Simulation modeling to extend clinical trials of adjuvant chemotherapy guided by a 21-gene expression assay in early breast cancer

Purpose: The 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. Methods: We 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. Results: The 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. Conclusions: Our 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.