Clinicopathological and molecular features of HR^(+)/HER2^(−)breast cancer patients with distinct endocrine resistance patterns  

作　　者：Siwei Zhang Han Wang Hang Zhang Qingyuan Zhuang Xiaohui Zhu Yi Xiao Yizhou Jiang 

机构地区：[1]Key Laboratory of Breast Cancer in Shanghai,Department of Breast Surgery,Fudan University Shanghai Cancer Center,Shanghai 200032,China [2]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China

出　　处：《Chinese Journal of Cancer Research》2025年第1期48-65,共18页中国癌症研究(英文版)

基　　金：supported by the National Key Research and Development Program of China(No.2020YFA0112304);the National Natural Science Foundation of China(No.82373167,82341003 and 92159301);the Natural Science Foundation of Shanghai(No.22ZR1479200);the Shanghai Key Laboratory of Breast Cancer(No.12DZ2260100);the SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals(No.SHDC12021103);Shanghai Medical Innovation Research Project(No.22Y11912700),and Shanghai Anticancer Association EYAS PROJECT(No.SACA-CY22A05).

摘　　要：Objective:Recurrence continues to be a pivotal challenge among hormone receptor-positive(HR^(+))/human epidermal growth factor receptor 2^(−)negative(HER2^(−))breast cancers.In the international consensus guidelines,HR^(+)/HER2^(−)breast cancer relapse patterns are divided into three distinct types:primary resistant,secondary resistant,and endocrine sensitive.However,owing to the lack of cohorts with treatment and follow-up data,the heterogeneity among different recurrence patterns remains uncharted.Current treatments still lack precision.Methods:This analysis included data from a large-scale multiomics study of a HR^(+)/HER2^(−)breast cancer cohort(n=314).Through the analysis of transcriptomics(n=312),proteomics(n=124),whole-exome sequencing(n=290),metabolomics(n=217),and digital pathology(n=228)data,we explored distinctive molecular features and identified putative therapeutic targets for patients experiencing recurrence.Results:We explored distinct clinicopathological characteristics,biological heterogeneity,and potential therapeutic strategies for recurrence.Based on a shared relapse signature,we stratified patients into high-and lowrecurrence-risk groups.Patients with different relapse patterns presented unique molecular features in primary tumors.Specifically,receptor tyrosine kinase(RTK)pathway activation in the primary resistant group suggested the utility of RTK inhibitors,whereas mammalian target of rapamycin(mTOR)and cell cycle pathway activation in the secondary resistant group highlighted the potential of mTOR and CDK4/6 inhibitors.Interestingly,the endocrine-sensitive group displayed a quiescent state and high genomic instability,suggesting that targeting quiescent cells and using poly-ADP-ribose polymerase(PARP)inhibitors could be effective strategies.Conclusions:These findings illuminate the clinicopathological and molecular landscape of HR^(+)/HER2^(−)breast cancer patients with distinct recurrence patterns,highlighting potential targeted therapies.

关 键 词：HR^(+)/HER2^(−)breast cancer endocrine resistance cancer recurrence multiomics analysis precise treatment 

分 类 号：R737.9[医药卫生—肿瘤]