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.

癌症患者浆细胞游离 DNA （cfDNA） 中的循环肿瘤 DNA （ctDNA） 与不良预后相关，但很难从低血浆量中检测到。在转移性去势抵抗性前列腺癌 （mCRPC） 中，需要 ctDNA 检测来预测雄激素受体 （AR） 抑制剂治疗患者的预后。我们开发了一种名为 AR-ctDETECT 的定制靶向 cfDNA 测序测定法，用于检测恩杂鲁胺联合或不联合阿比特龙的 Alliance A031201 随机 3 期试验中 mCRPC 患者可获得的限制血浆 cfDNA 中的 ctDNA。在 776 例患者中，59% 为 ctDNA 阳性，其中 26% 具有高 ctDNA 非整倍体，33% 具有高 ctDNA 非整倍体，但显示 AR 增益或结构重排、MYC/MYCN 增益或致病性突变。ctDNA 阳性患者的中位总生存期显著低于 ctDNA 阴性患者 （分别为 29.0 个月和 47.4 个月）。在这里，我们表明，尽管在 3 期试验中使用了强效 AR 抑制剂治疗，但使用 AR-ctDETECT 检测鉴定为 ctDNA 阳性的 mCRPC 患者生存率很差。