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	New Hormonal Therapy - the Aromatase Inhibitors Debu Tripathy, MD

Manipulating the function of hormones, particularly estrogen has long been a useful tool in treating breast cancer. In 1896, Sir George Beatson published the first report on temporary remissions of advanced breast cancer with oophorectomy, or removal of the ovaries. In the 70's and 80's, the drug tamoxifen, which has anti-estrogenic effects on breast cells and on breast cancer cells, was shown to also be effective in breast cancer and was also shown to lower the risk of recurrence after surgery for early stage breast cancer. In postmenopausal women, the ovaries no longer makes estrogen, and the body's main source of estrogen is the conversion of androgens, which are produced primarily in the adrenal glands. The enzyme that is responsible for this conversion is aromatase, made primarily in fat and other tissue, especially in the breast. New drugs that can inhibit this enzyme have been shown to be as effective or even more effective in advanced breast cancer in postmenopausal women whose tumors make either the estrogen or progesterone receptors. Still, this treatment is not curative in advanced breast cancer, but many studies were then started to test aromatase inhibitors in early stage breast cancer in hopes that it could lower recurrence and mortality in early stage breast cancer.

The first such study to be reported was a comparison of the aromatase inhibitor anastrozole (trade name Arimidex) to tamoxifen or to a combination of the two drugs. Early results of this trial were reported in December, 2001 at the San Antonio Breast Cancer Symposium. In this trial, anatrozole use led to a lower overall recurrence of 10% compared to 12% with tamoxifen or the combination. This included distant metastases (such as to the bone, lung and liver), local recurrences (in the same breast or under the arm) and new breast cancers in the other breast all added together. Also, there were fewer vaginal symptoms and hot flashes with anastrozole, but more muscle and joint pain and slightly more bone fractures.

As with any new finding from a clinical trial, it is difficult to know in whom to apply this new therapy. For women already on tamoxifen, this trial is not helpful in knowing if changing over to anastrozole would be better - therefore, continuing on tamoxifen is recommended unless intolerable or dangerous side effects from tamoxifen develop. There are ongoing trials that will anwer the questions of 2-3 years of tamoxifen followed by an aromatase inhibitor. For newly diagnosed breast cancer, using anastrozole instead of tamoxifen may be more useful in women whose risk of recurrence is higher than average, such as those who had positive lymph nodes. Since there may be a higher risk of osteoporosis due to depression of estrogen levels, as was evident in the slighly higher bone fracture rate in women on anastrozole, there needs to be caution in how to apply these data. Oncologists have several options to discuss with postmenopausal patients newly diagnosed with estrogen or progesterone receptor-positive breast cancer:

1. Wait until more data is in from the trials, especially long term side effects, before using anastrozole instead of tamoxifen
2. Use anastrozole and check bone mineral density periodically
3. Use anastrozole selectively in those with higher risk breast cancer

With longer term follow up and critical discussion from the scientific, clinical and patient advocacy communities, a firmer consensus will be reached. Also, there will be information from trials testing aromatase inhibitors following 5 years of tamoxifen. The other aromatase inhibitors, letrozole (Femara) and exemestane (Aromasin) are also being tested in early stage breast cancer. Finally, there is interest and studies already beginning to assess the role of these drugs for prevention, similar to the studies that examined tamoxifen and showed a lowering of the risk of new breast cancers in healthy women at higher risk.

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