Simulation Modeling to Extend Clinical Trials of Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Early Breast Cancer.

Abstract

PurposeThe Trial Assigning Individualized Options for Treatment (TAILORx) found chemotherapy could be omitted in many women with hormone receptor–positive, HER2-negative, node-negative breast cancer and 21-gene recurrence scores (RS) 11–25, but left unanswered questions. We used simulation modeling to fill these gaps. MethodsWe simulated women eligible for TAILORx using joint distributions of patient and tumor characteristics and RS from TAILORx data; treatment effects by RS from other trials; and competing mortality from the Surveillance, Epidemiology, and End Results program database. The model simulations replicated TAILORx design, and then tested treatment effects on 9-year distant recurrence-free survival (DRFS) in 14 new scenarios: eight subgroups defined by age (≤50 and >50 years) and 21-gene RS (11–25/16–25/16–20/21–25); six different RS cut points among women ages 18–75 years (16–25, 16–20, 21–25, 26–30, 26–100); and 20-year follow-up. Mean hazard ratios SD, and DRFS rates are reported from 1000 simulations.ResultsThe simulation results closely replicated TAILORx findings, with 75% of simulated trials showing noninferiority for chemotherapy omission. There was a mean DRFS hazard ratio of 1.79 (0.94) for endocrine vs chemoendocrine therapy among women ages 50 years and younger with RS 16–25; the DFRS rates were 91.6% (0.04) for endocrine and 94.8% (0.01) for chemoendocrine therapy. When treatment was randomly assigned among women ages 18–75 years with RS 26–30, the mean DRFS hazard ratio for endocrine vs chemoendocrine therapy was 1.60 (0.83). The conclusions were unchanged at 20-year follow-up.ConclusionsOur results confirmed a small benefit in chemotherapy among women aged 50 years and younger with RS 16–25. Simulation modeling is useful to extend clinical trials, indicate how uncertainty might affect results, and power decision tools to support broader practice discussions.