Tumor mutations in the gene encoding estrogen receptor alpha (ESR1) have been identified in metastatic breast cancer patients with endocrine therapy resistance. However, relatively little is known about the occurrence of mutations in the progesterone receptor (PGR) gene in this population. The study objective was to determine the frequency and prognostic significance of tumor PGR mutations for patients with estrogen receptor (ER)-positive metastatic breast cancer. Thirty-five women with metastatic or locally recurrent ER+ breast cancer were included in this IRB-approved, retrospective study. Targeted next-generation sequencing of the PGR gene was performed on isolated tumor DNA. Associations between mutation status and clinicopathologic factors were analyzed as well as overall survival (OS) from time of metastatic diagnosis. The effect of the PGR variant Y890C (c.2669A>G) identified in this cohort on PR transactivation function was tested using ER−PR− (MDA-MB-231), ER+PR+ (T47D), and ER+PR− (T47D PR KO) breast cancer cell lines. There were 71 occurrences of protein-coding PGR variants in 67% (24/36; 95% CI 49–81%) of lesions. Of the 49 unique variants, 14 are single nucleotide polymorphisms (SNPs). Excluding SNPs, the median OS of patients with PGR variants was 32 months compared to 79 months with wild-type PGR (p = 0.42). The most frequently occurring (4/36 lesions) non-SNP variant was Y890C. Cells expressing Y890C had reduced progestin-stimulated PR transactivation compared to cells expressing wild-type PR. PGR variants occur frequently in ER+ metastatic breast cancer. Although some variants are SNPs, others are predicted to be functionally deleterious as demonstrated with Y890C PR.

中文翻译：

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转移性雌激素受体阳性乳腺癌中的孕酮受体基因变异。

在具有内分泌治疗抵抗力的转移性乳腺癌患者中，已经确定了编码雌激素受体α（ESR1）的基因中的肿瘤突变。但是，关于该人群中孕酮受体（PGR）基因突变的发生知之甚少。本研究的目的是确定雌激素受体（ER）阳性转移性乳腺癌患者肿瘤PGR突变的频率和预后意义。这项IRB批准的回顾性研究包括了35例转移性或局部复发性ER +乳腺癌的女性。针对性的PGR下一代测序基因在分离的肿瘤DNA上进行。分析了突变状态与临床病理因素之间的关联以及转移诊断后的总生存期（OS）。使用ER-PR-（MDA-MB-231），ER + PR +（T47D）和ER + PR-（在此队列中鉴定的PGR变体Y890C（c.2669A> G）对PR反式激活功能的影响T47D PR KO）乳腺癌细胞系。在67％（24/36; 95％CI 49–81％）的病变中有71种蛋白质编码的PGR变异。在49个独特变体中，有14个是单核苷酸多态性（SNP）。除SNP外，PGR变异患者的中位OS为32个月，而野生型PGR为79个月（p = 0.42）。最常见的（4/36个病变）非SNP变异是Y890C。与表达野生型PR的细胞相比，表达Y890C的细胞减少了孕激素刺激的PR反式激活。PGR变体在ER +转移性乳腺癌中经常发生。尽管某些变体是SNP，但如Y890C PR所示，其他变体被认为在功能上有害。