University College London Cancer Institute, London, UK.
Englander Institute for Precision Medicine, Weill Cornell Medicine, New York-Presbyterian, New York, USA.
Ann Oncol. 2021 Jun;32(6):726-735. doi: 10.1016/j.annonc.2021.03.196. Epub 2021 Mar 29.
Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment.
Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS).
Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients.
Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.
血浆肿瘤 DNA 分数在转移性癌症中具有预后意义。这可以在开始新治疗之前改善风险分层。我们假设，在接受治疗的一个周期后采集的第二个样本可以改善基于治疗前血浆 DNA 采集而被确定为预后不良的患者的预后预测。
在醋酸阿比特龙（NCT01867710）的一项 II 期研究中，对 151 例化疗初治转移性去势抵抗性前列腺癌（mCRPC）患者的 128 个预处理、134 个周期 2 天 1 次（C2D1）和 49 个进展期的血浆 DNA 进行了靶向二代测序，该测序覆盖了这些基因的外显子：TP53、AR、RB1、PTEN、PIK3CA、BRCA1、BRCA2、ATM、CDK12、CHEK2、FANCA、HDAC2 和 PALB2。我们还捕获了 1500 个富含单核苷酸多态性的全基因组区域，以允许使用滚动 B-等位基因方法检测肿瘤 DNA。我们检测了与总生存期（OS）和无进展生存期（PFS）的相关性。
血浆肿瘤 DNA 的检测与较短的 OS [风险比（HR）：2.89，95%置信区间（CI）：1.77-4.73，P ≤ 0.0001]和 PFS（HR：2.05；95% CI：1.36-3.11，P < 0.001）相关。在包括血浆肿瘤 DNA 的多变量模型中，在预处理和 C2D1 时均具有 TP53、RB1 或 PTEN 基因突变的患者与在两个时间点均无突变的患者相比，OS 显著缩短（TP53：HR 7.13，95% CI 2.37-21.47，P < 0.001；RB1：HR 6.24，95% CI 1.97-19.73，P = 0.002；PTEN：HR 11.9，95% CI 3.6-39.34，P < 0.001）。在预处理时为阳性且转为不可检测的患者与在预处理时为不可检测的患者相比，其生存无差异（P = 0.48，P = 0.43，P = 0.5，分别）。进展样本均在所有预处理时具有增益的患者中携带 AR 增益（9/49），并且在 8/49 例患者中检测到新出现的 AR 体细胞点突变。
治疗一个周期后的血浆基因检测可改善预后预测，并可提供治疗获益的早期迹象。
