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  • 7α,25-dihydroxy Cholesterol br Introduction Detection of dri

    2019-10-25


    Introduction Detection of driver mutations in patients with advanced non-small cell lung cancer (NSCLC) is critical because they receive great benefit from kinase inhibitors [[1], [2], [3], [4]]. However, it is often difficult to obtain tumor tissue in advanced NSCLC patients. Cell-free DNA (cfDNA) from peripheral blood is a useful material to solve this problem. In epidermal growth factor receptor (EGFR) mutated patients, several studies demonstrated that plasma samples could be a substitute for tumor tissue in analyzing EGFR mutation [5,6]. Moreover, cfDNA analysis using cobas® EGFR mutation kit version.2 (Roche Molecular Diagnostics, Inc, CA) has already been introduced into clinical practice. Beyond this diagnostic approach, liquid biopsy may be an ideal method to monitor the genetic status of cancer during treatment because it can be done less invasively and repeatedly. Although several studies have already shown the feasibility of monitoring EGFR mutations in each patient [7,8], most of them focused on representative cases. Thus, as the statement paper suggested, it has not been proven whether sequential cfDNA monitoring is clinically meaningful or not, and also it has not been elucidated which patients are benefit from this approach [9]. Previously, we reported the establishment of multiplexed assay of three EGFR mutations (exon 19del, 7α,25-dihydroxy Cholesterol 20 T790 M and exon 21 L858R) using highly sensitive digital PCR [10]. Based on this, we conducted a multi-institutional biomarker study of EGFR mutated patients who were treated with afatinib (West Japan Oncology Group (WJOG) 8114LTR).
    Materials and methods
    Results Between February and December 2015, 57 patients were registered in the study. Clinical characteristics of the registered patients are shown in Table 1. Of those, 31 (53%) were female. Thirty-nine patients (68%) were stage IV and 16 (28%) were post-operative relapse. Number of each EGFR mutation (exon 19del and exon 21 L858R) of the patients were almost the same. After registration, two patients did not receive protocol treatment due to acute interstitial lung disease and rapid disease progression. Thus, 55 patients were recognized per protocol set and were analyzed for their efficacy and safety. Overall response rate was 78.6% (95% confidence interval (CI): 67.3–89.1%) and median PFS was 14.2 months (95%CI: 10.5–19.1 months). Profiles and severity of adverse events (data not shown) were similar to the pivotal study [12]. During study treatment, one patient died in a traffic accident; this event was considered unrelated to study treatment. Number of tissue and plasma samples obtained at each time point are described in Fig. 1. One tumor tissue specimen did not contain tumor cells so we analyzed 56 samples. During the first 12 weeks of treatment, about 90% of planned plasma samples were collected. At 24 weeks, 40 plasma samples were collected. Regarding tissue samples, results of sensitive EGFR mutation analyses using digital PCR corresponded to those based on institutional mutation analyses. In one patient (1.8%), de novo Exon 20 T790 M mutation was additionally detected by digital PCR analysis. Analyzing plasma samples, 35 of 56 patients (62.5%, 95% CI: 44.2–70.1%) were positive for sensitive EGFR mutation at baseline. Sites of EGFR mutation were completely identical between tissue and corresponding plasma samples. Characteristics of the patients who were positive or negative for EGFR mutation in plasma are shown in Table 1. Clinical stage was the only factor that correlated with detection rate. Patients with stage IV demonstrated the highest detection rate compared with patients who were stage III and post-operative relapse (81.6% versus. 0% and 31.2%, respectively). In more detail, the systemic spread of tumor seemed to correlate with higher detection rate (Fig. 2). Among stage IV disease, detection rate tended to be higher in patients with distant metastasis (M1b, 85.2%, 23 of 27 patients) than those without (M1a, 72.7%, eight of 11 patients). Similar tendency was observed among patients with post-operative relapse (57.1% in patients with metastatic relapse versus 11.1% in patients with localized relapse). Regarding efficacy, cfDNA-positive patients showed slightly shorter PFS than cfDNA-negative patients, but not significantly (median 13.0 months versus not reached, p = 0.11, Fig. 3).