Adapted from the NCI Cancer Bulletin.
Aromatase inhibitors (AIs), which interfere with the body’s ability to produce the hormone estrogen, are rapidly changing the standard of treatment for breast cancer. Researchers have now taken up the challenge of learning how and when to best use these drugs to reduce recurrence for women with hormone-receptor-positive breast cancer.
Two approaches dominate the development of hormone-based treatments for breast cancer. One approach focuses on preventing estrogen from binding to its receptor and activating cell-signaling pathways that accelerate tumor growth. This strategy led to the development of the drug tamoxifen (Nolvadex®), which belongs to a class of drug called selective estrogen-receptor modulators (SERMs).
Since its approval by the U.S. Food and Drug Administration (FDA) for the treatment of hormone-receptor-positive breast cancer in 1977, tamoxifen has become a mainstay of therapy. However, many women develop resistance to the drug over time, leading to cancer recurrence. In addition, because tamoxifen binds directly to the estrogen receptor, it can sometimes activate the signaling pathways it was designed to block.
“We knew that tamoxifen was a partial agonist - a weak estrogen,” explains Dr. Angela Brodie, professor of pharmacology and experimental therapeutics at the University of Maryland, who has worked on the development of AIs for more than 35 years. “So we thought it might not be optimally effective on tumors…and that it could cause side effects. In fact, it does increase the risk of stroke and endometrial cancer.”
A Different Mechanism
AIs take a different approach to hormone therapy - they prevent the bodies of postmenopausal women from producing estrogen rather than blocking its activity. AIs accomplish this by interfering with the enzyme aromatase, which catalyzes the final step in the synthesis of estrogen from its steroid precursors.
Two different types of AIs are in use in the clinic today. Steroidal AIs, such as exemestane (Aromasin®), bind permanently to aromatase. Nonsteroidal AIs, such as anastrozole (Arimidex®) and letrozole (Femara®), bind reversibly to aromatase and compete with the precursors of estrogen for the enzyme.
Both steroidal and nonsteroidal AIs have been shown in large-scale clinical trials to be superior to tamoxifen in extending survival in women with metastatic disease, and in preventing recurrence when used as primary adjuvant therapy. In addition, treatment with an AI after a full course of tamoxifen continues to improve recurrence-free survival, compared with cessation of hormone therapy.
The challenge remains to determine the best schedule for up-front AI treatment. Studies have shown that five years of an AI alone are more effective at preventing recurrence than five years of tamoxifen alone, and that switching women already taking tamoxifen to an AI after two or three years prevents more recurrences than continuing tamoxifen for a full five years. However, it is not clear yet if sequencing tamoxifen and an AI in women who have not yet been treated with hormone therapy confers a benefit over five years of an AI alone.
Results from trials where women have switched from tamoxifen to an AI cannot be applied to women who have not yet received any hormone therapy. “It’s important to understand that while the treatment is the same, the patients are not the same,” says Dr. Beat Thürlimann, president of the International Breast Cancer Study Group. “If you have already taken two or three years of tamoxifen and survived disease-free, you belong to a favorable prognostic group.”
“When you make a decision about treatment after surgery, you don’t know if you belong to this favorable category or not,” Dr. Thürlimann continues. “With sequencing trials, you’re looking at a broader patient population.” The Breast International Group trial BIG 1-98 is comparing sequencing of tamoxifen and letrozole to either tamoxifen or letrozole alone after surgery for early-stage breast cancer. The preliminary results from this part of the trial, expected in 2008, will provide valuable information on sequencing hormone therapies in women who have not yet received hormone therapy.
Other questions remain as AIs move to a more prominent position in breast cancer treatment. AIs have side effects of their own, most importantly loss of bone density, which can be especially hazardous for women already at risk for osteoporosis. Therefore, tamoxifen may still provide a more favorable risk/benefit ratio for some subgroups of women, which need to be identified.
In addition, the role of AIs in premenopausal patients remains to be defined. While AIs alone may not have an effect in premenopausal women, because the ovaries can override the inhibition by producing a large amount of aromatase, clinical trials are now testing AIs in premenopausal women in combination with drugs such as goserelin, which suppress ovarian function.
Because AIs have also reduced the occurrence of contralateral breast cancer in several studies, researchers are now testing the compounds as chemopreventive agents. Two large scale trials have begun testing exemestane and anastrozole in women at high risk for developing breast cancer. Although tamoxifen was approved in 1998 for the prevention of breast cancer in high-risk women, fewer women than expected have chosen to take it.
“One reason [healthy] women don’t want to take tamoxifen is fear of side effects,” explains Dr. Jennifer Eng-Wong, a clinical oncologist in the National Cancer Institute's Center for Cancer Research. If AIs prove to have both efficacy in preventing breast cancer occurrence and acceptable side effects, they and the new generation of SERMs such as raloxifene will provide women at high risk with additional options to help prevent the disease.