Knutson Todd P, Luo Bin, Kobilka Anna, Lyman Jacqueline, Guo Siyuan, Munro Sarah A, Li Yingming, Heer Rakesh, Gaughan Luke, Morris Michael J, Beltran Himisha, Ryan Charles J, Antonarakis Emmanuel S, Armstrong Andrew J, Halabi Susan, Dehm Scott M
Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
Nat Commun. 2024 Dec 11;15(1):10648. doi: 10.1038/s41467-024-54847-1.
Circulating tumor DNA (ctDNA) in plasma cell free DNA (cfDNA) of cancer patients is associated with poor prognosis, but is challenging to detect from low plasma volumes. In metastatic castration-resistant prostate cancer (mCRPC), ctDNA assays are needed to prognosticate outcomes of patients treated with androgen receptor (AR) inhibitors. We develop a custom targeted cfDNA sequencing assay, named AR-ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone. Of 776 patients, 59% are ctDNA-positive, with 26% having high ctDNA aneuploidy and 33% having low ctDNA aneuploidy but displaying AR gain or structural rearrangement, MYC/MYCN gain, or a pathogenic mutation. ctDNA-positive patients have significantly worse median overall survival than ctDNA-negative patients (29.0 months vs. 47.4 months, respectively). Here, we show that mCRPC patients identified as ctDNA-positive using the AR-ctDETECT assay have poor survival despite treatment with potent AR inhibitors in a phase 3 trial.
癌症患者血浆游离DNA（cfDNA）中的循环肿瘤DNA（ctDNA）与预后不良相关，但从少量血浆中检测ctDNA具有挑战性。在转移性去势抵抗性前列腺癌（mCRPC）中，需要进行ctDNA检测来预测接受雄激素受体（AR）抑制剂治疗的患者的预后。我们开发了一种定制的靶向cfDNA测序检测方法，名为AR-ctDETECT，用于在恩杂鲁胺联合或不联合阿比特龙的Alliance A031201随机3期试验中，检测mCRPC患者有限的血浆cfDNA中的ctDNA。在776名患者中，59%的患者ctDNA呈阳性，其中26%的患者ctDNA非整倍性高，33%的患者ctDNA非整倍性低，但显示AR扩增或结构重排、MYC/MYCN扩增或致病突变。ctDNA阳性患者的中位总生存期明显短于ctDNA阴性患者（分别为29.0个月和47.4个月）。在此，我们表明，在3期试验中，尽管使用了强效AR抑制剂进行治疗，但通过AR-ctDETECT检测被确定为ctDNA阳性的mCRPC患者的生存期仍较差。
