Division of Hematology, Oncology and Transplantation, University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA.
Foundation Medicine, Cambridge, Massachusetts, USA.
Prostate. 2022 May;82(7):867-875. doi: 10.1002/pros.24331. Epub 2022 Mar 14.
Liquid biopsy is a powerful tool that can enable treatment decisions for metastatic prostate cancer patients with difficult-to-biopsy tumors. However, the detection of genomic alterations via liquid biopsy is limited by the fraction (tumor fraction [TF]) of circulating tumor DNA (ctDNA) within the total cell-free DNA content. While prior work has preliminarily correlated TF with clinical features of prostate cancer, we sought to validate and provide additional resolution, such that a clinical practitioner might anticipate the probability of successful liquid biopsy profiling leveraging commonly assessed clinical and laboratory features.
A total of 813 liquid biopsy specimens were assessable, with 545 associated with a PSA prostate specific antigen measurement, collected in standard-of-care settings across approximately 280 US academic or community-based cancer clinics from September 2018 to July 2021. Deidentified data were captured into a real-world clinico-genomic database (CGDB). Comprehensive genomic profiling (CGP) was performed on extracted cell-free DNA from liquid biopsy samples.
In multivariable models, higher PSA level, lower hemoglobin, lower albumin, higher alkaline phosphatase (all p < 0.001), and collection of liquid biopsy blood draw within 60 days of new treatment initiation (p = 0.002) were the most strongly associated features with higher TF. At PSA levels of <5 ng/ml, 43% of patients had a TF of <1% indicating an increased likelihood of unevaluable results. Conversely, at PSA levels of >5 ng/ml, 78% of patients had a TF of at least 1% and 46% had a TF of ≥10%, suggesting improved sensitivity for detection of targetable alterations.
Universal genomic profiling of prostate cancers will require complementary use of liquid biopsy and tumor tissue profiling for suitable patients. The likelihood of adequate ctDNA shedding into plasma is one consideration when deciding whether to pursue CGP via liquid biopsy versus tumor profiling. Our real-world data suggest that PSA < 5 ng/ml is associated with lower ctDNA yield on liquid biopsy, potentially increasing the incidence of negative results or a need for confirmation with tissue testing.
液体活检是一种强大的工具，可以为肿瘤难以活检的转移性前列腺癌患者做出治疗决策。然而，液体活检中通过基因组改变的检测受到循环肿瘤 DNA（ctDNA）在总无细胞 DNA 含量中所占比例（肿瘤分数[TF]）的限制。虽然之前的工作已经初步将 TF 与前列腺癌的临床特征相关联，但我们试图进行验证并提供额外的分辨率，以便临床医生可以利用通常评估的临床和实验室特征来预测液体活检分析成功的概率。
共评估了 813 份液体活检标本，其中 545 份与 2018 年 9 月至 2021 年 7 月期间在大约 280 家美国学术或社区癌症诊所的标准护理环境中收集的 PSA 前列腺特异性抗原测量值相关联。从液体活检样本中提取无细胞 DNA 后进行综合基因组分析（CGP）。
在多变量模型中，较高的 PSA 水平、较低的血红蛋白、较低的白蛋白、较高的碱性磷酸酶（均 p<0.001）和在新治疗开始后 60 天内采集液体活检血液样本（p=0.002）是与较高 TF 最密切相关的特征。在 PSA 水平<5ng/ml 的情况下，43%的患者 TF<1%，这表明结果不可评估的可能性增加。相反，在 PSA 水平>5ng/ml 的情况下，78%的患者 TF 至少为 1%，46%的患者 TF 至少为 10%，这表明检测靶向改变的敏感性提高。
前列腺癌的通用基因组分析将需要液体活检和肿瘤组织分析的互补使用，适用于合适的患者。当决定是通过液体活检还是肿瘤分析来进行 CGP 时，考虑到 ctDNA 进入血浆的适当脱落程度是一个考虑因素。我们的真实世界数据表明，PSA<5ng/ml 与液体活检中 ctDNA 产量较低相关，这可能会增加阴性结果的发生率，或者需要进行组织检测确认。
