Results from two separate studies have indicated that the aromatase agents Femara® (letrozole) and Aromasin® (exemestane) improve outcomes compared with tamoxifen (Nolvadex®) as initial therapy in early, hormone-positive breast cancer. These results were presented at the 2008 San Antonio Breast Cancer Symposium (SABCS).

Although aromatase inhibitors have been widely accepted as standard adjuvant endocrine therapy for hormone-positive breast cancers among eligible women, follow-up of trials comparing these agents to tamoxifen, the historical standard, continue.

One trial presented at this year’s SABCS included long-term follow-up to the BIG 1-98 Phase III trial, which compared Femara to tamoxifen in postmenopausal, hormone-positive breast cancer. Patients were randomized to either Femara or tamoxifen monotherapy for five years or sequential therapy with these agents (tamoxifen for two years followed by Femara for three years or Femara for two years followed by tamoxifen for three years). Results emerged in 2005 indicating a reduction in recurrences on the Femara arm, so patients initially randomized to the tamoxifen-only arm were unblinded and allowed to cross-over to Femara for the remainder of the study. These updated results included a 76- month median follow-up among patients on the monotherapy arms as well as a 71-month follow-up and two pairwise comparisons among three blinded study arms (tamoxifen followed by Femara versus Femara; Femara followed by tamoxifen versus Femara).[1] 

• Patients treated with Femara for five years following surgery had a 13% reduced risk of death compared with those treated with tamoxifen (p=0.08).
• When patients who had crossed over to Femara were excluded from the analysis, the reduction in the mortality risk was 19%.
• Five-year survival rates were 87.9% for women treated with Femara only; 86.2% for those treated with two years of tamoxifen followed by three years of Femara; and 87.6% for those receiving two years of Femara followed by three years of tamoxifen.
• Benefit was most pronounced in patients with node-positive disease.
• Outcomes were similar between groups of patients who were treated with Femara monotherapy compared with those treated with initial Femara and switched to tamoxifen; however, those initially treated with tamoxifen and switched to Femara had a worse overall survival (HR=1.13) and disease-free survival (HR=1.05) compared with those on Femara monotherapy.
• Recurrences at five years were as follows: 7.3% for the groups of patients initially treated with Femara and those initially treated with Femara who switched to tamoxifen and 9.1% for those who were initially treated with tamoxifen and switched to Femara.
• There were no unexpected side effects in any arm of the study.

The researchers from this study stated that adjuvant endocrine therapy among postmenopausal women with hormone-positive breast cancer should be initiated with Femara as opposed to initial tamoxifen and that patients can switch to tamoxifen after two years if necessary.

The second trial comparing an aromatase inhibitor to tamoxifen in postmenopausal women with hormone-positive, early breast cancer was the TEAM (tamoxifen, exemestane adjuvant multinational) study, which was a randomized, multinational Phase III trial comparing Aromasin® (exemestane) to tamoxifen for five years in this patient population.[2] Patients were initially randomized to Aromasin or tamoxifen monotherapy for five years. However, as in the BIG 1-98 trial, planned interim analysis revealed improved outcomes for Aromasin, resulting in all patients on tamoxifen crossing-over to Aromasin after 2.5 to three years of tamoxifen therapy.  The results presented were from a 2.75-year follow-up of the amended trial, with five-year results expected in 2009.

• Disease-free survival was improved by 17% among those initially treated with Aromasin on-study (p=0.02).
• Patients initially treated with Aromasin also had a significant improvement in relapse-free survival and time to distant metastasis (p <0.05).
• No unexpected side effects occurred in any of the treatment arms.

The researchers stated that up-front therapy with Aromasin provides improved outcomes compared with initial therapy with tamoxifen for the treatment of hormone-positive, postmenopausal women with early breast cancer. These results remain consistent with those of other aromatase inhibitors in comparison to tamoxifen for treatment of this disease.

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