Background

Better blood tests to elucidate the behaviour of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed to drive therapeutic decisions. Plasma cell-free DNA (cfDNA) comprises normal and circulating tumour DNA (ctDNA). Low-pass whole-genome sequencing (lpWGS) of ctDNA can provide information on mCRPC behaviour.

Objective

To validate and clinically qualify plasma lpWGS for mCRPC.

Design, setting, and participants

Plasma lpWGS data were obtained for mCRPC patients consenting to optional substudies of two prospective phase 3 trials (FIRSTANA and PROSELICA). In FIRSTANA, chemotherapy-naïve patients were randomised to treatment with docetaxel (75 mg/m²) or cabazitaxel (20 or 25 mg/m²). In PROSELICA, patients previously treated with docetaxel were randomised to 20 or 25 mg/m² cabazitaxel. lpWGS data were generated from 540 samples from 188 mCRPC patients acquired at four different time points (screening, cycle 1, cycle 4, and end of study).

Outcome measurements and statistical analysis

lpWGS data for ctDNA were evaluated for prognostic, response, and tumour genomic measures. Associations with response and survival data were determined for tumour fraction. Genomic biomarkers including large-scale transition (LST) scores were explored in the context of prior treatments.

Results and limitations

Plasma tumour fraction was prognostic for overall survival in univariable and stratified multivariable analyses (hazard ratio 1.75, 95% confidence interval 1.08–2.85; p = 0.024) and offered added value compared to existing biomarkers (C index 0.722 vs 0.709; p = 0.021). Longitudinal changes were associated with drug response. PROSELICA samples were enriched for LSTs (p = 0.029) indicating genomic instability, and this enrichment was associated with prior abiraterone and enzalutamide treatment but not taxane or radiation therapy. Higher LSTs were correlated with losses of RB1/RNASEH2B, independent of BRCA2 loss.

Conclusions

Plasma lpWGS of ctDNA describes CRPC behaviour, providing prognostic and response data of clinical relevance. The added prognostic value of the ctDNA fraction over established biomarkers should be studied further.

Patient summary

We studied tumour DNA in blood samples from patients with prostate cancer. We found that levels of tumour DNA in blood were indicative of disease prognosis, and that changes after treatment could be detected. We also observed a “genetic scar” in the results that was associated with certain previous treatments. This test allows an assessment of tumour activity that can complement existing tests, offer insights into drug response, and detect clinically relevant genetic changes.

中文翻译：

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通过循环肿瘤 DNA 的低通全基因组测序阐明治疗期间的前列腺癌行为

背景

迫切需要更好的血液检测来阐明转移性去势抵抗性前列腺癌 (mCRPC) 的行为，以推动治疗决策。血浆游离 DNA (cfDNA) 包括正常和循环肿瘤 DNA (ctDNA)。ctDNA 的低通全基因组测序 (lpWGS) 可以提供有关 mCRPC 行为的信息。

客观的

验证和临床鉴定用于 mCRPC 的血浆 lpWGS。

设计、设置和参与者

获得 mCRPC 患者的血浆 lpWGS 数据，这些患者同意两项前瞻性 3 期试验（FIRSTANA 和 PROSELICA）的可选子研究。在 FIRSTANA 中，未接受过化疗的患者被随机分配接受多西他赛 (75 mg/m ² ) 或卡巴他赛 (20 或 25 mg/m ² ) 治疗。在 PROSELICA 中，先前用多西他赛治疗的患者被随机分配到 20 或 25 mg/m ²卡巴他赛组。lpWGS 数据来自 188 名 mCRPC 患者的 540 个样本，这些样本在四个不同的时间点（筛选、第 1 周期、第 4 周期和研究结束）获得。

结果测量和统计分析

评估 ctDNA 的 lpWGS 数据的预后、反应和肿瘤基因组测量。确定肿瘤分数与反应和生存数据的关联。在先前治疗的背景下探索了包括大规模转换 (LST) 评分在内的基因组生物标志物。

结果和局限性

在单变量和分层多变量分析中，血浆肿瘤分数可预测总生存期（风险比 1.75，95% 置信区间 1.08-2.85；p = 0.024），并且与现有生物标志物相比提供附加值（C 指数 0.722 对 0.709；p = 0.021） . 纵向变化与药物反应有关。PROSELICA 样本富含 LST ( p = 0.029)，表明基因组不稳定性，这种富集与先前的阿比特龙和恩杂鲁胺治疗有关，但与紫杉烷或放射治疗无关。较高的 LST 与RB1 / RNASEH2B的损失相关，与BRCA2损失无关。

结论

ctDNA 的血浆 lpWGS 描述了 CRPC 行为，提供了临床相关的预后和反应数据。应进一步研究 ctDNA 部分相对于已建立的生物标志物的附加预后价值。

患者总结

我们研究了前列腺癌患者血液样本中的肿瘤 DNA。我们发现血液中肿瘤 DNA 的水平可以指示疾病的预后，并且可以检测到治疗后的变化。我们还在结果中观察到与某些先前治疗相关的“遗传疤痕”。该测试允许评估肿瘤活动，可以补充现有测试，提供对药物反应的见解，并检测临床相关的基因变化。