Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment
Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment
复制标题
DOI：
10.1093/annonc/mdv005
复制
发表时间：
2015-04-01
影响因子：
50.5
通讯作者：
Kopetz, S.
中科院分区：
文献类型：
--
作者：
Morelli, M. P.;Overman, M. J.;Kopetz, S.
简介：转移性结直肠癌（mCRC）患者的KRAS和EGFR胞外域获得性突变与抗EGFR单克隆抗体（mAb）的获得性耐药相关。我们使用循环肿瘤DNA（ctDNA）研究了抗EGFR mAb难治性mCRC患者中获得性KRAS和EGFR突变的频率、共现和分布。通过高灵敏度乳液聚合酶链反应对来自抗EGFR mAb难治的KRAS（wt）mCRC患者的62份治疗后血浆和20份匹配的治疗前存档组织样本进行KRAS密码子12的评价，结果：血浆分析显示，分别在5/62 [8%; 95%置信区间（CI）0.02-0.18]和27/62（44%; 95% CI 0.3-0.56）样本中新检测到EGFR和KRAS突变。KRAS密码子61和146突变占主导地位（分别为33%和11%），在11/27（41%）例病例中检测到EGFR和/或KRAS多重突变。突变等位基因读数的百分比与EGFR mAb末次治疗后的时间呈负相关（P = 0.038）。在匹配的存档组织中，这些突变在抗EGFR mAb治疗后35%的血浆突变患者中可检测为低等位基因频率克隆，与无新突变的病例相比，这些突变与较短的无进展生存期（PFS）相关（3.0 vs 8.0个月，P = 0.0004）。在抗EGFR治疗难治性患者的血浆ctDNA中新检测到的KRAS和/或EGFR突变似乎来源于罕见的，原发肿瘤中已有的克隆。这些罕见克隆与接受抗EGFR治疗的患者的PFS较短相关。ctDNA中KRAS和EGFR的多个同时突变以及患者亚组中抗EGFR治疗停止后等位基因频率的下降表明，几种耐药机制可以共存，并且相对克隆负荷可能随时间而变化。通过ctDNA测序监测治疗诱导的遗传改变可以识别用于抗EGFR难治性患者的治疗筛选的生物标志物。
Introduction: KRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs). We investigated the frequency, co-occurrence, and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA).Patients and methods: Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS(wt) mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12, 13, 61, and 146 and EGFR 492 mutations.Results: Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8%; 95% confidence interval (CI) 0.02-0.18] and 27/62 (44%; 95% CI 0.3-0.56) samples, respectively. KRAS codon 61 and 146 mutations were predominant (33% and 11%, respectively), and multiple EGFR and/or KRAS mutations were detected in 11/27 (41%) cases. The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs (P = 0.038). In the matching archival tissue, these mutations were detectable as low-allele-frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival (PFS) compared with the cases with no new mutations (3.0 versus 8.0 months, P = 0.0004).Conclusion: Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare, pre-existing clones in the primary tumors. These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment. Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time. Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.