Relative Effectiveness of Letrozole Compared With Tamoxifen for Patients With Lobular Carcinoma in the BIG 1-98 Trial

Abstract

Purpose: To evaluate the relative effectiveness of letrozole compared with tamoxifen for patients with invasive ductal or lobular carcinoma.

Patients and methods: Patients diagnosed with early-stage invasive ductal carcinoma (IDC) or classic invasive lobular carcinoma (ILC) who were randomly assigned onto the Breast International Group (BIG) 1-98 trial and who had centrally reviewed pathology data were included (N = 2,923). HER2-negative IDC and ILC were additionally classified as hormone receptor-positive with high (luminal B [LB] -like) or low (luminal A [LA] -like) proliferative activity by Ki-67 labeling index. Survival analyses were performed with weighted Cox models that used inverse probability of censoring weighted modeling.

Results: The median follow-up time was 8.1 years. In multivariable models for disease-free survival (DFS), significant interactions between treatment and histology (ILC or IDC; P = .006) and treatment and subgroup (LB like or LA like; P = .01) were observed. In the ILC subset, there was a 66% reduction in the hazard of a DFS event with letrozole for LB (hazard ratio [HR], 0.34; 95% CI, 0.21 to 0.55) and a 50% reduction for LA subtypes (HR, 0.50; 95% CI, 0.32 to 0.78). In the IDC subset, there was a significant 35% reduction in the hazard of a DFS event with letrozole for the LB subtype (HR, 0.65; 95% CI, 0.53 to 0.79), but no difference between treatments was noted for IDC and the LA subtype (HR, 0.95; 95% CI, 0.76 to 1.20).

Conclusion: The magnitude of benefit of adjuvant letrozole is greater for patients diagnosed with lobular carcinoma versus ductal carcinoma.

Trial registration: ClinicalTrials.gov NCT00004205.

Fig 1.

CONSORT diagram showing the analytic cohort of 2,923 patients with tumors classified as ductal (n = 2,599) and lobular (n = 324) enrolled in the monotherapy arm of the BIG 1-98 clinical trial that compared 5 years of letrozole with 5 years of tamoxifen. ER, estrogen receptor; HER2, human epidermal growth factor receptor; PgR, progesterone receptor.

Fig 2.

Inverse probability of censoring weighted Kaplan-Meier estimates of (A) disease-free survival and (B) overall survival according to histology (ductal, lobular) and treatment (letrozole, tamoxifen) among the 2,923 patients in the analytic cohort. HR, hazard ratio; L, letrozole; T, tamoxifen.

Fig 3.

Inverse probability of censoring weighted Kaplan-Meier estimates of disease-free survival according to treatment and histology within subgroups defined as (A) luminal A–like and (B) luminal B–like. HR, hazard ratio; L, letrozole; T, tamoxifen.

Fig 4.

Disease-free survival and overall survival hazard ratio (HR) estimates and 95% CIs comparing the efficacy of letrozole versus tamoxifen for histologic subgroups. The results were based on multivariable models that included classic clinicopathologic variables as predictors: age, tumor size, nodal status, histologic grade, histology (ductal/lobular), local therapy, subtype (luminal A or B), and treatment. The box size is inversely proportional to the SE of the HR; the extended horizontal lines indicate the 95% CIs. (*) Treatment by histology (ductal/lobular), P = .006; treatment by subtype (LA/LB), P = .01. (†) Treatment by histology (ductal/lobular), P = .035.

Fig A1.

Inverse probability of censoring weighted (IPCW) and intention-to-treat (ITT) hazard ratio (HR) estimates of the relative effect of letrozole versus tamoxifen for disease-free survival and overall survival.