Medical Prognosis Institute, Hørsholm, Denmark.
Medical Prognosis Institute, Hørsholm, Denmark ; Now at the Department of Clinical Epidemiology at Aarhus University Hospital, Aarhus C, Denmark.
PLoS One. 2014 Feb 5;9(2):e87415. doi: 10.1371/journal.pone.0087415. eCollection 2014.
Fulvestrant is a selective estrogen receptor antagonist. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of fulvestrant, as well as the baseline gene expression of the 60 cell lines, a gene expression score that predicts response to fulvestrant was developed. The score is based on 414 genes, 103 of which show increased expression in sensitive cell lines, while 311 show increased expression in the non-responding cell lines. The sensitivity genes primarily sense signaling through estrogen receptor alpha, whereas the resistance genes modulate the PI3K signaling pathway. The latter genes suggest that resistance to fulvestrant can be overcome by drugs targeting the PI3K pathway. The level of this gene expression score and its correlation with fulvestrant response was measured in a panel of 20 breast cancer cell lines. The predicted sensitivity matched the measured sensitivity well (CC = -0.63, P = 0.003). The predictor was applied to tumor biopsies obtained from a Phase II clinical trial. The sensitivity of each patient to treatment with fulvestrant was predicted based on the RNA profile of the biopsy taken before neoadjuvant treatment and without knowledge of the subsequent response. The prediction was then compared to clinical response to show that the responders had a significantly higher sensitivity prediction than the non-responders (P = 0.01). When clinical covariates, tumor grade and estrogen receptor H-score, were included in the prediction, the difference in predicted senstivity between responders and non-responders improved (P = 0.003). Using a pre-defined cutoff to separate patients into predicted sensitive and predicted resistant yielded a positive predictive value of 88% and a negative predictive value of 100% when compared to clinical data. We conclude that pre-screening patients with the new gene expression predictor has the potential to identify those postmenopausal women with locally advanced, estrogen-receptor-positive breast cancer most likely to respond to fulvestrant.
氟维司群是一种选择性雌激素受体拮抗剂。根据氟维司群存在时对 60 个人类癌细胞系（NCI60）生长抑制的测定，以及 60 个细胞系的基线基因表达情况，开发了一种预测对氟维司群反应的基因表达评分。该评分基于 414 个基因，其中 103 个在敏感细胞系中表达增加，而 311 个在无反应细胞系中表达增加。敏感基因主要感知雌激素受体 α 的信号传导，而耐药基因则调节 PI3K 信号通路。后者的基因表明，针对 PI3K 通路的药物可以克服对氟维司群的耐药性。在 20 个乳腺癌细胞系的面板中测量了该基因表达评分的水平及其与氟维司群反应的相关性。预测的敏感性与测量的敏感性非常吻合（CC = -0.63，P = 0.003）。该预测因子应用于来自 II 期临床试验的肿瘤活检。根据新辅助治疗前获得的活检的 RNA 谱，并在不了解后续反应的情况下，预测每位患者对氟维司群治疗的敏感性。然后将预测结果与临床反应进行比较，表明反应者的敏感性预测明显高于无反应者（P = 0.01）。当将临床协变量、肿瘤分级和雌激素受体 H 评分纳入预测时，反应者和无反应者之间预测敏感性的差异得到改善（P = 0.003）。使用预定义的截止值将患者分为预测敏感型和预测耐药型，与临床数据相比，阳性预测值为 88%，阴性预测值为 100%。我们得出的结论是，使用新的基因表达预测因子对患者进行预筛选有可能识别出那些患有局部晚期、雌激素受体阳性乳腺癌的绝经后妇女，她们最有可能对氟维司群产生反应。
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