Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal patients with hormone receptor positive breast cancer
Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal patients with hormone receptor positive breast cancer
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DOI：
10.1007/s10549-010-0984-y
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发表时间：
2011-06-01
影响因子：
3.8
通讯作者：
Mouridsen, Henning T.
中科院分区：
文献类型：
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作者：
Nielsen, Kirsten Vang;Ejlertsen, Bent;Mouridsen, Henning T.
雌激素受体（ER）是他莫昔芬的靶点，但内分泌治疗并不能使所有ER阳性肿瘤患者获益。因此，我们假设ESR 1基因（编码ER）的拷贝数变化赋予耐药性。在一系列连续的ER阳性，绝经后患者分配到5年他莫昔芬，我们确定了61例复发少于4年，48例患者没有复发至少7年后，开始辅助他莫昔芬。从97名患者（89%）中收集了含有原发性肿瘤的存档组织。使用FISH分析肿瘤样品的ESR 1拷贝数变化，所述FISH具有覆盖6 q25处的ESR 1基因的探针和覆盖染色体6的着丝粒的参考探针。在120个正常乳腺样本的材料中验证了该测定。ESR 1的FISH分析在91例患者（94%）中成功。在50例早期复发患者中有11例（22%）观察到扩增（ESR 1/CEN-6比值为每千日元2.0），而41例无复发患者中有2例（5%）观察到扩增。差异具有统计学意义（P = 0.033）。在两组中，确定了两名具有ESR 1缺失的患者（比率ESR 1/CEN-6 < 0.8）。ESR 1扩增与无病生存率（P = 0.0054）和总生存率（P = 0.0004）显著相关。这项初步研究支持了我们的假设，即在ER阳性的早期乳腺癌中，ESR 1扩增与他莫昔芬辅助治疗后的不良结局相关。这项研究还揭示了ESR 1缺失的存在。ESR 1拷贝数变化的预后和预测影响需要在临床试验中进一步探索。
The estrogen receptor (ER) is the target of tamoxifen, but endocrine therapies do not benefit all patients with ER positive tumors. We therefore hypothesized that copy number changes in the ESR1 gene, encoding ER, confer resistance. Within a consecutive series of ER positive, postmenopausal patients allocated to 5 years tamoxifen, we identified 61 patients with recurrence less than 4 years and 48 patients without recurrence at least 7 years after initiation of adjuvant tamoxifen. Archival tissue containing primary tumor was collected from 97 patients (89%). Tumor samples were analyzed for ESR1 copy number changes using FISH with a probe covering the ESR1 gene at 6q25 and a reference probe covering the centromere of chromosome 6. The assay was validated in a material of 120 normal breast samples. FISH analysis for ESR1 was successful in 91 patients (94%). Amplification (ratio ESR1/CEN-6 a parts per thousand yen 2.0) was observed in 11 of 50 (22%) patients with early recurrence, compared to two of 41 (5%) patients without recurrence. The difference is statistically significant (P = 0.033). In both groups, two patients with ESR1 deletion (ratio ESR1/CEN-6 < 0.8) were identified. ESR1 amplification was significantly associated with poor disease-free survival (P = 0.0054) and overall survival (P = 0.0004). This pilot study supports our hypothesis that ESR1 amplification is associated with a poorer outcome following adjuvant treatment with tamoxifen in ER positive early breast cancer. This study also revealed the existence of ESR1 deletions. The prognostic and predictive impact of ESR1 copy number changes needs further exploration in clinical trials.