Driver genes as predictive indicators of brain metastasis in patients with advanced NSCLC: EGFR, ALK, and RET gene mutations.

A retrospective analysis verified the role of gene mutations in brain metastasis in patients with non-small cell lung cancer (NSCLC). Data from 552 patients with advanced NSCLC treated from January 2015 to June 2017 in the Affiliated Cancer Hospital of Zhengzhou University were retrospectively analyzed. Next-generation sequencing was used to detect mutations in eight reported driver genes and various risk factors were evaluated. Of the 552 patients with advanced NSCLC, 153 (27.7%) had brain metastases. The univariate analysis showed that age (P = .008), gender (P = .016), smoking history (P = .010), lymph node metastasis (P = .003), and three driver genes, positive epidermal growth factor receptor (EGFR) mutation (P = .001), positive anaplastic lymphoma kinase (ALK) gene fusion (P = .021), and positive rearranged during transfection (RET) gene fusion (P = .003), were the factors influencing the incidence of brain metastasis. Logistic multivariate regression analysis revealed that positive EGFR mutation (P = .012), positive ALK gene fusion (P = .015), positive RET gene fusion (P = .003), pathological type (P = .009), lymph node N2-3 metastasis (P < .001), and a younger age (P < .001) were independent risk factors for brain metastasis. In addition, a receiver operating characteristic (ROC) curve was plotted with the above factors with an area under the curve = 0.705 (P < .001). An EGFR mutation, ALK gene fusion, and RET gene fusion in advanced NSCLC patients play roles in brain metastasis as positive driver genes. An EGFR mutation, and ALK and RET gene fusions are risk factors for brain metastasis in advanced NSCLC patients.

Wang H ，Wang Z ，Zhang G ，Zhang M ，Zhang X ，Li H ，Zheng X ，Ma Z ... -  《Cancer Medicine》

Benefit of Targeted DNA Sequencing in Advanced Non-Small-Cell Lung Cancer Patients Without EGFR and ALK Alterations on Conventional Tests.

Genetic sequencing testing has become widely used to inform treatment decisions for advanced non-small-cell lung cancer (NSCLC) patients. We analyzed benefits of genetic sequencing testing in real practice. We retrospectively reviewed 209 NSCLC patients who had no EGFR and ALK alterations on routine molecular tests and underwent next-generation targeted DNA sequencing of 380 cancer-related genes between November 2013 and October 2016. Median patient age was 59 years. A total of 96 patients (46%) were never smokers, and 195 patients (93%) had adenocarcinoma. Among 209 total patients, 64 (31%) demonstrated actionable genetic alterations; 20 had EGFR mutations (6 L858R, 8 exon 19 deletions, 1 L861Q, 1 G719S, 4 exon 20 duplications), 4 ALK fusions, 9 ROS1 fusions, 6 BRAF V600E mutations, 15 RET fusions, 1 MET high-level amplification, 6 MET exon 14 skipping mutations, and 3 ERBB2 exon 20 insertion mutations. Of the 64 patients harboring actionable alterations, 28 patients received therapy targeted to their own actionable alterations (15 EGFR, 3 ALK, 1 ROS1, 8 RET, 1 BRAF). There were significant differences in overall survival between individuals with no actionable alterations, those with actionable alterations but no targeted therapy, and those with actionable alterations and targeted therapy (20.1 vs. 17.1 vs. 66.2 months, P < .001). The results of targeted DNA sequencing testing could provide improved treatment options for some NSCLC patients and result in a survival benefit to NSCLC patients with no EGFR and ALK alterations on routine tests who are treated with targeted therapy.

Byeon S ，Lee B ，Park WY ，Choi YL ，Jung HA ，Sun JM ，Ahn JS ，Ahn MJ ，Park K ，Lee SH ... -  《-》

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

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. 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. 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. 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. 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 patients harbored multi ALK rearrangement, and seven new partner genes were identified.

Wen S ，Dai L ，Wang L ，Wang W ，Wu D ，Wang K ，He Z ，Wang A ，Chen H ，Zhang P ，Dong X ，Dong YA ，Wang K ，Yao M ，Wang M ... -  《-》

Response rate of patients with baseline brain metastases from recently diagnosed non-small cell lung cancer receiving radiotherapy according to EGFR, ALK and KRAS mutation status.

Previous studies have identified that patients with EGFR mutations tend to have better responses to targeted therapy, as well as chemotherapy; however, the effect of genetic alterations in terms of radiotherapy (RT)-related outcomes has not been fully assessed. We studied the impact of common non-small cell lung cancer (NSCLC) genetic alterations (EGFR, ALK and KRAS) in relation to objective response rate (ORR) to RT in patients with brain metastases. From 2009-2015, 153 patients with an available genotyping status were treated with whole-brain irradiation (WBI) before receiving systemic therapy. Primary outcome was ORR; secondary outcomes included intracranial progression-free survival (IPFS) and overall survival (OS). Overall, ORR was 47.1%. ORR to RT varied significantly according to molecular status: EGFR (64.5%) ALK (54.5%) KRAS (20%) and WT (35.4%) (P = 0.001). EGFR mutation was the only independently associated factor for response to WBI (RR 3.52 [95% CI 1.6-7.7]; P = 0.002). Median IPFS was 10.8 months [95% CI 8.2-13.5] overall; however, IPFS also varied significantly according to molecular status: EGFR (18.2 months), ALK (18.4 months), KRAS (6.0 months) and WT (8.7 months) (P < 0.0001). OS for EGFR, ALK, KRAS and WT patients was 36.6, 32.2, 15.5 and 22.4 months, respectively (P = 0.014). Intracranial-ORR (HR 0.4 [95% CI 0.2-0.6], P < 0.001) and mutation status (HR 0.7 [95% CI 0.6-0.9], P < 0.042) were independently associated with a higher OS. RT response varies as per tumor molecular status. The presence of EGFR mutations favors the organ-specific response to RT, and is associated with longer OS in patients with NSCLC and BM. This study addressed for the first time the difference in radiotherapy-related outcomes in patients with different genotypes of non-small cell lung cancer (NSCLC) before they received systemic therapy. Results show that response to radiotherapy varies as per tumor molecular status, particularly EGFR-mutated tumors, have a favorable response to radiotherapy, contrary to KRAS-mutated tumors.

Arrieta O ，Ramírez-Tirado LA ，Caballé-Perez E ，Mejia-Perez A ，Zatarain-Barrón ZL ，Cardona AF ，Lozano-Ruíz F ，Segura-González M ，Cruz-Rico G ，Maldonado F ，Rosell R ... -  《-》

Impact of EGFR mutation and ALK rearrangement on the outcomes of non-small cell lung cancer patients with brain metastasis.

Balasubramanian SK ，Sharma M ，Venur VA ，Schmitt P ，Kotecha R ，Chao ST ，Suh JH ，Angelov L ，Mohammadi AM ，Vogelbaum MA ，Barnett GH ，Jia X ，Pennell NA ，Ahluwalia MS ... -  《-》