Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): a phase 2, single-arm, multicentre clinical trial

Wang, Zhijie; Cheng, Ying; An, Tongtong; Gao, Hongjun; Wang, Kai; Zhou, Qing; Hu, Yanping; Song, Yong; Ding, Cuimin; Peng, Feng; Liang, Li; Hu, Yi; Huang, Cheng; Zhou, Caicun; Shi, Yuankai; Zhang, Li; Ye, Xin; Zhang, Meizhuo; Chuai, Shaokun; Zhu, Guoqiang; Hu, Jie; Wu, Yi‐Long; Wang, Jie

doi:10.1016/s2213-2600(18)30264-9

Cited by 183 publications

(160 citation statements)

References 35 publications

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“…This result suggests that patients without gene mutations in plasma could have longer survival before LM, although the difference between subgroups was not significant. A similar result was observed in the BENEFIT study …”

Section: Discussionsupporting

confidence: 89%

“…Similarly, ctDNA in plasma provides an alternative to tumor samples for EGFR mutation analysis, and plasma gene mutations showed greater advantages than solid tumor cells for revealing the genetic landscape of primary and metastatic lesions, which are relatively limited. In the BENEFIT clinical trial, EGFR mutations reappeared in ctDNA with plasma samples when the disease progressed in 46% (56/123) of patients . In our study, 37.9% (11/29) of patients had EGFR driver mutations and ROS‐1 in plasma when LM appeared, which is relatively low compared to the results of the BENEFIT analysis.…”

Section: Discussioncontrasting

confidence: 68%

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Prognostic significance of molecular characteristics of cerebrospinal fluid for non‐small cell lung cancer patients with leptomeningeal metastasis

Liu

Duan

et al. 2019

Thoracic Cancer

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Background Studies in EGFR+ non‐small cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM) comparing survival rates and gene mutation detection with matched cerebrospinal fluid (CSF) and plasma are relatively scarce. We evaluated gene mutations, treatment strategies, and clinical outcomes in EGFR+ NSCLC patients with LM. Methods We retrospectively reviewed gene mutation status in the CSF and plasma of 32 EGFR+ NSCLC patients with LM for prognostic significance. Results The rate of LM disease control was significantly higher in patients that switched EGFR‐tyrosine kinase inhibitor (TKI) treatments, initiated EGFR‐TKIs, or received high‐dose EGFR‐TKI treatment than those who continued their current EGFR‐TKI treatment, received chemotherapy, or were not administered antitumor treatment (24/24, 100.0% vs. 1/8, 12.5%; P = 0.000). Overall survival was 27.0 months (95% confidence interval [CI] 19.0–37.5), median survival after LM was 7.0 months (95% CI 5.0–11.0), and median survival before LM was 17.0 months (95% CI 12–25.5). Median survival after LM was significantly shorter in patients with “worse” status (n = 7) than in those with “improved/stable” status (n = 25; 4.2 [95% CI 2.2–6.1] vs. 33.7 [95% CI 25.5–41.8] months, HR 10.114, 95% CI 0.29–1.37; P = 0.008). Conclusions EGFR‐TKIs should be the priority course of treatment in EGFR+ NSCLC patients after a diagnosis of LM. Liquid biopsy in both plasma and CSF, as well as dynamic detection, play important roles in the direction of treatment for such patients.

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Section: Discussionsupporting

confidence: 89%

Section: Discussioncontrasting

confidence: 68%

Prognostic significance of molecular characteristics of cerebrospinal fluid for non‐small cell lung cancer patients with leptomeningeal metastasis

Liu

Duan

et al. 2019

Thoracic Cancer

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“…Besides, it was noteworthy that comutation of EGFR and TP53 was frequently found in female patients in this study; another study showed that it was more likely to occur in young patients <45 years of age . At the same time, the common mutation of EGFR and TP53 is correlated with a poor prognosis . It seems that young women should pay more attention to screening for NSCLC because their prognosis is poor in the event of NSCLC.…”

Section: Discussionmentioning

confidence: 57%

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Dai

Wang

et al. 2019

The Oncologist

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Background Non‐small cell lung cancer (NSCLC) is one of the most common human malignancies and the leading cause of cancer‐related death. Over the past few decades, genomic alterations of cancer driver genes have been identified in NSCLC, and molecular testing and targeted therapies have become standard care for lung cancer patients. Here we studied the unique genomic profile of driver genes in Chinese patients with NSCLC by next‐generation sequencing (NGS) assay. Materials and Methods A total of 1,200 Chinese patients with NSCLC were enrolled in this study. The median age was 60 years (range: 26–89), and 83% cases were adenocarcinoma. NGS‐based genomic profiling of major lung cancer‐related genes was performed on formalin‐fixed paraffin‐embedded tumor samples and matched blood. Results Approximately 73.9% of patients with NSCLC harbored at least one actionable alteration recommended by the National Comprehensive Cancer Network guideline, including epidermal growth factor receptor (EGFR), ALK, ERBB2, MET, BRAF, RET, and ROS1. Twenty‐seven patients (2.2%) harbored inherited germline mutations of cancer susceptibility genes. The frequencies of EGFR genomic alterations (both mutations and amplification) and ALK rearrangement were identified as 50.1% and 7.8% in Chinese NSCLC populations, respectively, and significantly higher than the Western population. Fifty‐six distinct uncommon EGFR mutations other than L858R, exon19del, exon20ins, or T790M were identified in 18.9% of patients with EGFR‐mutant NSCLC. About 7.4% of patients harbored both sensitizing and uncommon mutations, and 11.6% of patients harbored only uncommon EGFR mutations. The uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. In patients <40 years of age, the ALK‐positive percentage was up to 28.2%. Moreover, 3.2% of ALK‐positive patients harbored multi ALK rearrangements, and seven new partner genes were identified. Conclusion More unique features of cancer driver genes in Chinese NSCLC were identified by next‐generation sequencing. These findings highlighted that NGS technology is more feasible and necessary than other molecular testing methods, and suggested that the special strategies are needed for drug development and targeted therapy for Chinese patients with NSCLC. Implications for Practice Molecular targeted therapy is now the standard first‐line treatment for patients with advanced non‐small cell lung cancer (NSCLC). Samples of 1,200 Chinese patients with NSCLC were analyzed through next‐generation sequencing to characterize the unique feature of uncommon EGFR mutations and ALK fusion. The results showed that 7.4% of EGFR‐mutant patients harbored both sensitizing and uncommon mutations and 11.6% harbored only uncommon mutations. Uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. ALK fusion was more common in younger patients, and the frequency decreased monotonically with age. 3.2% of ALK‐positive patien...

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“…In contrast to current ctDNA detection approaches that typically interrogate a single locus and have low multiplexing capabilities, such as digital droplet PCR60, next-generation sequencing (NGS) methodologies can be used to interrogate larger portions of the tumor genome and track multiple tumor-associated mutations. For instance, some researchers utilized a ctDNA-based NGS analysis of blood samples in 179 patients and identified three subgroups according to their genetic mutations, which favored predictions of drug resistance [177]. Similar practices have also been adopted in prostate carcinoma [178], colorectal cancer [86], and hepatocellular carcinoma [179] among others.…”

Section: Ctdna Tumor Heterogeneity and Therapeutic Resistancementioning

confidence: 99%

The interplay of circulating tumor DNA and chromatin modification, therapeutic resistance, and metastasis

Zhang

Liang

et al. 2019

Mol Cancer

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Peripheral circulating free DNA (cfDNA) is DNA that is detected in plasma or serum fluid with a cell-free status. For cancer patients, cfDNA not only originates from apoptotic cells but also from necrotic tumor cells and disseminated tumor cells that have escaped into the blood during epithelial-mesenchymal transition. Additionally, cfDNA derived from tumors, also known as circulating tumor DNA (ctDNA), carries tumor-associated genetic and epigenetic changes in cancer patients, which makes ctDNA a potential biomarker for the early diagnosis of tumors, monitory and therapeutic evaluations, and prognostic assessments, among others, for various kinds of cancer. Moreover, analyses of cfDNA chromatin modifications can reflect the heterogeneity of tumors and have potential for predicting tumor drug resistance.

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Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): a phase 2, single-arm, multicentre clinical trial

Cited by 183 publications

References 35 publications

Prognostic significance of molecular characteristics of cerebrospinal fluid for non‐small cell lung cancer patients with leptomeningeal metastasis

Prognostic significance of molecular characteristics of cerebrospinal fluid for non‐small cell lung cancer patients with leptomeningeal metastasis

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

The interplay of circulating tumor DNA and chromatin modification, therapeutic resistance, and metastasis

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