Letrozole (Page 9 of 12)

14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months

A double-blind, randomized, placebo-controlled trial 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 7.

Table 7: Selected Study Population Demographics (Modified ITT Population)

Baseline Status

Letrozole

N = 2,582

Placebo

N = 2,586

Hormone Receptor Status

(%)

ER+ and/or PgR+

98

98

Both Unknown

2

2

Nodal Status (%)

Node Negative

50

50

Node Positive

46

46

Nodal Status Unknown

4

4

Chemotherapy

46

46

Table 8 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.

Table 8: Extended Adjuvant Study Results
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). P -value based on stratified logrank test.
*
First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause.
Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization).

Letrozole

N = 2,582

Placebo

N = 2,586

Hazard Ratio (95% CI)

P -Value

Disease Free Survival (DFS) * Events

122 (4.7%)

193 (7.5%)

0.62 (0.49, 0.78)

0.00003

Local Breast Recurrence

9

22

Local Chest Wall Recurrence

2

8

Regional Recurrence

7

4

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

14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months

Table 9: Update of Extended Adjuvant Study Results
*
Adjusted by receptor status, nodal status and prior chemotherapy.
Stratified logrank test, stratified by receptor status, nodal status and prior chemotherapy.
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.
§
Protocol definition does not include deaths from any cause.

Letrozole

N = 2,582

(%)

Placebo

N = 2,586

(%)

Hazard Ratio * (95% CI)

P -Value

Disease Free Survival (DFS) events

344 (13.3)

402 (15.5)

0.89 (0.77, 1.03)

0.12

Breast cancer recurrence

(Protocol definition of DFS events §)

209

286

0.75 (0.63, 0.89)

0.001

Local Breast Recurrence

15

44

Local Chest Wall Recurrence

6

14

Regional Recurrence

10

8

Distant Recurrence

140

167

Distant Recurrence (first or subsequent events)

142

169

0.88 (0.70,1.10)

0.246

Contralateral Breast Cancer

37

53

Deaths Without Recurrence or Contralateral Breast Cancer

135

116

Updated analyses were conducted at a median follow-up of 62 months. In the letrozole arm, 71% of the patients were treated for at 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 9, 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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