BACKGROUND: ESR1 mutations are frequently detected in ER+ MBC, and have been reported to be associated with endocrine therapy resistance. However, there are little researches to validate whether dynamic monitoring of ESR1 mutations could serve as a predictive plasma biomarker of acquired resistance to endocrine therapy. Therefore, in this study, we performed longitudinal circulating tumor DNA (ctDNA) detection to evaluate the clinical implications of monitoring ESR1 mutations. METHODS: We performed longitudinal dynamic mutation analyses of plasma samples from 45 patients with metastatic breast cancer (MBC) and sequencing paired biopsy tissues, using a targeted NGS panel of 425 genes. These patients were treated at the Second Affiliated Hospital of Dalian Medical University between January 2017 and February 2019 with written informed consent. RESULTS: Mutations profiles were highly concordant between plasma and paired tissue samples from 45 MBC patients (r = 0.96, P < 0.0001). ESR1 mutations were enriched in ER+ MBC patients after AI therapy (17.8%, 8/45). The median time from AI endocrine therapies to the initial detection of ESR1 mutation was 39 months (95% CI 21.32–57.57). Some hotspot mutations (Y537S (n = 5), Y537N (n = 1), D538G (n = 2), E380Q (n = 2)) and several rare mutations (L345SfsX7, 24fs, G344delinsGC) were identified in our cohort. In addition, we observed that two patients obtained multiple ESR1 mutations over the course of treatment (Y537N/Y537S/D538G, L345SfsX7/24fs/E380Q). Through dynamically monitoring ESR1 mutations by ctDNA, we demonstrated that the change of allele frequency of ESR1 mutations was an important biomarker, which could predict endocrine resistance of ER+ MBC in our study. We also observed that the combination of everolimus in four cases with acquired ESR1 mutations showed longer PFS than other therapies without everolimus. CONCLUSION: The dynamic monitoring of ESR1 mutations by ctDNA is a promising tool to predict endocrine therapy resistance in ER+ MBC patients.

背景： ESR1突变是经常在ER + MBC中检测到的，并且据报道与内分泌治疗耐药有关。然而，很少有研究来验证对ESR1突变的动态监测是否可以作为获得性对内分泌治疗耐药性的预测性血浆生物标志物。因此，在这项研究中，我们进行了纵向循环肿瘤DNA（ctDNA）检测，以评估监测ESR1突变的临床意义。方法：我们使用425个基因的靶向NGS组，对45例转移性乳腺癌（MBC）患者的血浆样品进行了纵向动态突变分析，并对配对的活检组织进行测序。这些患者于2017年1月至2019年2月在获得知情同意的情况下在大连医科大学第二附属医院接受治疗。结果： 45名MBC患者的血浆和配对组织样本之间的突变谱高度一致（r  = 0.96，P  <0.0001）。AI治疗后，ER + MBC患者的ESR1突变丰富（17.8％，8/45）。从AI内分泌疗法到初次发现ESR1突变的中位时间为39个月（95％CI为21.32-57.57）。一些热点突变（Y537S（n = 5），Y537N（n  = 1），D538G（n  = 2），E380Q（n  = 2））和几个罕见突变（L345SfsX7、24fs，G344delinsGC）被确定。此外，我们观察到两名患者在治疗过程中获得了多个ESR1突变（Y537N / Y537S / D538G，L345SfsX7 / 24fs / E380Q）。通过用ctDNA动态监测ESR1突变，我们证明ESR1突变的等位基因频率变化是重要的生物标志物，在我们的研究中可以预测ER + MBC的内分泌抗性。我们还观察到，在4例获得性ESR1突变的病例中，依维莫司的组合显示的PFS比无依维莫司的其他疗法更长。结论： ctDNA对ESR1突变的动态监测是预测ER + MBC患者内分泌治疗耐药性的有前途的工具。