Objective:The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor(HR)-positive advanced breast cancer.Circulating tumor DNA(ctDNA)has been allowed for the assessment of the genomic profiles of patients with advanced cancer.We performed this study to search for molecular markers of endocrine therapy efficacy and to explore the clinical value of ctDNA to guide precise endocrine therapy for HR-positive/human epidermal growth factor receptor-2(HER-2)-negative metastatic breast cancer patients.Methods:In this open-label,multicohort,prospective study,patients were assigned to four parallel cohorts and matched according to mutations identified in ctDNA:1)activation of the phosphatidylinositol-3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR)signaling pathway preferred mTOR inhibitor combined with endocrine therapy;2)estrogen receptor 1(ESR1)mutation preferred fulvestrant;3)HER-2 mutations preferred pyrotinib;and 4)no actionable mutations received treatment according to the clinical situation.In all cohorts,patients were divided into compliance group and violation group.The primary outcome measure was progression-free survival(PFS),and the secondary outcome measure was overall survival(OS).Results:In all cohorts,the combined median PFS was 4.9 months,and median PFS for the compliance and violation groups was 6.0 and 3.0 months,respectively[P=0.022,hazard ratio(HR)=0.57].Multivariate Cox regression model showed the risk of disease progression was lower in compliance group than in violation group(P=0.023,HR=0.55).Among the patients with HER-2 mutations,the median PFS was 11.1 months in the compliance group and 2.2 months in the violation group(P=0.011,HR=0.20).There was no significant difference in the median PFS between patients who did and did not comply with the treatment protocol in patients with activation of the PI3K/AKT/mTOR or ESR1 mutation.Conclusions:The results suggest that ctDNA may help to guide the optimal endocrine therapy strategy for metastatic breast cancer patients and to achieve a better PFS.Next-generation sequencing(NGS)detection could aid in distinguishing patients with HER-2 mutation and developing new treatment strategies.

Dan Lyu;Binliang Liu;Bo Lan;Xiaoying Sun;Lixi Li;Jingtong Zhai;Haili Qian;Fei Ma

Department of Medical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China;Department of Breast Cancer Medical Oncology,Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine,Central South University,Changsha 410013,China;Department of Medical Oncology,Cancer Hospital of Huanxing Chaoyang District,Beijing 100122,China;State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China

中国癌症研究（英文版）

[1]Dan Lyu;Binliang Liu;Bo Lan;Xiaoying Sun;Lixi Li;Jingtong Zhai;Haili Qian;Fei Ma-.Clinical value of next-generation sequencing in guiding decisions regarding endocrine therapy for advanced HR-positive/HER-2-negative breast cancer)[J].中国癌症研究（英文版）,2022(04):343-352

multicohort,fulvestrant,pyrotinib

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