Predictive and Prognostic Biomarker Identification in a Large Cohort of Androgen Receptor-Positive Salivary Duct Carcinoma Patients Scheduled for Combined Androgen Blockade.
Predictive and Prognostic Biomarker Identification in a Large Cohort of Androgen Receptor-Positive Salivary Duct Carcinoma Patients Scheduled for Combined Androgen Blockade.
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DOI：
10.3390/cancers13143527
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发表时间：
2021-07-14
期刊：
影响因子：
5.2
通讯作者：
Verhaegh GW
中科院分区：
文献类型：
--
作者：
Lassche G;Tada Y;van Herpen CML;Jonker MA;Nagao T;Saotome T;Hirai H;Saigusa N;Takahashi H;Ojiri H;van Engen-Van Grunsven ACH;Schalken JA;Fushimi C;Verhaegh GW
雄激素受体信号在侵袭性涎腺导管癌中起关键作用。然而，雄激素剥夺疗法（ADT）经常失败，强调需要生物标志物来预测治疗反应。在这里，几种可能的肿瘤驱动途径的活动被量化，并与一个大的SDC患者队列的临床结果相关。我们的研究结果表明，AR通路活性和SRD 5A 1表达水平可用于预测ADT的反应，这可能会在临床实践中防止过度治疗。患有复发性或转移性（R/M）唾液腺导管癌（SDC）的患者通常用联合雄激素阻断（CAB）治疗。然而，CAB经常失败，导致预后更差。因此，迫切需要能够预测治疗失败的生物标志物。从治疗前肿瘤标本中提取了76例接受醋酸亮丙瑞林联合比卡鲁胺治疗的R/M雄激素受体（AR）阳性SDC患者的mRNA。根据靶基因的表达水平测定AR、Notch、MAPK、TGFβ、雌激素受体（ER）、Hedgehog（HH）和PI 3 K信号通路活性评分（PAS）。此外，还测定了5-α还原酶1型（SRD 5A 1）的表达。这些标志物与临床获益（完全/部分缓解或病情稳定≥6个月）以及无进展生存期和总生存期（PFS/OS）相关。SRD 5A 1表达对临床获益和阳性预测值具有最高的一般预测值（PPV：85.7%）。AR PAS的阴性预测值最高（NPV：93.3%）。多变量模型的拟合导致将SRD 5A 1、TGFβ和Notch PAS鉴定为最具预测性的组合。高AR、高Notch、高ER、低HH PAS和高SRD 5A 1表达对于PFS和SRD 5A 1表达水平对于OS也具有预后重要性。AR、Notch PAS和SRD 5A 1表达具有预测SDC患者中CAB治疗的临床益处的潜力。SRD 5A 1表达可以识别将经历临床益处的患者和将不经历临床益处的AR PAS患者（PPV和NPV分别为85.7%和93.3%）。SRD 5A 1表达的预测潜力形成了在SDC患者的治疗中包括SRD 5A 1抑制剂的合理基础。
Androgen receptor signaling seems pivotal in aggressive salivary duct carcinoma. However, androgen deprivation therapy (ADT) frequently fails, emphasizing the need for biomarkers to predict treatment response. Here, the activities of several possible tumor-driving pathways were quantified and related to clinical outcome in a large cohort of SDC patients. Our results indicated that AR pathway activity and SRD5A1 expression levels can be used to predict response to ADT, which could prevent overtreatment in clinical practice. Patients suffering from recurrent or metastatic (R/M) salivary duct carcinoma (SDC) are often treated with combined androgen blockade (CAB). However, CAB frequently fails, resulting in a worse prognosis. Therefore, biomarkers that can predict treatment failure are urgently needed. mRNA from 76 R/M androgen receptor (AR)-positive SDC patients treated with leuprorelin acetate combined with bicalutamide was extracted from pre-treatment tumor specimens. AR, Notch, MAPK, TGFβ, estrogen receptor (ER), Hedgehog (HH), and PI3K signaling pathway activity scores (PAS) were determined based on the expression levels of target genes. Additionally, 5-alpha reductase type 1 (SRD5A1) expression was determined. These markers were related to clinical benefit (complete/partial response or stable disease ≥6 months) and progression-free and overall survival (PFS/OS). SRD5A1 expression had the highest general predictive value for clinical benefit and positive predictive value (PPV: 85.7%). AR PAS had the highest negative predictive value (NPV: 93.3%). The fitting of a multivariable model led to the identification of SRD5A1, TGFβ, and Notch PAS as the most predictive combination. High AR, high Notch, high ER, low HH PAS, and high SRD5A1 expression were also of prognostic importance regarding PFS and SRD5A1 expression levels for OS. AR, Notch PAS, and SRD5A1 expression have the potential to predict the clinical benefit of CAB treatment in SDC patients. SRD5A1 expression can identify patients that will and AR PAS patients that will not experience clinical benefit (85.7% and 93.3% for PPV and NPV, respectively). The predictive potential of SRD5A1 expression forms a rational basis for including SRD5A1-inhibitors in SDC patients’ treatment.
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影响因子：
6.4
作者：
Boon, Eline;Bel, Miranda;van Herpen, Carla M. L.
通讯作者：
van Herpen, Carla M. L.
DOI：
10.1200/jco.2016.67.5264
发表时间：
2017-01-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Ferrarotto R;Mitani Y;Diao L;Guijarro I;Wang J;Zweidler-McKay P;Bell D;William WN Jr;Glisson BS;Wick MJ;Kapoun AM;Patnaik A;Eckhardt G;Munster P;Faoro L;Dupont J;Lee JJ;Futreal A;El-Naggar AK;Heymach JV
通讯作者：
Heymach JV
影响因子：
3.7
作者：
Otsuka K;Imanishi Y;Tada Y;Kawakita D;Kano S;Tsukahara K;Shimizu A;Ozawa H;Okami K;Sakai A;Sato Y;Ueki Y;Sato Y;Hanazawa T;Chazono H;Ogawa K;Nagao T
通讯作者：
Nagao T
影响因子：
15.9
作者：
Ho, Allen S.;Ochoa, Angelica;Morris, Luc G. T.
通讯作者：
Morris, Luc G. T.
影响因子：
45.3
作者：
Ballman, Karla V.
通讯作者：
Ballman, Karla V.