Five Years of Letrozole Compared With Tamoxifen As Initial Adjuvant Therapy for Postmenopausal Women With Endocrine-Responsive Early Breast Cancer: Update of Study BIG 1-98

TLDR

Previous analyses of the BIG 1‑98 trial compared letrozole and tamoxifen, including patients assigned to sequential therapy whose data were censored at treatment change. The present analysis was limited to patients assigned to continuous therapy to avoid bias from early events, and included protocol‑defined updated results. Disease‑free survival was the primary endpoint, with 352 events among 2,463 letrozole patients and 418 among 2,459 tamoxifen patients at a median 51‑month follow‑up. The updated analysis demonstrated an 18 % lower risk of disease‑free survival events with letrozole versus tamoxifen (HR 0.82, 95 % CI 0.71–0.95; P = 0.007), with no differential benefit in predefined subgroups; adverse event profiles differed, with tamoxifen associated with more thromboembolic, endometrial, and menopausal symptoms, and letrozole with more bone fractures, arthralgia, hypercholesterolemia, and non‑ischemic cardiovascular events.

Abstract

Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results.Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point.At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure.The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.