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

Abstract

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 Ib/II 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 (CI): 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% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 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 Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.

Fig. 1. The FUTURE trial schema: integrating TNBC subtyping and genomic targeting.

n, number of the patients; TNBC, triple-negative breast cancer; FUSCC, Fudan University Shanghai Cancer Center; LAR, luminal androgen receptor; IM, immunomodulatory; BLIS, basal-like immune-suppressed; MES, mesenchymal-like; AR, androgen receptor; PD-1, programmed cell death-1; PARPi, poly ADP-ribose polymerase inhibitor; VEGFR, vascular endothelial growth factor receptor.

Fig. 2. Summary of therapy response.

a Summary of the category of the best response in each arm of the FUTURE trial. b Duration of treatment in the FUTURE and of the last previous therapy in 18 patients in the PP population with available previous treatment duration information. c, f Best percentage change from baseline in the sum of the longest diameters of target lesions in arm C (c) and arm E (f). d, g Time to and durability of treatment in arm C (d) and arm E (g). e, h Longitudinal change from baseline in the sum of the longest diameters of target lesions in arm C (e) and arm E (h). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; AE, adverse event.

Fig. 3. Genomic landscape of refractory TNBC.

a The genomic landscape of the patients in the FUTURE trial. b, c Comparison of mutation frequency between primary and metastatic TNBC (b) and between FUSCC and MSKCC metastatic TNBC (c). MSKCC,  Memorial Sloan-Kettering Cancer Center; FDR, false discovery rate.

Fig. 4. Potential predictors of response for immunotherapy in IM subtype of TNBC.

a TOP2A mutation in PR and non-PR patients of arm C. b Relationship between TOP2A mutation and tumor remission rate of arm C. c The change of amino acid positions related to TOP2A mutations in non-PR patients of arm C.