Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence

Abstract

Purpose: To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial.

Methods: The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor-positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards models were used to evaluate the relationship between DFS and treatment adherence (persistence [duration] and compliance with dosage). Competing risks regression was used to assess demographic, disease, and treatment characteristics of the women who stopped treatment early because of adverse events.

Results: Both aspects of low adherence (early cessation of letrozole and a compliance score of < 90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event.

Conclusion: Both persistence and compliance are associated with DFS. Toxicity management and, for sequential treatments, patient and physician awareness, may improve adherence.

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.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

CONSORT diagram showing the derivation of the 6,144 women in the analytic cohort. Let, letrozole; Tam, tamoxifen.

Fig 2.

Unadjusted Anderson-Simon-Makuch survival estimates of disease-free survival (DFS) comparing patients (Pts) who received ≥ 36 months of assigned endocrine treatment (blue line) with those who received

Fig 3.

Conditional landmark (54 months) disease-free survival (DFS) comparisons of patients (Pts) who received at least 54 months of protocol-assigned endocrine treatment according to the compliance score dichotomized at 90%. Results from the Cox regression model show a statistically significant 61% increase in the risk of a future DFS event for treatment completers if less than 90% of the drug packs were taken per protocol. HR, hazard ratio.

Fig 4.

Cumulative incidence of stopping protocol-assigned endocrine treatment because of an adverse event according to treatment assigned in the Breast International Group 1-98 clinical trial. The sequential treatment (gray and red lines) had the highest incidence of stopping early after the endocrine agent switch at 2 years. Tamoxifen (Tam; blue line) continued to have lowest incidence of stopping early. Let, letrozole.

Fig 5.

Adverse events reported as reason for stopping protocol-assigned endocrine treatment early according to treatment group. Let, letrozole; Tam, tamoxifen.