In patients with metastatic estrogen-receptor (ER)-positive HER2-negative breast cancer, the loss of ER expression and the mutation ofESR1—the gene encoding the ER receptor—are mechanisms for resistance to endocrine therapy. We aimed to determine the frequency of these mechanisms and their interaction. Metastases were retrieved from our pathology files.ESR1hotspot mutations resulting in p.(D538G), p.(Y537S), and p.(L536H) were determined by means of pyrosequencing. Clinical data were retrieved from electronic medical records. A total of 136 metastases were available for analysis. ER loss was found in 23 metastases (17%).ESR1mutations were found in 18 metastases (13%), including p.(D538G) in 9, p.(Y537S) in 7, and p.(L536H) in 2.ESR1mutation and ER loss were mutually exclusive (p= 0.042), andESR1mutation was associated with endocrine therapy (p= 0.002).ESR1mutation was found in two primary breast cancers.ESR1mutations are rare in primary breast cancer and develop in metastases during endocrine therapy. Furthermore, ER loss had a statistically significant negative effect on overall survival when compared to patients without ER loss, with a rate ratio of 3.21 (confidence interval 1.95–5.26). No such effect was observed forESR1mutations, with a rate ratio of 1.15 (confidence interval 0.67–1.95). We conclude that ER loss andESR1mutation together account for 30% of the resistance to endocrine therapy.
在转移性雌激素受体（ER）阳性、HER2阴性乳腺癌患者中，ER表达缺失以及编码ER受体的ESR1基因突变是导致内分泌治疗耐药的重要机制。本研究旨在评估这两种机制的发生频率及其相互作用关系。我们从病理档案中提取转移灶样本，通过焦磷酸测序技术检测导致p.(D538G)、p.(Y537S)和p.(L536H)氨基酸改变的ESR1热点突变，临床数据则来源于电子病历系统。 共纳入136例可分析的转移灶样本。其中23例（17%）出现ER表达缺失，18例（13%）检出ESR1突变（包括9例p.(D538G)、7例p.(Y537S)和2例p.(L536H)）。统计分析显示ESR1突变与ER缺失呈互斥现象（p=0.042），且ESR1突变与内分泌治疗史显著相关（p=0.002）。值得注意的是，仅在2例原发性乳腺癌中检测到ESR1突变，提示该突变在原发性乳腺癌中罕见，主要在内分泌治疗过程中于转移灶内发生。 生存分析表明，与ER未缺失患者相比，ER缺失患者的总生存期显著缩短，风险比为3.21（置信区间1.95-5.26）。而ESR1突变患者未观察到类似生存差异，其风险比为1.15（置信区间0.67-1.95）。本研究结论表明，ER缺失与ESR1突变共同构成约30%的内分泌治疗耐药机制。
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