For postmenopausal women with breast cancer, there are multiple options for hormonal therapy to prevent recurrence. Below is a summary of the published data, as they relate to CYP2D6 metabolization.

Tamoxifen for Hormone-Positive Postmenopausal Breast Cancer
Adjuvant Studies Comparing Tamoxifen to AIs for Postmenopausal Women
Conclusion from Adjuvant AI Studies
Tamoxifen and AI Toxicity Profiles

Tamoxifen for Hormone-Positive Postmenopausal Breast Cancer

Until recently, tamoxifen was the standard of care for the hormonal treatment of breast cancer. Tamoxifen is a selective estrogen receptor modulator (SERM) that works by binding to the estrogen receptor, preventing estrogen from binding and stimulating cellular processes such as growth and metastasis. The Early Breast Cancer Trialists Collaborative (EBCTCG) performed a meta-analysis of over 37,000 women treated for breast cancer enrolled in large cooperative group trials and found a 47% reduction in disease-free survival and a 26% decline in mortality for women taking tamoxifen versus those who did not.[1] From these studies it was also determined that the optimal duration of tamoxifen was 5 years; both shorter and longer durations were not as efficacious.

Adjuvant Studies Comparing Tamoxifen to AIs for Postmenopausal Women

More recent research has compared tamoxifen to aromatase inhibitors (AIs) as adjuvant hormonal treatment for postmenopausal women. AIs work by blocking the enzyme aromatase, which is responsible for converting androgen to estrogen, the final step in estrogen synthesis. Unlike tamoxifen, AIs block estrogen production outside the ovary and therefore inhibit circulating estrogen from stimulating hormone-positive tumor cells as well as stimulating stromal cells that contribute to tumor growth and metastasis. Because they do not affect estrogen production from within the ovary, AIs are not recommended for premenopausal women, for whom over 90% of estrogen is produced in the ovary. Because the ovaries still produce hormones, AIs may produce an estrogen surge if given to premenopausal women. Two types of AIs exist, steroidal (exemestane, Aromasin^tm) and nonsteroidal (anastrozole, Arimidex^tm and letrozole, Femara^tm). Steroidal inhibitors are irreversible and nonsteroidals are reversible.

There are at least 10 ongoing or completed clinical trials evaluating the use of AIs in the postmenopausal setting and several ongoing studies evaluating the use of AIs plus OS in the premenopausal setting. The first published study, Arimidex, Tamoxifen, Alone or in Combination Trial (ATAC) evaluated over 9000 women who were randomized to receive 5 years of tamoxifen, 5 years of anastrozole, or 5 years of both. The results were published in 2002 after a median follow-up of 4 years. The use of anastrozole led to a significant increase in disease-free survival (p=0.03, HR=0.86) and TTR (p=0.015, HR=0.83) over tamoxifen but as of today, no benefit in overall survival has been demonstrated.[2] Patients taking anastrozole had a higher incidence of fractures (7.1% vs. 4.4%, p<0.001) compared to patients taking tamoxifen.

The Intergroup Exemestane Study (IES) evaluated the benefit of 2-3 years of exemestane after 2-3 years of tamoxifen versus 5 years of tamoxifen in 4700 postmenopausal women.[3] After a median follow-up of 31 months, exemestane showed a significant 4.7% absolute benefit in DFS (p<0.001, HR=0.68) and a significant benefit in OS in patients who were estrogen receptor-positive (p=0.005, HR=0.83). There was a higher frequency of osteoporosis and arthralgias in the exemestane group compared with tamoxifen (7.4% vs. 5.7% and 5.4% vs. 3.6% for exemestane and tamoxifen, respectively). There was no significant increase in fractures. In both ATAC and IES, rates of endometrial cancer, strokes, and blood clots were higher in patients taking tamoxifen.

Several studies have addressed or are currently addressing whether the use of an AI after 5 years of tamoxifen is beneficial. The MA-17 study addressed this question evaluating the use of letrozole after 5 years of tamoxifen therapy.[4] The use of letrozole demonstrated a superior DFS (93% vs. 87%) at 2.4 years, causing the study to close early to allow the women on placebo to take letrozole. Overall survival to date has not been shown to be statistically different for the 2 arms. Women on the study who completed 5 years of letrozole are now being offered to be re-randomized to 5 more years of letrozole versus placebo in a continuation arm of the study. Compared with placebo, letrozole was associated with increased rates of strokes and deep venous thrombosis. The ARNO study reported at ASCO in 2006 demonstrated both a disease-free survival (p=0.049, HR 0.66 (0.44, 1.00) and overall survival (p=0.045, HR-0.53 (0.28, 0.99) benefit after a median follow-up of 30.1 months for switching to anastrozole for an additional 3 years after 2 years of tamoxifen compared to completing 5 years of tamoxifen.[5]

The BIGFEMTA trial is an ongoing, four-arm study evaluating 5 years of letrozole versus 5 years of tamoxifen versus 2-3 years of tamoxifen followed by letrozole versus 2-3 years of initial letrozole therapy followed by tamoxifen for total treatment duration of 5 years. This study will address whether 5 years of an AI is superior to sequential therapy with tamoxifen and an AI for postmenopausal women.

Conclusion from Adjuvant AI Studies

These collective data indicate that standard of care for postmenopausal women is either 5 years of an AI or 2-5 years of tamoxifen followed by 2-5 years of an AI. A recent Markov modeling analysis using existing data has shown that the sequential use of AIs after 2-3 years of tamoxifen therapy provides a relative risk reduction of 6% compared to 5 years of an AI, suggesting that sequential therapy may be the optimal treatment for hormone-positive postmenopausal women.[6] Results from the ongoing AI studies will provide data in the coming years as to whether 5 years of an AI is equivalent to sequential treatment with tamoxifen and an AI and whether more than 5 years of adjuvant hormonal therapy provides added benefit.

Tamoxifen and AI Toxicity Profiles

Tamoxifen and AIs differ in toxicity profile, but in general both classes of drugs are well tolerated. Some patients will have contraindications to one class or the other based on a personal history of blood clots, strokes, or severe osteoporosis.

Tamoxifen is associated with increased vaginal side effects compared with AIs and in particular, an increased risk of endometrial cancer.[2] Tamoxifen produces an increased risk of thromboembolic events including pulmonary emboli, stroke, and deep venous thrombosis compared to AIs. AIs are associated with increased musculoskeletal symptoms including arthralgias and fractures compared with tamoxifen; but because tamoxifen is associated with increased bone formation, the negative effect of AIs seen in randomized studies compared with tamoxifen might be in part a result of tamoxifen's protective effect on bone. The risks of these side effects need to be weighed against the potential benefit of the therapy.