Background

Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment.

Objective

To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy.

Design, setting, and participants

Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75 mg/m²) or cabazitaxel (20 or 25 mg/m²) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25 mg/m²) as second-line chemotherapy (PROSELICA).

Outcome measurements and statistical analysis

Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies.

Results and limitations

In 2502 samples, baseline log₁₀ cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR] = 1.54; 95% confidence interval [CI]: 1.15–2.08; p = 0.004), and shorter OS on taxane therapy (HR = 1.53; 95% CI: 1.18–1.97; p = 0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log₁₀ cfDNA concentrations during the first four cycles of treatment (per cycle −0.03; 95% CI: −0.044 to −0.009; p = 0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA.

Conclusions

We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes.

Patient summary

In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3–9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA.

中文翻译：

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来自两个 III 期试验（FIRSTANA 和 PROSELICA）的紫杉烷治疗转移性去势抵抗性前列腺癌的血浆无细胞 DNA 浓度和结果

背景

需要无创生物标志物来指导转移性去势抵抗性前列腺癌 (mCRPC) 治疗。

客观的

临床上将基线和治疗中的无细胞 DNA (cfDNA) 浓度作为紫杉烷化疗后患者结果的生物标志物。

设计、设置和参与者

用于 cfDNA 分析的血液是从参与两项 III 期临床试验 FIRSTANA (NCT01308567) 和 PROSELICA (NCT01308580) 的 571 名 mCRPC 患者中前瞻性收集的。患者接受多西他赛 (75 mg/m ² ) 或卡巴他赛 (20 或 25 mg/m ² ) 作为一线化疗 (FIRSTANA)，卡巴他赛 (20 或 25 mg/m ² ) 作为二线化疗 (PROSELICA)。

结果测量和统计分析

使用逻辑回归模型测试了 cfDNA 浓度与前列腺特异性抗原 (PSA) 反应之间的关联。使用 Kaplan-Meier 方法对按四分位数分组的 cfDNA 浓度估计存活率。在每项研究中，Cox 比例风险模型测试了与放射学无进展生存期 (rPFS) 和总生存期 (OS) 的关联，并通过多变量分析调整了基线预后变量。两阶段个体患者荟萃分析结合了两项研究的 cfDNA 浓度结果。

结果和限制

在 2502 个样本中，基线 log ₁₀ cfDNA 浓度与已知的预后因素、较短的 rPFS（风险比 [HR] = 1.54；95% 置信区间 [CI]：1.15–2.08；p  = 0.004）以及紫杉烷治疗的 OS 较短相关（ HR = 1.53；95% CI：1.18–1.97；p  = 0.001）。在多变量分析中，基线 cfDNA 浓度是一线和二线化疗环境中 rPFS 和 OS 的独立预后变量。患者具有PSA响应经历了日志的下降₁₀ 95％CI;（每个循环-0.03治疗的第一四个周期期间cfDNA浓度：-0.044到-0.009; p = 0.003）。研究的局限性包括并非所有患者都必须采集血液样本，以及无法对 cfDNA 中肿瘤来源的 cfDNA 部分进行特异性定量。

结论

我们报告说，cfDNA 浓度的变化与接受一线和二线紫杉烷治疗的患者的 rPFS 和 OS 相关，并且可以作为对紫杉烷反应的独立预后生物标志物。

患者总结

在过去十年中，已经为诊断出患有转移性前列腺癌的男性引入了几种新疗法。尽管转移性前列腺癌仍然无法治愈，但与过去十年相比，这些新型药物延长了患者的生存期并提高了他们的生活质量。为了进一步优化治疗分配和个性化患者护理，需要更好的测试（生物标志物）来指导提供改进和更精确的护理。在本报告中，我们评估了来自前列腺癌男性的 2500 多份血液样本中的 cfDNA，这些男性被招募到两项独立的国际研究并接受紫杉烷化疗。我们量化了血浆中 cfDNA 片段的浓度，部分来源于肿瘤。我们发现，在开始紫杉烷化疗之前，循环 cfDNA 片段的浓度更高，可用于识别侵袭性前列腺癌患者。在从紫杉烷化疗中获益的患者中，在开始紫杉烷治疗后的前 3-9 周内，cfDNA 浓度下降。这些结果将循环 cfDNA 确定为转移性前列腺癌侵袭性疾病的新生物标志物，并暗示 cfDNA 的研究具有临床效用，支持进一步努力开发基于循环的肿瘤衍生 DNA 的血液检测。