Internal Medicine III, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.
BMC Cancer. 2020 Feb 6;20(1):103. doi: 10.1186/s12885-020-6593-1.
Epidermal growth factor receptor (EGFR)-sensitizing mutation, exon 19 deletion consists of several molecular variants. Influences of these variants on clinical response to EGFR tyrosine kinase inhibitors remain elusive.
West Japan Oncology Group 8114LTR is a prospective, multi-institutional biomarker study. Treatment naïve, advanced non-small-cell lung cancer patients with EGFR-sensitizing mutation received afatinib monotherapy. We conducted a preplanned subset analysis of patients harboring exon 19 deletion. Tumor tissue exon 19 deletion molecular variants were identified by blocking-oligo-dependent polymerase chain reaction (PCR) and by Luminex Technology. Plasma cfDNA was also obtained before and after the treatment and EGFR mutations were detected with multiplexed, pico-droplet digital PCR assay.
Among 57 registered patients, twenty-nine patients were exon 19 deletion. Tissue DNA and cfDNA were available in 26 patients. Among the detected seven molecular variants, the most frequent was p.E746_A750delELREA (65.4%). According to the various classifications of molecular variants, twenty one (80.8%) were classified into 15-nucleotide deletion, one (3.8%) into 18-nucleotide deletion, and four patients (15.4%) into other insertion/substitution variant subgroups. The patient subgroup with 15-nucleotide deletion showed significantly longer progression-free survival than patients in other mixed insertion/substitution variant subgroup (p = 0.0244).
The clinical significance of molecular variants of exon 19 deletion on the first line afatinib monotherapy is reported here for the first time. Further investigation is needed for development of better therapeutic strategies.
This trial was registered at UMIN Clinical Trials Registry at 2014/12/4 (UMIN000015847).
表皮生长因子受体（EGFR）-敏感突变，外显子 19 缺失由几种分子变异体组成。这些变异体对 EGFR 酪氨酸激酶抑制剂临床反应的影响仍不清楚。
西日本肿瘤学组 8114LTR 是一项前瞻性、多机构生物标志物研究。接受 EGFR 敏感突变的初治、晚期非小细胞肺癌患者接受阿法替尼单药治疗。我们对携带外显子 19 缺失的患者进行了预先计划的亚组分析。通过阻断寡核苷酸依赖性聚合酶链反应（PCR）和 Luminex 技术鉴定肿瘤组织外显子 19 缺失的分子变异体。在治疗前后还获得了血浆 cfDNA，并使用多重、皮克滴数字 PCR 检测 EGFR 突变。
在 57 名登记患者中，有 29 名患者存在外显子 19 缺失。26 名患者可提供组织 DNA 和 cfDNA。在检测到的七种分子变异体中，最常见的是 p.E746_A750delELREA（65.4%）。根据分子变异体的各种分类，21 例（80.8%）归为 15 个核苷酸缺失，1 例（3.8%）归为 18 个核苷酸缺失，4 例（15.4%）归为其他插入/取代变异体亚组。15 个核苷酸缺失患者亚组的无进展生存期明显长于其他混合插入/取代变异体亚组（p=0.0244）。
这是首次报道外显子 19 缺失的分子变异体在一线阿法替尼单药治疗中的临床意义。需要进一步研究以制定更好的治疗策略。
该试验于 2014 年 12 月 4 日在 UMIN 临床试验注册处注册（UMIN000015847）。
