Metastatic castration-resistant prostate cancer (mCRPC) includes a subset of patients with particularly unfavorable prognosis characterized by combined defects in at least two of three tumor suppressor genes: PTEN , RB1 , and TP53 as aggressive variant prostate cancer molecular signature (AVPC-MS). We aimed to identify circulating tumor cells (CTC) signatures that could inform treatment decisions of patients with mCRPC with cabazitaxel–carboplatin combination therapy versus cabazitaxel alone. Liquid biopsy samples were collected prospectively from 79 patients for retrospective analysis. CTCs were detected, classified, enumerated through a computational pipeline followed by manual curation, and subjected to single-cell genome-wide copy-number profiling for AVPC-MS detection. On the basis of immunofluorescence intensities, detected rare cells were classified into 8 rare-cell groups. Further morphologic characterization categorized CTC subtypes from 4 cytokeratin-positive rare-cell groups, utilizing presence of mesenchymal features and platelet attachment. Of 79 cases, 77 (97.5%) had CTCs, 24 (30.4%) were positive for platelet-coated CTCs (pc.CTCs) and 25 (38.5%) of 65 sequenced patients exhibited AVPC-MS in CTCs. Survival analysis indicated that the presence of pc.CTCs identified the subset of patients who were AVPC-MS–positive with the worst prognosis and minimal benefit from combination therapy. In AVPC-MS–negative patients, its presence showed significant survival improvement from combination therapy. Our findings suggest the presence of pc.CTCs as a predictive biomarker to further stratify AVPC subsets with the worst prognosis and the most significant benefit of additional platinum therapy. Implications: HDSCA3.0 can be performed with rare cell detection, categorization, and genomic characterization for pc.CTC identification and AVPC-MS detection as a potential predictive biomarker of mCRPC.

中文翻译：

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血小板包被的循环肿瘤细胞是转移性去势抵抗性前列腺癌患者的预测生物标志物

转移性去势抵抗性前列腺癌 (mCRPC) 包括具有特别不利预后的患者子集，其特征在于三个肿瘤抑制基因中至少两个的组合缺陷：PTEN、RB1 和 TP53 作为侵袭性变异前列腺癌分子特征 (AVPC-MS) . 我们旨在确定循环肿瘤细胞 (CTC) 特征，这些特征可以为 mCRPC 患者使用卡巴他赛-卡铂联合治疗与单独使用卡巴他赛治疗决策提供信息。前瞻性地从 79 名患者中收集液体活检样本进行回顾性分析。通过计算管道检测、分类、枚举 CTC，然后进行手动管理，并进行单细胞全基因组拷贝数分析以进行 AVPC-MS 检测。根据免疫荧光强度，检测到的稀有细胞分为8个稀有细胞组。进一步的形态学特征利用间充质特征和血小板附着的存在对来自 4 个细胞角蛋白阳性稀有细胞组的 CTC 亚型进行了分类。在 79 例病例中，77 例（97.5%）有 CTC，24 例（30.4%）血小板涂层 CTC（pc.CTC）呈阳性，65 名测序患者中有 25 例（38.5%）在 CTC 中表现出 AVPC-MS。生存分析表明，pc.CTCs 的存在确定了 AVPC-MS 阳性患者的亚组，其预后最差，联合治疗的益处最小。在 AVPC-MS 阴性患者中，它的存在显示联合治疗显着改善了生存率。我们的研究结果表明存在 pc。CTCs 作为一种预测性生物标志物，可进一步对预后最差的 AVPC 亚群进行分层，以及额外铂类治疗的最显着益处。启示：HDSCA3.0 可用于 pc.CTC 鉴定和 AVPC-MS 检测的稀有细胞检测、分类和基因组表征，作为 mCRPC 的潜在预测生物标志物。