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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

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.