Yaeger Rona, Martini Jean-François, Pasquina Lincoln, Tunquist Brian, Zhang Xiaosong, Kaiser Fatima, Pantoja Galicia Norberto, Deng Shibing, Gong Siliang, Guo Cui, Kiely Jimmy, Ng Ta-Chou Vincent, Ferrier Graham, Tabernero Josep, Kopetz Scott
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Translational Science Operations, Pfizer, Inc., La Jolla, California.
Cancer Res Commun. 2025 Sep 1;5(9):1566-1573. doi: 10.1158/2767-9764.CRC-25-0002.
The BRAF inhibitor encorafenib (Enco) plus the anti-EGFR antibody cetuximab (Cetux) improved overall survival, objective response rate, and progression-free survival in previously treated BRAFV600E-mutant metastatic colorectal cancer in BEACON, a phase III randomized trial, leading to regulatory approval for this indication. To support rapid, plasma-based testing for BRAFV600E identification, clinical validity of a ctDNA-based assay, FoundationOneLiquid CDx (F1LCDx), was assessed against the reference tumor-based clinical trial assay (CTA) in liquid biopsy-evaluable samples from BEACON and commercially obtained tissue-matched plasma samples.
Pretreatment tissue samples were collected in BEACON to confirm BRAF mutational status using the central single gene PCR assay. Concordance between the CTA and liquid biopsy tests was assessed, and clinical validity of liquid biopsy testing was examined using clinical outcomes from BEACON.
Of the 523 evaluable patients, 433 with matched tissue and plasma samples had CTA and F1LCDx results available (BEACON, n = 328; commercial, n = 105). A strong concordance in detecting BRAFV600E was found between F1LCDx and CTA, with a positive percent agreement of 87.2% and negative percent agreement of 97.1%. Among 42 F1LCDx-/CTA+ samples, 41 (97.6%) had ctDNA tumor fraction <1%. Among samples with ctDNA tumor fraction >1%, the positive percent agreement was 99.4% and negative percent agreement was 86.7%. Clinical outcomes with Enco plus Cetux were similar between those identified as F1LCDx+/CTA+ and CTA+ overall.
This study supports using liquid biopsies as a clinically valid assay for identifying BRAFV600E alterations in patients with metastatic colorectal cancer, particularly when ctDNA tumor fraction was >1%.
In the phase III BEACON trial, which established Enco plus Cetux as a standard of care for previously treated BRAFV600E-mutant metastatic colorectal cancer, mutational status was confirmed through testing of tumor tissue. To support rapid, less invasive testing for BRAFV600E in plasma, this retrospective study assessed a ctDNA-based assay and found strong concordance between the liquid biopsy test and the tumor-based assay in detecting BRAFV600E.
在一项III期随机试验BEACON中，BRAF抑制剂恩考芬尼（Enco）联合抗表皮生长因子受体（EGFR）抗体西妥昔单抗（Cetux）可改善既往接受过治疗的BRAFV600E突变转移性结直肠癌患者的总生存期、客观缓解率和无进展生存期，因此该联合疗法获得了这一适应症的监管批准。为支持基于血浆的BRAFV600E快速检测，在BEACON中可进行液体活检评估的样本以及商业获取的组织匹配血浆样本中，对基于循环肿瘤DNA（ctDNA）的检测方法FoundationOneLiquid CDx（F1LCDx）相对于基于肿瘤组织的临床试验检测方法（CTA）的临床有效性进行了评估。
在BEACON中收集预处理组织样本，使用中心单基因聚合酶链反应（PCR）检测方法确认BRAF突变状态。评估CTA与液体活检检测结果的一致性，并利用BEACON的临床结局检查液体活检检测的临床有效性。
在523例可评估患者中，433例有匹配的组织和血浆样本，可获得CTA和F1LCDx检测结果（BEACON研究中328例，商业样本中105例）。F1LCDx与CTA在检测BRAFV600E方面具有高度一致性，阳性一致率为87.2%，阴性一致率为97.1%。在42例F1LCDx阴性/CTA阳性样本中，41例（97.6%）的ctDNA肿瘤分数<1%。在ctDNA肿瘤分数>1%的样本中，阳性一致率为99.4%，阴性一致率为86.7%。总体而言，被鉴定为F1LCDx阳性/CTA阳性的患者与CTA阳性的患者接受Enco联合Cetux治疗后的临床结局相似。
本研究支持将液体活检作为一种临床有效的检测方法，用于识别转移性结直肠癌患者中的BRAFV600E改变，尤其是当ctDNA肿瘤分数>1%时。
在III期BEACON试验中，Enco联合Cetux被确立为既往接受过治疗的BRAFV600E突变转移性结直肠癌的治疗标准，通过对肿瘤组织的检测确认了突变状态。为支持对血浆中BRAFV600E进行快速、侵入性较小的检测，这项回顾性研究评估了一种基于ctDNA的检测方法，发现液体活检检测与基于肿瘤组织的检测方法在检测BRAFV600E方面具有高度一致性。
