Transcriptomic Heterogeneity of Androgen Receptor Activity Defines a de novo low AR-Active Subclass in Treatment Naive Primary Prostate Cancer
Transcriptomic Heterogeneity of Androgen Receptor Activity Defines a de novo low AR-Active Subclass in Treatment Naive Primary Prostate Cancer
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DOI：
10.1158/1078-0432.ccr-19-1587
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发表时间：
2019-11-15
影响因子：
11.5
通讯作者：
Schaeffer, Edward M.
中科院分区：
文献类型：
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作者：
Spratt, Daniel E.;Alshalalfa, Mohammed;Schaeffer, Edward M.
目的：雄激素受体(AR)活性(AR-A)的异质性在经高度治疗的转移性去势耐受前列腺癌(MCRPC)中有很好的特征。然而，AR-A在治疗初发前列腺癌中的多样性和临床意义在很大程度上是未知的。我们试图确定AR-A在局限性前列腺癌中的特征，并了解其分子和临床意义。实验设计：使用来自19470名患者的前列腺切除或活检样本的全基因组表达谱，所有研究均有独立的病理回顾。这包括前瞻性发现(n=5,239)和验证(n=12,728)队列，6个有长期临床结果数据的回溯性机构队列(n=1,170)，以及癌症基因组图谱(n=333)。结果：确定了一个低AR活性亚类，占每个队列的9%-11%，其特征是免疫信号增加，神经内分泌表达增加，DNA修复减少。这些肿瘤以ERG和基底亚型为主。多因素分析显示，AR活性低的肿瘤发生复发或转移的速度明显快于队列[HR，2.61；95%可信区间(CI)1.22~5.6；P=0.014]。AR活性低的肿瘤对PARP抑制、铂类化疗和放射治疗更敏感，而对多西紫杉醇和雄激素剥夺治疗不敏感。这在临床上得到了验证，因为AR活性低的肿瘤对雄激素剥夺治疗不那么敏感(OR，0.41；95%CI，0.21-0.80；P=0.008)。结论：利用大规模转录数据可以识别一种侵袭性的亚型，即治疗未成熟的原发性前列腺癌，其分子特征更类似于mCRPC。这表明，先前存在的一组患者可能患有肿瘤，这些肿瘤容易导致当前的多种护理标准治疗失败，需要进行专门的治疗性研究。
Purpose: The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatmentnaive primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications.Experimental Design: Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (n = 5,239) and validation (n = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n = 1,170), and The Cancer Genome Atlas (n = 333).Results: A low AR-active subclass was identified, which comprised 9%-11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22-5.60; P = 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21-0.80; P = 0.008).Conclusions: Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naive primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.