Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study

Abstract

Purpose: Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy.

Patients and methods: Of 8,010 postmenopausal women with hormone receptor-positive, early breast cancer enrolled on the Breast International Group (BIG) 1-98 study, 4,922 were randomly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen. Of 2,459 patients enrolled in the tamoxifen treatment arm, 619 (25.2%) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005. To gain better estimates of relative treatment effects in the presence of selective crossover, we used inverse probability of censoring weighted (IPCW) modeling.

Results: Weighted Cox models, by using IPCW, estimated a statistically significant, 18% reduction in the hazard of an OS event with letrozole treatment (hazard ratio [HR], 0.82; 95% CI, 0.70 to 0.95). Estimates of 5-year OS on the basis of IPCW were 91.8% and 90.4% for letrozole and tamoxifen, respectively. The HRs of DFS and TDR events by using IPCW modeling were 0.83 (95% CI, 0.74 to 0.94) and 0.80 (95% CI, 0.67 to 0.94), respectively (P < .05 for DFS, OS, and TDR). Median follow-up was 74 months.

Conclusion: Adjuvant treatment with letrozole, compared with tamoxifen, significantly reduces the risk of death, the risk of recurrent disease, and the risk of recurrence at distant sites in postmenopausal women with hormone receptor-positive breast cancer.

Fig 1.

Consort diagram of Breast International Group 1-98 trial. The shaded boxes, which denote the sequential therapy groups, are not included in this analysis. L, letrozole; T, tamoxifen.

Fig 2.

Weighted inverse probability of censoring weighted (IPCW) Kaplan-Meier estimates of (A) disease-free survival (DFS), (B) overall survival (OS), and (C) time to distant recurrence (TDR) comparing letrozole with tamoxifen. The median follow-up time was 74 months, and all patients completed the protocol treatment period. HR, hazard ratio; Dist Recur, distant recurrence.

Fig 3.

Inverse probability of censoring weighted Cox model results of (A) primary and secondary end points and (B) subgroups with primary end point of overall survival (OS). The size of the boxes was inversely proportional to the standard error of the hazard ratio. The solid vertical line was placed at 0.82, which was the hazard ratio estimate for the overall analysis of the OS end point. DFS, disease-free survival; L, letrozole; T, tamoxifen; ER, estrogen receptor; PgR, progesterone receptor; Nx, regional lymph nodes. TDR, time to distant recurrence. (*) Other includes ER+/PgR unknown, ER unknown/PgR+, ER−/PgR− (ineligible), ER−/PgR unknown, and ER unknown/PgR unknown.

Fig 4.

Kaplan-Meier cumulative incidence of (A) cardiac events (any grade), (B) thromboembolic events (any grade), (C) osteoporosis (grade 3) or bone fractures (any grade), and (D) hot flushes or night sweats (any grade) comparing letrozole with tamoxifen. AE, adverse event.