Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer:the FUTURE trial

摘要

Triple-negative breast cancer(TNBC)is a highly heterogeneous disease,and molecular subtyping may result in improved diagnostic precision and targeted therapies.Our previous study classified TNBCs into four subtypes with putative therapeutic targets.Here,we conducted the FUTURE trial(ClinicalTrials.gov identifier:NCT03805399),a phase lb/11 subtyping-based and genomic biomarker-guided umbrella trial,to evaluate the efficacy of these targets.Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers,and assigned to one of these seven arms:(A)pyrotinib with capecitabine,(B)androgen receptor inhibitor with CDK4/6 inhibitor,(C)anti PD-1 with nab-paclitaxel,(D)PARP inhibitor included,(E)and(F)anti-VEGFR included,or(G)mTOR inhibitor with nab-paclitaxel.The primary end point was the objective response rate(ORR).We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy(range,1-8).Objective response was achieved in 20(29.0％,95％confidence interval(Cl):18.7％-41.2％)of the 69 intention-to-treat(ITT)patients.Our results showed that immunotherapy(arm C),in particular,achieved the highest ORR(52.6％,95％Cl:28.9％-75.6％)in the ITT population.Arm E demonstrated favorable ORR(26.1％,95％Cl:10.2％-48.4％in the ITT population)but with more high grade(≥3)adverse events.Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC.In conclusion,the phase lb/ll FUTURE trial suggested a new concept for TNBC treatment,demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.