Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.
Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.
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DOI：
10.1158/1078-0432.ccr-13-2332
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发表时间：
2014-04-01
期刊：
影响因子：
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通讯作者：
Miller VA
中科院分区：
文献类型：
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作者：
Jeselsohn R;Yelensky R;Buchwalter G;Frampton G;Meric-Bernstam F;Gonzalez-Angulo AM;Ferrer-Lozano J;Perez-Fidalgo JA;Cristofanilli M;Gómez H;Arteaga CL;Giltnane J;Balko JM;Cronin MT;Jarosz M;Sun J;Hawryluk M;Lipson D;Otto G;Ross JS;Dvir A;Soussan-Gutman L;Wolf I;Rubinek T;Gilmore L;Schnitt S;Come SE;Pusztai L;Stephens P;Brown M;Miller VA
我们进行了这项研究，以确定雌激素受体(ER) α (ESR1)突变在激素依赖性乳腺癌的自然历史中的患病率，并描述最常检测到的改变的功能作用。我们共研究了208例患者的249例肿瘤标本。标本包括134例ER阳性（ER+/HER2 -）和115例ER阴性（ER -）肿瘤作为对照。ER+样本包括58例原发性乳腺癌和76例转移性乳腺癌样本。使用针对雌激素受体编码序列和另外182个癌症相关基因的下一代测序，对所有肿瘤进行了高独特覆盖率的测序。在ER+转移性疾病中检测到ER配体结合域内密码子537和538的反复体细胞突变。总体而言，在转移性肿瘤中，这些突变的频率为12% (9/76,95% CI 6%-21%)，在平均接受7种治疗的患者亚组中，这些突变的频率为20% （5/25,95% CI 7%-41%）。这些突变未在原发性或治疗naïve ER+癌或ER -疾病的任何阶段检测到。细胞系模型的功能研究表明，这些突变使雌激素受体具有组成活性，并对目前可用的内分泌治疗产生部分抗性。在这项研究中，我们展示了功能性ESR1突变作为雌激素受体阳性乳腺癌进展过程中内分泌抵抗的潜在驱动因素的时间选择的证据。
We undertook this study to determine the prevalence of estrogen receptor (ER) α (ESR1) mutations throughout the natural history of hormone dependent breast cancer and to delineate the functional roles of the most commonly detected alterations. We studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER positive (ER+/HER2–) and, as controls, 115 ER negative (ER−) tumors. The ER+ samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes. Recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ER+ metastatic disease. Overall, the frequency of these mutations was 12% (9/76, 95% CI 6%-21%) in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25, 95% CI 7%-41%). These mutations were not detected in primary or treatment naïve ER+ cancer or in any stage of ER− disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments. In this study we show evidence for the temporal selection of functional ESR1 mutations as potential drivers of endocrine resistance during the progression of ER positive breast cancer.