Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus.
Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus.
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DOI：
10.1155/2018/3756981
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发表时间：
2018
影响因子：
--
通讯作者：
Piacentini F
中科院分区：
文献类型：
--
作者：
Omarini C;Filieri ME;Bettelli S;Manfredini S;Kaleci S;Caprera C;Nasso C;Barbolini M;Guaitoli G;Moscetti L;Maiorana A;Conte PF;Cascinu S;Piacentini F
依维莫司已被证明可克服激素受体阳性的晚期乳腺癌患者的内分泌耐药性。在原发性乳腺癌组织中对依维莫司疗效的预测性生物标志物进行了研究，但未得出明确结果。本研究的目的是调查接受依维莫司加依西美坦治疗的内分泌耐药肿瘤转移部位的突变负荷。
使用Mass Array Sequenom平台分析了25例来自转移病灶的存档肿瘤标本以及可获取的接受依维莫司和依西美坦治疗晚期疾病患者的原发性匹配乳腺癌组织中18个癌症相关基因的遗传状态。对依维莫司在无进展生存期获益和单基因突变方面的疗效进行了探索性分析。
转移和原发性乳腺癌样本的总体突变检出率分别为30%和38%。AKT1E17K是最常见的突变基因。没有原发性乳腺癌及其匹配的复发灶保持相同的突变谱。考虑分子通路，大多数基因属于PI3K通路（AKT1E17K、PI3KCAE545K和KITG565R、S709F）。在乳腺和/或复发组织中检测到突变的患者中，中位无进展生存期为5.6个月，而在无突变的患者亚组中，中位无进展生存期为7.5个月。
乳腺癌复发的突变状态可识别一些可能与肿瘤对依维莫司的反应/耐药相关的基因。最常突变的基因涉及PI3K/AKT/mTOR通路，这突出表明该通路在复发中的失调在依维莫司耐药/敏感机制中起着关键作用。由于样本量小且研究具有回顾性，这些相关性需要在大型前瞻性研究中进行验证。
Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane. Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out. The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively. AKT1E17K was the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (AKT1E17K, PI3KCAE545K, and KITG565R,S709F). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months. The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
--
作者：
Janku F;Wheler JJ;Naing A;Stepanek VM;Falchook GS;Fu S;Garrido-Laguna I;Tsimberidou AM;Piha-Paul SA;Moulder SL;Lee JJ;Luthra R;Hong DS;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
64.8
作者：
Navin N;Kendall J;Troge J;Andrews P;Rodgers L;McIndoo J;Cook K;Stepansky A;Levy D;Esposito D;Muthuswamy L;Krasnitz A;McCombie WR;Hicks J;Wigler M
通讯作者：
Wigler M
影响因子：
51.1
作者：
Badve, Sunil;Nakshatri, Harikrishna
通讯作者：
Nakshatri, Harikrishna
影响因子：
45.3
作者：
Bachelot, Thomas;Bourgier, Celine;Pujade-Lauraine, Eric
通讯作者：
Pujade-Lauraine, Eric