难治型晚期三阴性乳腺癌分型精准治疗
众所周知，如果乳腺癌不表达雌激素受体、孕激素受体、人类表皮生长因子受体HER2，就被统称为三阴性乳腺癌。此类乳腺癌对抗激素治疗和抗HER2靶向治疗不敏感，目前主要依靠化疗，客观缓解比例仅5%～10%。虽然三阴性乳腺癌仅占全部乳腺癌的10%～20%，但是其中还有大量已知和未知的分子亚型，具有不同的临床意义，需要不同的治疗策略。根据分子特征对三阴性乳腺癌进一步分型，可提高精准诊断和靶向治疗的水平。2019年3月7日，美国《细胞》旗下《癌细胞》（影响因子：26.602）在线发表复旦大学附属肿瘤医院等单位的研究报告，根据大样本患者全部基因和转录分子特征以及临床数据分析，首先将三阴性乳腺癌进一步分为具有不同治疗靶点的四种分子亚型：管腔雄激素受体亚型、免疫调节亚型、基底样免疫抑制亚型、间质样亚型，为三阴性乳腺癌的分型施策奠定了基础。
2020年7月27日，英国《自然》旗下《细胞研究》（影响因子：20.507）在线发表复旦大学附属肿瘤医院江一舟、刘引、肖毅、胡欣、蒋麟、左文佳、马丁、王中华、邵志敏、恒瑞医药朱晓宇和邹建军等学者的FUTURE临床研究报告，首次将四种分子亚型以及基因突变用于中国难治型晚期三阴性乳腺癌患者的分型精准治疗。
FUTURE (FUSCC Refractory TNBC Umbrella): Precision Treatment of Refractory Triple Negative Breast Cancer Based on Molecular Subtyping -- FUSCC-TNBC Umbrella Trial (NCT03805399)
该单中心Ib/II期临床研究利用三阴性乳腺癌分子亚型和基因突变，将69例难治型（既往1～8个治疗方案失败，中位3个）晚期三阴性乳腺癌患者分为7组进行治疗：
A组2例（管腔雄激素受体亚型HER2突变）卡培他滨＋吡咯替尼
B组14例（管腔雄激素受体亚型HER2未突变）雄激素受体抑制剂SHR3680＋CDK4/6抑制剂SHR6390
C组19例（免疫调节亚型）PD-1抑制剂卡瑞利珠单抗＋白蛋白紫杉醇
D组4例（基底样免疫抑制亚型BRCA突变）PARP抑制剂氟唑帕利
E组23例（基底样免疫抑制亚型BRCA未突变）VEGFR抑制剂阿帕替尼
F组5例（间质样亚型PI3K→AKT信号通路未激活）VEGFR抑制剂阿帕替尼
G组2例（间质样亚型PI3K→AKT信号通路激活）mTOR抑制剂依维莫司＋白蛋白紫杉醇
主要研究终点为客观缓解比例。
结果，客观缓解20例，客观缓解比例高达29.0%，95%置信区间：18.7%～41.2%）。
C组免疫治疗的客观缓解比例高达52.6%（95%置信区间：28.9%～75.6%）。
虽然E组VEGFR抑制剂的客观缓解比例较高（26.1%，95%置信区间：10.2%～48.4%）但是≥3级不良事件发生比例较高。
体细胞DNA拓扑异构酶TOP2A和杀伤型T淋巴细胞表面抗原CD8突变的免疫组织化学评分可能具有预测三阴性乳腺癌免疫调节亚型免疫治疗效果的潜力。
因此，该研究结果表明，根据分子亚型进行靶向治疗，对于难治型晚期三阴性乳腺癌可以临床获益，故有必要进一步开展大样本多中心III期临床研究进行验证。
相关链接
Cell Res. 2020 Jul 27. Online ahead of print.
Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial.
Yi-Zhou Jiang, Yin Liu, Yi Xiao, Xin Hu, Lin Jiang, Wen-Jia Zuo, Ding Ma, Xiaoyu Zhu, Jianjun Zou, Claire Verschraegen, Daniel G Stover, Virginia Kaklamani, Zhong-Hua Wang, Zhi-Ming Shao.
Fudan University Shanghai Cancer Center; Shanghai Medical College, Fudan University, Shanghai, China; Jiangsu Hengrui Medicine Co Ltd, Lianyungang, China; The Ohio State University College of Medicine, Columbus, OH, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
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 triple-negative breast cancers (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 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 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.
DOI: 10.1038/s41422-020-0375-9