BC Cancer, University of British Columbia, Vancouver, BC, Canada.
Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada.
J Clin Oncol. 2023 Jan 20;41(3):485-496. doi: 10.1200/JCO.22.00364. Epub 2022 Aug 25.
Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance.
Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment.
ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including ( = .0007), ( = .0017), ( = .0046), ( = .0086), ( = .018), ( = .018), ( = .048), and ( = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including ( < .0001), ( < .0001), ( < .0001), ( = .0002), ( = .0002), ( = .0006), ( = .004), and ( = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without ( = .010). Although tumor mutation burden (TMB) did not differ pretreatment ( = .63), anti-EGFR exposure increased TMB ( = .028), whereas lack of anti-EGFR exposure resulted in declining TMB ( = .014).
Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.
抗表皮生长因子受体（EGFR）抗体是转移性结直肠癌的有效治疗方法。对获得性耐药机制的深入了解可能有助于循环肿瘤 DNA（ctDNA）监测、抗 EGFR 再挑战以及组合策略以延迟耐药。
在 CO.26 试验中，有 169 名治疗耐药转移性结直肠癌患者入组，与基线和第 8 周的 GuardantOMNI 检测 ctDNA 评估相比，这些患者进行了抗 EGFR 治疗前组织全外显子组测序（WES）。比较了有（n=66）和没有（n=103）既往抗 EGFR 治疗的患者之间的获得性改变。抗 EGFR 治疗发生在 ctDNA 评估前中位数 111 天。
ctDNA 在抗 EGFR 治疗后鉴定出 12 个基因突变频率增加的基因，包括 （=0.0007）、 （=0.0017）、 （=0.0046）、 （=0.0086）、 （=0.018）、 （=0.018）、 （=0.048）和 （=0.048）。获得性突变表现为多个同时发生的亚克隆改变，大多数随着时间的推移而衰减。在抗 EGFR 暴露后，29 个基因的拷贝增益频率显著增加，其中包括 （＜0.0001）、 （＜0.0001）、 （＜0.0001）、 （=0.0002）、 （=0.0002）、 （=0.0006）、 （=0.004）和 （=0.006）。8 周后，拷贝增益没有衰减，似乎很稳定。在 11 名患者中发现了 13 个基因融合，其中除了一个与之前的抗 EGFR 治疗有关外，其余都与之前的抗 EGFR 治疗有关。多克隆耐药很常见，与 21%有既往抗 EGFR 治疗的患者相比，5%无抗 EGFR 治疗的患者有≥10 个耐药相关改变（=0.010）。虽然肿瘤突变负荷（TMB）在预处理时没有差异（=0.63），但抗 EGFR 暴露增加了 TMB（=0.028），而缺乏抗 EGFR 暴露则导致 TMB下降（=0.014）。
配对的组织和 ctDNA 测序鉴定出多种与抗 EGFR 治疗相关的新突变、拷贝增益和融合，这些突变、拷贝增益和融合在同一患者中经常作为亚克隆改变共同发生。
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