Candiolo Cancer Institute-FPO, IRCCS.
Department of Oncology, University of Torino, Candiolo.
Ann Oncol. 2017 Jun 1;28(6):1302-1308. doi: 10.1093/annonc/mdx095.
Monitoring response and resistance to kinase inhibitors is essential to precision cancer medicine, and is usually investigated by molecular profiling of a tissue biopsy obtained at progression. However, tumor heterogeneity and tissue sampling bias limit the effectiveness of this strategy. In addition, tissue biopsies are not always feasible and are associated with risks due to the invasiveness of the procedure. To overcome these limitations, blood-based liquid biopsy analysis has proven effective to non-invasively follow tumor clonal evolution.
We exploited urine cell-free, trans-renal DNA (tr-DNA) and matched plasma circulating tumor DNA (ctDNA) to monitor a metastatic colorectal cancer patient carrying a CAD-ALK translocation during treatment with an ALK inhibitor.
Using a custom next generation sequencing panel we identified the genomic CAD-ALK rearrangement and a TP53 mutation in plasma ctDNA. Sensitive assays were developed to detect both alterations in urine tr-DNA. The dynamics of the CAD-ALK rearrangement in plasma and urine were concordant and paralleled the patient's clinical course. Detection of the CAD-ALK gene fusion in urine tr-DNA anticipated radiological confirmation of disease progression. Analysis of plasma ctDNA identified ALK kinase mutations that emerged during treatment with the ALK inhibitor entrectinib.
We find that urine-based genetic testing allows tracing of tumor-specific oncogenic rearrangements. This strategy could be effectively applied to non-invasively monitor tumor evolution during therapy. The same approach could be exploited to monitor minimal residual disease after surgery with curative intent in patients whose tumors carry gene fusions. The latter could be implemented without the need of patient hospitalization since urine tr-DNA can be self-collected, is stable over time and can be shipped at specified time-points to central labs for testing.
监测激酶抑制剂的反应和耐药性对于精准癌症医学至关重要，通常通过在进展时获得的组织活检进行分子谱分析来进行研究。然而，肿瘤异质性和组织采样偏差限制了这种策略的有效性。此外，组织活检并不总是可行的，并且由于该过程的侵入性而存在风险。为了克服这些限制，基于血液的液体活检分析已被证明可有效地非侵入性地跟踪肿瘤克隆进化。
我们利用尿细胞游离的跨肾 DNA（tr-DNA）和匹配的血浆循环肿瘤 DNA（ctDNA）来监测携带 CAD-ALK 易位的转移性结直肠癌患者在接受 ALK 抑制剂治疗期间的情况。
使用定制的下一代测序面板，我们在血浆 ctDNA 中鉴定出了基因组 CAD-ALK 重排和 TP53 突变。开发了灵敏的检测方法来检测尿液 tr-DNA 中的这两种改变。血浆和尿液中 CAD-ALK 重排的动力学是一致的，并与患者的临床过程平行。尿液 tr-DNA 中 CAD-ALK 基因融合的检测预测了疾病进展的影像学确认。对血浆 ctDNA 的分析鉴定了在接受 ALK 抑制剂 entrectinib 治疗期间出现的 ALK 激酶突变。
我们发现基于尿液的基因检测可追踪肿瘤特异性致癌重排。这种策略可有效地应用于非侵入性监测治疗期间的肿瘤演变。同样的方法可用于监测携带基因融合的患者在具有治愈意图的手术后的微小残留疾病。后者可以在不需要患者住院的情况下实施，因为尿液 tr-DNA 可以自行采集，随着时间的推移保持稳定，并且可以在特定时间点运送到中央实验室进行检测。
