Letrozole (Page 7 of 9)

14.4 First-Line Treatment of Advanced Breast Cancer

A randomized, double-blind, multinational trial (P025) compared letrozole 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 11.

Table 11: Selected Study Population Demographics
Baseline Status Letrozole T amoxifen
N=458 N=458
Stage of Disease
IIIB6%7%
IV93%92%
Receptor Status
ER and PgR Positive38%41%
ER or PgR Positive26%26%
Both Unknown34%33%
ER or PgR /Other Unknown <1%0
Previous Antiestrogen Therapy
Adjuvant19%18%
None81%82%
Dominant Site of Disease
Soft Tissue25%25%
Bone32%29%
Viscera43%46%

Letrozole was superior to tamoxifen in TTP and rate of objective tumor response (see Table 12).

Table 12 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P -values.)

Table 12: Results of First-Line Treatment of Advanced Breast Cancer
Letrozole Tamoxifen Hazard or Odds
2.5 mg 20 mg Ratio (95% CI)
N=453 N=454 P -Value (2-Sided)
Median Time to Progression 9.4 months6.0 months0.72 (0.62, 0.83) 1
P <0.0001
Objective Response Rate
(CR + PR)145 (32%)95 (21%)1.77 (1.31, 2.39) 2
P =0.0002
(CR)42 (9%)15 (3%)2.99 (1.63, 5.47) 2
P =0.0004
Duration of Objective Response
Median18 months 16 months
(N=145)(N=95)
Overall Survival 35 months 32 months
(N=458)(N=458)P =0.5136 3

1 Hazard ratio

2 Odds ratio

3 Overall log-rank test

Figure 2 shows the Kaplan-Meier curves for TTP.

Figure 2  Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study)
(click image for full-size original)

Table 13 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 14 , results by disease site and Table 15, the results by receptor status.

Table 13: Efficacy in Patients Who Received Prior Antiestrogen Therapy
Variable Letrozole T amoxifen
2.5 mg 20 mg
N=84 N=83
Median Time to Progression (95% CI) 8.9 months (6.2, 12.5) 5.9 months (3.2, 6.2)
Hazard Ratio for TTP (95% CI) 0.60 (0.43, 0.84)
Objective Response Rate
(CR + PR)22 (26%)7 (8%)
Odds Ratio for Response (95% CI)3.85 (1.50, 9.60)

Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Table 14: Efficacy by Disease Site
Letrozole Tamoxifen
2.5 mg 20 mg
Dominant Disease Site
Soft Tissue: N=113N=115
Median TTP12.1 months6.4 months
Objective Response Rate50%34%
Bone: N=145N=131
Median TTP9.5 months6.3 months
Objective Response Rate23%15%
Viscera: N=195N=208
Median TTP8.3 months4.6 months
Objective Response Rate28%17%
Table 15: Efficacy by Receptor Status
Variable Letrozole Tamoxifen
2.5 mg 20 mg
Receptor Positive N=294N=305
Median Time to Progression (95% CI)9.4 months (8.9, 11.8)6.0 months (5.1, 8.5)
Hazard Ratio for TTP (95% CI)0.69 (0.58, 0.83)
Objective Response Rate (CR+PR)97 (33%)66 (22%)
Odds Ratio for Response 95% CI)1.78 (1.20, 2.60)
Receptor Unknown N=159N=149
Median Time to Progression (95% CI)9.2 months (6.1, 12.3)6.0 months (4.1, 6.4)
Hazard Ratio for TTP (95% CI) 0.77 (0.60, 0.99)
Objective Response Rate (CR+PR)48 (30%)29 (20%)
Odds Ratio for Response (95% CI)1.79 (1.10, 3.00)

Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Figure 3: shows the Kaplan-Meier curves for survival.

Figure 3  Survival by Randomized Treatment Arm
(click image for full-size original)

Legend: Randomized letrozole: n=458, events 57%, median overall survival 35 months (95% CI 32 to 38 months)

Randomized tamoxifen: n=458, events 57%, median overall survival 32 months (95% CI 28 to 37 months)

Overall log-rank P =0.5136 (i.e., there was no significant difference between treatment arms in overall survival).

The median overall survival was 35 months for the letrozole group and 32 months for the tamoxifen group, with a P -value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with letrozole (n=219, 95% Cl 29 to 43 months) vs. 20 months with tamoxifen (n=229, 95% Cl 16 to 26 months).

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