Volume 31, No 2, Feb 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 2, February 2021: 178-186   |  Open Access

ORIGINAL ARTICLES

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

Yi-Zhou Jiang^1,2 , Yin Liu^1,2 , Yi Xiao^1,2 , Xin Hu^1,2 , Lin Jiang^1,2 , Wen-Jia Zuo^1,2 , Ding Ma^1,2 , Jiahan Ding^1,2 , Xiaoyu Zhu³ , Jianjun Zou³ , Claire Verschraegen⁴ , Daniel G. Stover⁵ , Virginia Kaklamani⁶ , Zhong-Hua Wang^1,2,* , Zhi-Ming Shao^1,2,*

¹Department of Breast Surgery, Fudan University Shanghai Cancer Center; Key Laboratory of Breast Cancer in Shanghai, Shanghai 200032, China
²Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
³Jiangsu Hengrui Medicine Co Ltd, Lianyungang, Jiangsu 222002, China
⁴Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA
⁵The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
⁶Division of Hematology/Oncology, University of Texas Health Science Center San Antonio, San Antonio, TX 78284, USA
These authors contributed equally: Yi-Zhou Jiang, Yin Liu, Yi Xiao Correspondence: Zhong-Hua Wang(zhonghuawang95@hotmail.com)Zhi-Ming Shao(zhimingshao@yahoo.com)

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.

https://doi.org/10.1038/s41422-020-0375-9

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