Ciardiello D, Boscolo Bielo L, Pietrantonio F, Martini G, Troiani T, Martinelli E, Natangelo S, Bosco M F, Pisconti S, Nisi C, Tortora G, Salvatore L, Sartore-Bianchi A, Siena S, Blasi L, Messina M, Ongaro E, Zaniboni A, Pinto C, Antonuzzo L, Avallone A, Normanno N, Santabarbara G, Zampino M G, Berardi R, Cogoni A A, Leo S, Lotesoriere C, Latiano T P, Maiello E, Fazio N, Curigliano G, Bordonaro R, De Vita F, Ciardiello F, Napolitano S
Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.
Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
ESMO Open. 2025 Jun 23;10(7):105491. doi: 10.1016/j.esmoop.2025.105491.
Biomarker-guided therapies are needed for patients with refractory metastatic colorectal cancer (mCRC). Liquid biopsy (LBx) circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) could contribute to the clinical tailoring of molecular targeted therapies for these patients.
The CAVE-2 GOIM trial is a randomized phase II trial assessing the efficacy of adding avelumab to cetuximab compared with cetuximab monotherapy as anti-epidermal growth factor receptor (EGFR) rechallenge in refractory ctDNA RAS/BRAF wild-type mCRC patients. Baseline plasma ctDNA CGP was carried out using the Foundation One Liquid CDx.
LBx-based CGP was available for 324 patients out of 328 screened. A total of 1969 pathogenic variants (PVs) were detected. One hundred and thirty-five cases (41.7%) had single RAS/BRAF PVs, with 24 tumors (17.6%) having multiple RAS/BRAF PVs. Of 166 RAS/BRAF PVs, 95 (57.2%) consisted of subclonal alterations {median variant allele frequency [VAF] of 0.37% [interquartile range (IQR) 0.18%-1.0%] versus median VAF of 4.0% [IQR 0.65%-11.25%] in 71 cases of clonal PV; P < 0.0001}. Single RAS/BRAF alterations had higher clonality compared with co-occurring RAS/BRAF alterations [12.8% (IQR 1.93%-56.0%) versus 0.67% (IQR 0.37-3.35), P < 0.0001]. Among other genes potentially involved in anti-EGFR drug resistance, 174 non-RAS/BRAF PV were observed with 73 cases having both co-occurring RAS/BRAF and non-RAS/BRAF PV, while in 43 cases only non-RAS/BRAF PV were detected. Tumors harboring co-occurring non-RAS/BRAF PV had significantly lower clonality as compared with RAS/BRAF PV [1.52 (0.46-8.88) versus 17.0 (3.75-71.0), P < 0.0001]. Finally, a total of 332 genomic alterations with therapeutic relevance according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) were detected for 171 patients (52.7%). Of these, 120 tier I alterations were detected among 111 (34.3%) patients, which included high tumor mutational burden (≥10 mut/Mb, n = 101), BRAF (n = 11), KRAS (n = 7), and RET (n = 1).
LBx-based CGP might guide the appropriate use of anti-EGFR drug rechallenge or of other therapeutically actionable gene alterations in refractory mCRC.
难治性转移性结直肠癌（mCRC）患者需要生物标志物引导的治疗。液体活检（LBx）循环肿瘤DNA（ctDNA）综合基因组分析（CGP）有助于为这些患者临床定制分子靶向治疗。
CAVE-2 GOIM试验是一项随机II期试验，评估在难治性ctDNA RAS/BRAF野生型mCRC患者中，与西妥昔单抗单药治疗相比，加用阿维鲁单抗进行抗表皮生长因子受体（EGFR）再挑战治疗的疗效。使用Foundation One Liquid CDx进行基线血浆ctDNA CGP检测。
328例筛查患者中，324例患者可获得基于LBx的CGP检测结果。共检测到1969个致病变异（PVs）。135例（41.7%）有单个RAS/BRAF PVs，24个肿瘤（17.6%）有多个RAS/BRAF PVs。在166个RAS/BRAF PVs中，95个（57.2%）为亚克隆改变{71例克隆性PVs的中位变异等位基因频率[VAF]为0.37%[四分位间距（IQR）0.18%-1.0%]，而71例克隆性PVs的中位VAF为4.0%[IQR 0.65%-11.25%]；P<0.0001}。与同时存在的RAS/BRAF改变相比，单个RAS/BRAF改变的克隆性更高[12.8%（IQR 1.93%-56.0%）对0.67%（IQR 0.37-3.35），P<0.0001]。在其他可能与抗EGFR耐药相关的基因中，观察到174个非RAS/BRAF PVs，73例同时存在RAS/BRAF和非RAS/BRAF PVs，而43例仅检测到非RAS/BRAF PVs。与RAS/BRAF PVs相比，同时存在非RAS/BRAF PVs的肿瘤克隆性显著更低[1.52（0.46-8.88）对17.0（3.75-71.0），P<0.0001]。最后，根据欧洲医学肿瘤学会（ESMO）分子靶点临床可操作性量表（ESCAT），共检测到171例患者（52.7%）有332个具有治疗相关性的基因组改变。其中，111例（34.3%）患者检测到120个I级改变，包括高肿瘤突变负荷（≥10个突变/Mb，n=101）、BRAF（n=11）、KRAS（n=7）和RET（n=1）。
基于LBx的CGP可能指导难治性mCRC患者抗EGFR药物再挑战或其他具有治疗可操作性的基因改变的合理应用。
