A double-blind, randomized, placebo-controlled trial (MA-17, NCT00003140) of letrozole was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen.
The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable letrozole effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up.
Selected baseline characteristics for the study population are shown in Table 8.
|Hormone Receptor Status (%)|
|ER+ and/or PgR+||98||98|
|Nodal Status (%)|
|Nodal Status Unknown||4||4|
Table 9 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.
|Letrozole N = 2582||Placebo N = 2586||Hazard Ratio (95% CI)||P -Value|
|Disease Free Survival (DFS) 1 Events||122 (4.7%)||193 (7.5%)||0.62 (0.49, 0.78) 2||0.00003|
|Local Breast Recurrence||9||22|
|Local Chest Wall Recurrence||2||8|
|Distant Recurrence||55||92||0.61 (0.44 to 0.84)||0.003|
|Contralateral Breast Cancer||19||29|
|Deaths Without Recurrence or Contralateral Breast Cancer||30||38|
|CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of letrozole (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with letrozole). 1 First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause 2 Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P -value based on stratified log-rank test.|
14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months
|Letrozole N = 2582 (%)||Placebo N = 2586 (%)||Hazard Ratio 1 (95% CI)||P -Value 2|
|Disease Free Survival (DFS) events 3||344 (13.3)||402 (15.5)||0.89 (0.77, 1.03)||0.12|
|Breast cancer recurrence (Protocol definition of DFS events 4)||209||286||0.75 (0.63, 0.89)||0.001|
|Local Breast Recurrence||15||44|
|Local Chest Wall Recurrence||6||14|
|Distant Recurrence (first or subsequent events) Contralateral Breast Cancer||142 37||169 53||0.88 (0.70,1.10)||0.246|
|Deaths Without Recurrence or Contralateral Breast Cancer||135||116|
|1 Adjusted by receptor status, nodal status and prior chemotherapy 2 Stratified log-rank test, stratified by receptor status, nodal status and prior chemotherapy 3 DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to letrozole in 60% of the placebo arm. 4 Protocol definition does not include deaths from any cause|
Updated analyses were conducted at a median follow-up of 62 months. In the letrozole arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to letrozole.
In this updated analysis shown in Table 10 letrozole significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P =0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to letrozole and accounting for 64% of the total placebo patient- years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival.
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