BACKGROUND Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~ 1%) but are relatively common (10-50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagnosed metastatic disease. METHODS We collected 130 archival tumor samples from 103 breast cancer patients treated with endocrine therapy prior to their local/metastatic recurrence. The cohort consisted of 41 patients having at least 1 sample from local/loco-regional recurrence and 62 patients with metastatic disease (of whom 41 newly diagnosed and 28 with advanced disease). The 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed either by targeted sequencing or by droplet digital PCR. Progression-free survival (PFS), disease-free survival (DFS), and distant recurrence-free survival (DRFS) were statistically tested by Kaplan-Meier analysis. RESULTS The prevalence of ESR1 mutations was 5/41 (12%) in newly diagnosed metastatic patients and 5/28 (18%) for advanced metastases, detected at allele frequency > 1%. All mutations in advanced metastases were detected in patients previously treated with both tamoxifen (TAM) and aromatase inhibitors (AI). However, in newly diagnosed metastatic patients, 4/5 mutations occurred in patients treated with TAM alone. PFS on AI treatment in metastatic patients was significantly shorter for ESR1 mutation carriers (p = 0.017). In the local recurrence cohort, ESR1 mutations were identified in 15/41 (36%) patients but only 4/41 (10%) were detected at allele frequency > 1%. Again, most mutations (3/4) were detected under TAM monotherapy. Notably, 1 patient developed ESR1 mutation while on neoadjuvant endocrine therapy. DFS and DRFS were significantly shorter (p = 0.04 and p = 0.017, respectively) in patients that had ESR1 mutations (> 1%) in their loco-regional recurrence tumor. CONCLUSIONS Clinically relevant ESR1 mutations are prevalent in newly diagnosed metastatic and local recurrence of endocrine-treated breast cancer. Since local recurrences are amenable to curative therapy, these mutations may inform the selection of subsequent endocrine therapies.

中文翻译：

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ESR1 突变在内分泌治疗的乳腺癌新诊断的转移性和局部区域复发中很常见，并且预后较差。

背景 编码雌激素受体 (ER) 的 ESR1 基因中出现的突变与对内分泌治疗的抗性有关。ESR1 突变很少存在于原发性肿瘤中 (~ 1%)，但在转移性、内分泌治疗耐药的癌症中相对常见 (10-50%)，并且与较短的无进展生存期相关。关于这些突变在早期复发事件（例如局部复发或新诊断的转移性疾病）中的发生率和临床意义知之甚少。方法 我们收集了 103 名在局部/转移复发前接受内分泌治疗的乳腺癌患者的 130 份存档肿瘤样本。该队列包括 41 名至少有 1 个局部/局部区域复发样本的患者和 62 名转移性疾病患者（其中 41 名新诊断的患者和 28 名晚期疾病患者）。通过靶向测序或液滴数字 PCR 分析了 5 个最常见的 ESR1 热点突变（D538G、L536R、Y537S/N/C）。无进展生存期（PFS）、无病生存期（DFS）和无远处复发生存期（DRFS）通过 Kaplan-Meier 分析进行统计检验。结果 ESR1 突变在新诊断的转移患者中为 5/41 (12%)，在等位基因频率 > 1% 时检测到的晚期转移患者为 5/28 (18%)。在既往接受过他莫昔芬 (TAM) 和芳香酶抑制剂 (AI) 治疗的患者中，检测到晚期转移灶中的所有突变。然而，在新诊断的转移患者中，4/5 突变发生在单独接受 TAM 治疗的患者中。对于 ESR1 突变携带者，转移患者 AI 治疗的 PFS 显着更短（p = 0.017）。在局部复发队列中，在 15/41 (36%) 患者中发现了 ESR1 突变，但在等位基因频率 > 1% 时仅检测到 4/41 (10%)。同样，大多数突变 (3/4) 是在 TAM 单药治疗下检测到的。值得注意的是，1 名患者在接受新辅助内分泌治疗时发生了 ESR1 突变。在其局部区域复发肿瘤中具有 ESR1 突变（> 1%）的患者中，DFS 和 DRFS 显着缩短（分别为 p = 0.04 和 p = 0.017）。结论临床相关的 ESR1 突变在内分泌治疗的乳腺癌新诊断的转移性和局部复发中普遍存在。由于局部复发适合治愈性治疗，