Newly published data in The New England Journal of Medicine affirm five-year upfront use of letrozole following surgery as an optimal treatment approach versus tamoxifen for postmenopausal women with early stage breast cancer (hormone-receptor positive).

The data include an analysis from the Breast International Group (BIG) 1-98 trial that evaluated patients taking either a sequence of letrozole and tamoxifen for five years or letrozole as monotherapy for five years. Also included is the update of the Monotherapy Arms Analysis (MAA) conducted 10 years after initiation of the study, comparing five years of letrozole alone versus five years of tamoxifen alone following surgery. The BIG 1-98 trial was conducted by the International Breast Cancer Study Group (IBCSG).

Results from the Sequential Treatments Analysis (STA) concluded that sequential treatment with tamoxifen and letrozole in the first five years after breast cancer surgery did not improve disease-free survival compared with letrozole alone for the same duration after surgery. In the 10-year MAA analysis, letrozole monotherapy demonstrated significant long-term improvement of disease-free survival (p=0.03) and significant long-term reduction in risk of metastasis (p=0.05) compared with tamoxifen. In patients treated with letrozole monotherapy, a non-statistically significant relative reduction in the risk of death of 13% versus tamoxifen (p=0.08) was observed.

"The BIG 1-98 study results suggest survival benefit with five years of letrozole therapy after surgery compared to tamoxifen for the same time period following surgery, confirming the benefit of initial use of letrozole in the adjuvant breast cancer setting," said Henning T. Mouridsen, M.D., Ph.D., Professor of Oncology, Copenhagen University Hospital and BIG 1-98 investigator. "Letrozole is the only aromatase inhibitor versus tamoxifen to demonstrate early and significant reduction in the risk of distant metastases, significant improvement in disease-free survival and this suggestion in overall survival benefit in primary breast cancer patients."

"A primary goal in treating adjuvant breast cancer is to reduce the number of early, life-threatening distant metastases. The data show the significant long-term benefit of Letrozole and these results will have an impact on clinical practice in the US," said Kimberly Blackwell, M.D., associate professor of medicine at the Duke University Medical Center. "A treatment strategy of letrozole for five years immediately following surgery may help protect postmenopausal women with hormone-receptor positive breast cancer from recurrence of their disease."

Results of the Sequestial Treatments Analysis (STA) (median follow-up of 71 months) concluded that sequential treatment with tamoxifen did not improve disease-free survival compared with letrozole alone. In the study, patients either received sequential treatment with letrozole and tamoxifen (two years of letrozole followed by three years of tamoxifen or two years of tamoxifen followed by three years of letrozole) or five years of letrozole alone. Five-year disease-free survival rates for the three groups of patients in the STA were 87.9% for those patients receiving Letrozole only, 86.2% for those patients receiving tamoxifen followed by Letrozole and 87.6% for those patients receiving Letrozole followed by tamoxifen.

Updated results from the Monotherapy Arms Analysis (MAA) (median follow-up of 76 months) confirm the significant long-term benefit of letrozole. The data demonstrated that patients who took Letrozole alone for five years following surgery experienced a significant reduction in the risk of distant metastases (15%, p=0.05) with a corresponding reduction in risk of disease-free survival events (12%, p=0.03) compared with patients treated with tamoxifen alone for the same duration.

The analysis also revealed a non-significant trend towards an overall survival benefit with five years of letrozole therapy following surgery (13% reduced risk of death, P=0.08) versus tamoxifen for five years following surgery. This occurred even though approximately 25% of patients in the tamoxifen arm selectively crossed over to letrozole therapy after the tamoxifen arm was unblinded in 2005 due to the superiority of letrozole over tamoxifen. This crossover confounds the evaluation of the true differences between letrozole and tamoxifen. The study group therefore, conducted a retrospective censored analysis that was not protocol-defined and in which observation times were censored at the date of crossover. Time and events beyond the crossover were ignored in patients who selectively crossed over to letrozole. In this censored analysis, there was an improved survival benefit for patients receiving five years of letrozole versus tamoxifen (19%; HR 0.81; 95% CI: 0.68, 0.96). According to the authors, these censored results may be an overestimate of the letrozole benefit since women who had recurrent disease were not candidates for the crossover. It is likely that the most accurate assessment of the survival benefit with letrozole is between these two analyses - 13-19% reduction in the relative risk of death compared with tamoxifen.

BIG 1-98 is the only clinical trial designed to explore both a head-to-head comparison of an aromatase inhibitor versus tamoxifen monotherapy, as well as sequencing of an aromatase inhibitor and tamoxifen therapy in the first five years following breast cancer surgery, in order to determine the most effective way to minimize breast cancer recurrence. In the initial adjuvant setting, letrozole is the only aromatase inhibitor to have consistently demonstrated an early significant reduction in distant metastases versus tamoxifen at a median follow-up of 26, 51 and 76 months.

This Phase III, randomized, double-blind, controlled clinical trial enrolled more than 8,000 postmenopausal women with early breast cancer in 27 countries.

Patients were randomly assigned one of four treatment regimens: (1) five years of tamoxifen only; (2) five years of letrozole only; (3) two years of tamoxifen followed by three years of letrozole; (4) two years of letrozole followed by three years of tamoxifen.

The primary endpoint of the study was disease-free survival, defined as the time from randomization to the first of any of the following events: recurrence at local, regional, or distant sites; a new invasive cancer in the contralateral breast; any second, non-breast cancer; or death without a previous cancer event. Other endpoints included time to breast cancer recurrence, time to distant breast cancer recurrence and overall survival.

In 2005, following initial results showing superiority of letrozole monotherapy over tamoxifen monotherapy in improving disease-free survival and reducing the risk of recurrence, the tamoxifen-only treatment arm was unblinded and approximately one quarter of those patients selectively crossed over to Letrozole treatment. The other three treatment arms remained blinded. Subsequent analyses were designed to estimate the extent to which the crossover affected the comparative benefit of letrozole.

With the long-term follow-up in the analysis conducted more than 10 years after the start of the study, adverse events for letrozole and tamoxifen were found to be consistent with the known safety profiles of both drugs. Patients will be monitored for the rest of their lives to track disease status, safety and overall survival.