Lyu Dan, Liu Binliang, Lan Bo, Sun Xiaoying, Li Lixi, Zhai Jingtong, Qian Haili, Ma Fei
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.
Chin J Cancer Res. 2022 Aug 30;34(4):343-352. doi: 10.21147/j.issn.1000-9604.2022.04.03.
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.
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).
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.
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.
获得性基因突变机制在激素受体（HR）阳性晚期乳腺癌内分泌治疗耐药中起主要作用。循环肿瘤DNA（ctDNA）已被用于评估晚期癌症患者的基因组图谱。我们开展本研究以寻找内分泌治疗疗效的分子标志物，并探索ctDNA指导HR阳性/人表皮生长因子受体2（HER-2）阴性转移性乳腺癌患者精准内分泌治疗的临床价值。
在这项开放标签、多队列、前瞻性研究中，患者被分配到四个平行队列，并根据ctDNA中鉴定的突变进行匹配：1）磷脂酰肌醇-3-激酶（PI3K）/AKT/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路激活者优先使用mTOR抑制剂联合内分泌治疗；2）雌激素受体1（ESR1）突变者优先使用氟维司群；3）HER-2突变者优先使用吡咯替尼；4）无可操作突变者根据临床情况接受治疗。在所有队列中，患者被分为依从组和违规组。主要结局指标为无进展生存期（PFS），次要结局指标为总生存期（OS）。
在所有队列中，联合中位PFS为4.9个月，依从组和违规组的中位PFS分别为6.0个月和3.0个月[P = 0.022，风险比（HR）= 0.57]。多变量Cox回归模型显示，依从组疾病进展风险低于违规组（P = 0.023，HR = 0.55）。在HER-2突变患者中，依从组中位PFS为11.1个月，违规组为2.2个月（P = 0.011，HR = 0.20）。PI3K/AKT/mTOR激活或ESR1突变患者中，依从和不依从治疗方案的患者中位PFS无显著差异。
结果表明，ctDNA可能有助于指导转移性乳腺癌患者的最佳内分泌治疗策略并实现更好的PFS。下一代测序（NGS）检测有助于鉴别HER-2突变患者并制定新的治疗策略。
