Results of a multinational phase III clinical trial involving women with breast cancer in 27 countries found that adjuvant therapy with the aromatase inhibitor letrozole following surgical excision conferred greater survival benefit than tamoxifen.
Results of a multinational phase III clinical trial involving women with breast cancer in 27 countries found that adjuvant therapy with the aromatase inhibitor letrozole (Femara) following surgical excision conferred greater survival benefit than tamoxifen. From 1998-2003, researchers from the International Breast Cancer Study Group (IBCSG) randomized 8010 postmenopausal women with hormone receptor-positive early stage breast cancer to receive either tamoxifen or letrozole monotherapy for 5 years (n = 4922), tamoxifen for 2 years followed by letrozole for 3 years, or letrozole for 2 years followed by tamoxifen for 2 years.
Preliminary results from the Breast International Group (BIG) 1-98 study, released in 2005, showed that letrozole significantly reduced the rates of breast cancer recurrence and distant metastases compared with tamoxifen. Final data presented today at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium further demonstrated a 13% overall reduction in the risk of death for women taking letrozole. Excluding from the results those patients who initiated therapy with tamoxifen before switching to letrozole upped letrozole’s survival advantage to 19% (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.69-0.94).
“These data represent an important milestone in the treatment of women with breast cancer,” said the study’s lead author, Henning T. Mouridsen, MD, PhD, professor of oncology at Copenhagen University Hospital. “For the first time, we are seeing suggested survival benefit with aromatase inhibitor therapy for 5 years compared with tamoxifen for the same time period,” he added. Dr. Mouridsen suggested that the apparent decline in the risk of death might be partially attributable to letrozole’s previously reported success in reducing breast cancer recurrence and distant metastases.
In addition to improving overall survival, the IBCSG researchers said that their final analysis showed letrozole decreased the risk of disease-free survival events by 12% (P = .03; HR, 0.88; 95% CI, 0.78-0.99) and lowered the risk of distant metastases by 15% (P = .05; HR, 0.85; 95% CI, 0.72-1.00) compared with tamoxifen over a 5-year period. A retrospective analysis of results determined that letrozole was associated with a 30% reduction in the spread of cancer to other parts of the body in the first 2 years after surgery versus tamoxifen.
Nearly one-third of women treated for estrogen receptor-positive early breast cancer will redevelop cancer. More than half of recurrences occur more than 5 years postsurgery, but patients are at the greatest risk for recurrence in the first 2 to 3 years after surgery. Approximately 75% of cancer recurrences that develop within 3 years of primary treatment occur in organs and tissues other than the breast. Prolonging disease-free survival past the 5-year mark might contribute to greater overall survival for women treated for early breast cancer.
The long-term follow-up analysis of the BIG 1-98 study, conducted more than 10 years after its initiation, found that treatment-related adverse events for both drugs used in the study were as expected per their known safety profiles. The most common adverse affects associated with adjuvant treatment with letrozole include hot flashes, joint pain, night sweats, weight gain, nausea, tiredness, heart-related events, and bone fractures. Previous research suggests that additional studies are needed to evaluate the risk of treatment-related bone fractures with extended use of letrozole.
In the United States, letrozole is the only aromatase inhibitor approved as an immediate postsurgical adjuvant treatment for postmenopausal women with hormone receptor-positive early stage breast cancer. The US Food and Drug Administration has also approved letrozole as an extended adjuvant treatment for postmenopausal women who have already completed 5 years of tamoxifen therapy for hormone receptor-positive early stage breast cancer.
The 2007 St. Gallen guidelines affirmed various study findings that aromatase inhibitors are superior to tamoxifen in reducing the rate of breast cancer recurrence in the adjuvant setting. The upcoming FACE trial (Femara vs Anastrozole Clinical Evaluation) trial has recently concluded enrollment and plans to conduct a head-to-head comparison of the efficacy and safety of the aromatase inhibitors letrozole and anastrozole (Arimidex) in postmenopausal women with node-positive early breast cancer following tumor excision.