to tamoxifen in the prevention setting.

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