Determination of Somatic Mutations and Tumor Mutation Burden in Plasma by CAPP-Seq during Afatinib Treatment in NSCLC Patients Resistance to Osimertinib
Determination of Somatic Mutations and Tumor Mutation Burden in Plasma by CAPP-Seq during Afatinib Treatment in NSCLC Patients Resistance to Osimertinib
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DOI：
10.1038/s41598-020-57624-4
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发表时间：
2020-01-20
影响因子：
4.6
通讯作者：
Nishio, Kazuto
中科院分区：
文献类型：
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作者：
Ishii, Hidenobu;Azuma, Koichi;Nishio, Kazuto
第三代表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)被开发用于靶向对第一代或第二代EGFR-TKIs耐药的非小细胞肺癌(NSCLC)患者的EGFR T790M耐药突变。为了探讨阿法替尼治疗对奥西美替尼耐药的EGFR T790M阳性非小细胞肺癌患者的疗效，以及阿法替尼治疗期间血浆循环肿瘤DNA(CtDNA)中体细胞突变和肿瘤突变负荷(TMB)的变化，我们进行了一项前瞻性研究，采用CAPP-Seq技术进行癌症个性化测序。9例携带EGFR T790M突变的非小细胞肺癌患者对第三代EGFR-TKI表现出耐药，并接受阿法替尼治疗。分别在治疗前、治疗后4周和疾病进展时采集血浆样本。用CAPP-Seq法分析突变谱和血浆ctDNA中的TMB。与阿法替尼相关的客观缓解率和中位无进展生存期分别为0%和2.0个月。在1例患者和2例阿法替尼治疗患者中观察到C797S突变介导的奥西美替尼耐药，C797S突变与T790M突变发生在相同的等位基因上。经阿法替尼治疗后，对阿法替尼敏感的突变等位基因ERBB2和TMB减少。我们已经证明，用CAPP-Seq检测ctDNA的突变等位基因频率和TMB有助于确定阿法替尼的有效性和耐药性。尽管阿法替尼单一治疗耐药的T790M阳性非小细胞肺癌的疗效较差，但对多克隆突变等位基因和TMB的作用可能有助于进一步的治疗策略。
Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were developed to target the EGFR T790M resistance mutation in non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs. To investigate the efficacy of afatinib treatment for EGFR T790M-positive NSCLC patients showing resistance to osimertinib and alterations in somatic mutations and tumor mutation burden (TMB) in plasma circulating tumor DNA (ctDNA) during afatinib treatment, we conducted a prospective study using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq). Nine NSCLC patients with EGFR T790M mutation who showed resistance to third-generation EGFR-TKIs were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. The mutation profile and TMB in plasma ctDNA were analyzed by CAPP-Seq. The objective response rate and median progression-free survival associated with afatinib were 0% and 2.0 months, respectively. The C797S mutation-mediated resistance to osimertinib was observed in one patient and following afatinib treatment in two patients; the C797S mutations occurred in the same allele as the T790M mutation. After afatinib treatment, afatinib-sensitive mutant alleles, such as ERBB2, and TMB decreased. We have demonstrated that detection of mutant allele frequency and TMB of ctDNA by CAPP-Seq could help determine the effectiveness of and resistance to afatinib. Although afatinib monotherapy for T790M-positive NSCLC resistant to osimertinib was less effective, the action for multiclonal mutant alleles and TMB might contribute to further treatment strategy.