Nicolazzo Chiara, Barault Ludovic, Caponnetto Salvatore, De Renzi Gianluigi, Belardinilli Francesca, Bottillo Irene, Bargiacchi Simone, Macagno Marco, Grammatico Paola, Giannini Giuseppe, Cortesi Enrico, Di Nicolantonio Federica, Gazzaniga Paola
Cancer Liquid Biopsy Unit, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy.
Department of Oncology, University of Torino, Strada Provinciale, 142 km 3,95, 10060, Candiolo, TO, Italy; Candiolo Cancer Institute, FPO - IRCCS, Strada Provinciale, 142 km 3,95, 10060, Candiolo, TO, Italy.
Cancer Lett. 2021 Jun 1;507:89-96. doi: 10.1016/j.canlet.2021.03.014. Epub 2021 Mar 18.
The paucity of targeted treatments available in patients with RAS mutant colorectal cancers contributes to the poor prognosis of this patient group compared to those with RAS wild-type disease. Recent liquid biopsy-driven studies have demonstrated that RAS mutant clones might disappear in plasma during the clonal evolution of the disease, opening new unforeseen perspectives for EGFR blockade in these patients. Nevertheless, the lack of detection of RAS mutations in plasma might depend on the low amount of released circulating tumor DNA (ctDNA), making it necessary a more accurate selection of patients with true RAS mutation conversions. In this liquid biopsy-based study, we assessed RAS mutational status in initially RAS-mutant patients at the time of progressive disease from any line of therapy and investigated the incidence of true conversions to plasma RAS wild-type, comparing a colon cancer specific methylation profile with a mutational signature of ctDNA. Globally, considering either mutational panel or methylation profile as reliable tests to confirm or exclude the presence of ctDNA, the percentage of "true RAS converters" was 37.5%. In our series we observed a trend toward a better PFS in patients who received anti-EGFR as second or subsequent treatment lines compared to those who did not.
与RAS野生型疾病患者相比，RAS突变型结直肠癌患者可用的靶向治疗方法匮乏，导致该患者群体预后较差。最近基于液体活检的研究表明，在疾病的克隆进化过程中，RAS突变克隆可能会在血浆中消失，为这些患者的EGFR阻断开辟了新的意外前景。然而，血浆中未检测到RAS突变可能取决于释放的循环肿瘤DNA（ctDNA）量低，因此有必要更准确地选择真正发生RAS突变转化的患者。在这项基于液体活检的研究中，我们评估了最初为RAS突变型的患者在任何治疗线出现疾病进展时的RAS突变状态，并通过比较结肠癌特异性甲基化谱与ctDNA的突变特征，研究了真正转化为血浆RAS野生型的发生率。总体而言，将突变检测 panel 或甲基化谱视为确认或排除ctDNA存在的可靠测试，“真正的RAS转化者”的百分比为37.5%。在我们的系列研究中，我们观察到与未接受抗EGFR治疗的患者相比，接受抗EGFR作为二线或后续治疗线的患者有更好的无进展生存期（PFS）的趋势。
