Chinese Non-small Cell Lung Cancer Research Articles

Genomic characteristics in Chinese non-small cell lung cancer patients and its value in prediction of postoperative prognosis.

BackgroundThe genomic profile of non-small cell lung cancer (NSCLC) in Asians is distinct from that of Caucasians, but comprehensive genetic profiling reports have been limited for Asian patients. We aimed to elucidate genomic characteristics of Chinese NSCLC patients and develop potential model including genomic characteristics to predict postoperative prognosis.MethodsResected tumor samples from 511 patients with stage I–IV lung cancer were subjected to targeted sequencing using a panel of 295 cancer-related genes. Based on the molecular profiles and clinical features, we established nomogram models with predictors consisting of integrated clinical and genomic characteristics to provide post-operative risk stratification.ResultsCompared to the TCGA population (mainly Caucasians), there was a significantly higher frequency of EGFR (53.7% vs. 14.4%) and NOTCH3 (8.4% vs. 1.3%) mutations and less mutated KRAS (11.0% vs. 32.6%), KEAP1 (4.4% vs. 17.4%) and LRP1B (16.3% vs. 29.6%) in Chinese lung adenocarcinomas (LUAD). Distinct patterns of mutually exclusive and co-occurring mutations were identified between LUAD and lung squamous cell carcinoma (LUSC), indicating the unique histology-specific tumorigenesis mechanism of each subtype. We observed alterations in pathways correlated with clinical characteristics. Additionally, we constructed nomogram model with predictors consisting of clinical and genomic characteristics, which were more accurate than models with clinical characteristics or TNM staging only both in stage I–IIIA patients and T1-2N0M0 sub-cohort.ConclusionsThis study revealed Chinese NSCLC patients have unique genomic profile. Furthermore, the nomogram model combining clinical features with genomic characteristics could improve risk stratification in early-stage NSCLC.

Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua.

BackgroundWe describe the clinical features, genetic profile, and their correlation in NSCLC patients.MethodsA total of 256 Chinese patients with NSCLC were enrolled in this study. NGS‐based genomic profiling of major lung cancer‐related genes was performed on formalin‐fixed paraffin‐embedded tumor samples.ResultsOf 256 patients with NSCLC, 219 were adenocarcinoma and most of them were in the early stage. Among patients, 63.3% patients have more than two gene mutations. By analyzing variant allele frequency (VAF), we found that the median VAF has significant differences between squamous cell carcinoma and adenocarcinoma, as well as early stage and advanced stage. The frequency of mutations in EGFR, MET, and RET were significantly higher in nonsmokers than in smokers. Besides, Pearson correlation analysis found that ALK, BRAF, and MET mutations had a strong correlation with age. Notably, higher frequencies of ALK and BRAF alterations were associated with younger age, while more frequent MET mutations appear in the patients at age 55 or older.ConclusionMore unique features of cancer driver genes in Chinese NSCLC were identified by next‐generation sequencing. These findings highlighted that it is necessary to carry out targeted detection according to different clinical features for NSCLC.

Changes and Influential Factors of Chemotherapy Usage for Non-Small Cell Lung Cancer Patients in China: A Multicenter 10-Year (2005-2014) Retrospective Study.

BackgroundChemotherapy has improved the survival of non-small cell lung cancer (NSCLC) patients over the past few decades. However, there have not been any epidemiological studies on chemotherapy for Chinese NSCLC patients.Patients and MethodsThe patients diagnosed as primary lung cancer between January 1, 2005, and December 31, 2014, in eight hospitals from eight provinces in China were retrospectively reviewed. Demographic and clinical data were extracted from medical history systems. Chi-square test and logistic regression were used to analyze the changes of chemotherapy usage and influential factors.ResultsA total of 7184 lung cancer cases were eligible, among which 6481 NSCLC cases were included in this analysis. Among stage I/II patients, the percentages of receiving adjuvant chemotherapy did not change significantly between the earlier (28.5%) and the latter five years (25.7%) (p = 0.1288). Among stage IIIA patients, the percentages of chemotherapy usage did not change significantly between the earlier and the latter five years in neo-adjuvant (7.5% vs 5.6%, p = 0.1478) and adjuvant (23.1% vs 26.8%, p = 0.1129) treatment. The proportions of first-line platinum-based doublets for stage IIIB/IV patients changed significantly over the 10 years (p < 0.0001). Patients from provinces with inferior gross domestic product, with lower medical reimbursement rates and without smoking history were more likely to use the docetaxel/paclitaxel doublets, comparing with the gemcitabine doublets.ConclusionFrom 2005 to 2014, there was no significant change in the chemotherapy pattern of early NSCLC. Economic factors mainly contributed to the significant changes in the first-line chemotherapy regimen selection for advanced patients.

Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients

BackgroundThe KRAS mutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients. At the 2019th World Conference of Lung Cancer, the KRAS G12C-specific inhibitor AMG510 showed promising results in the phase I clinical trial. However, the frequency, clinical characteristics, and prognostic significance of the KRAS G12C mutation in Chinese NSCLC patients are rarely reported.MethodsNext-generation sequencing was used to confirm the KRAS mutation status in 40,804 NSCLC patients from multiple centers (mCohort). Survival data were collected retrospectively from 1456 patients at one of the centers, the Guangdong Lung Cancer Institute (iCohort).ResultsIn the mCohort, 3998 patients (9.8%) were confirmed to harbor a KRAS mutation, of whom 1179 (29.5%) had the G12C subtype. In the iCohort, 130 NSCLC patients (8.9%) had a KRAS mutation and 42 (32.3%) had the G12C subtype. The G12C subgroup included more male patients (85.2% vs 67.4%, P < 0.0001) and more smokers (76.2% vs 53.4%, P = 0.02) than did the non-G12C subgroup. Both the KRAS mutation group and KRAS G12C mutation subgroup were associated with a shorter median overall survival (OS) than wildtype tumors (15.1 vs 26.7 months, hazard ratio [HR]KRAS = 1.50, P = 0.002; 18.3 vs 26.7 months, HRG12C = 1.66, P = 0.007). In Cox regression analysis, smoking (HR = 1.39, P = 0.05) and stage IV disease (HR = 2.72, P < 0.001) remained as independent predictors of shorter OS. Both the KRAS mutation (HR = 1.30, P = 0.07) and KRAS G12C mutation (HR = 1.47, P = 0.07) reached borderline significance.ConclusionsIn the largest sample used thus for, our study found that approximately 10% of Chinese NSCLC patients had KRAS mutations. Of these, nearly 30% harbored the KRAS G12C mutation subtype, which was most common in male smokers. The KRAS G12C mutation is a biomarker of poor prognosis in Chinese NSCLC patients, which could potentially be improved by G12C-specific inhibitors in the future.(296 words)

Dynamics of Serum Tumor Markers Can Serve as a Prognostic Biomarker for Chinese Advanced Non-small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors.

Background: Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers were associated with the efficacy and prognosis of Chinese late-stage NSCLC patients treated with programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors.Methods: We initiated a longitudinal prospective study on advanced NSCLC patients treated with PD-1/PD-L1 inhibitors in Chinese PLA general hospital (Beijing, China). Blood samples of baseline and after 6 weeks' treatment were collected. CT scan were used by all patients to evaluate treatment efficacy according to RECIST 1.1. Serum tumor markers levels were measured with an electrochemical luminescence for SCC-Ag and with a chemiluminescent microparticle immunoassay for serum CEA, CA125, and CYFRA21-1. At least 20% decreases of the biomarkers from baseline were considered as meaningful improvements after 6 weeks of treatment with immune checkpoint inhibitors (ICIs). Optimization-based method was used to balance baseline covariates between different groups. Associations between serum tumor biomarker improvements and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed.Results: A total of 308 Chinese patients with advanced NSCLC were enrolled in the study. After balancing baseline covariates, patients with meaningful improvements in <2 out of 4 biomarkers (CEA, CA125, CYFRA21-1, and SCC-Ag) was ended up with lower ORR (0.08 vs. 0.35, p < 0.001), shorten PFS (median: 5.4 vs. 12.5 months, p < 0.001), and OS (median: 11.7 vs. 25.6 months, p < 0.001) in the total population. Subgroup analysis of patients with adenocarcinoma revealed that patients with meaningful improvements in <2 out of 4 biomarkers had significant lower ORR (0.06 vs. 0.36, p < 0.001), shorten PFS (median: 4.1 vs. 11.9 months, p < 0.001), and OS (median: 11.9 vs. 24.2 months, p < 0.001). So as in patients with squamous cell carcinoma, meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs. 0.08, p = 0.014), longer PFS (median: 13.1 vs. 5.6 months, p = 0.001), and OS (median: 25.6 vs. 10.9 months, p = 0.06).Conclusions: The dynamic change of CEA, CA125, CYFRA21-1, and SCC-Ag from baseline have prognostic value for late-stage NSCLC patients treated with PD-1/PD-L1 inhibitors. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.

A phase I, dose-escalation and expansion study of TQ-B3139, a novel ALK TKI, in Chinese ALK or ROS1 positive advanced non-small cell lung cancer (NSCLC).

9585 Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients. Methods: Patients with advanced NSCLC and failed at least one systemic anti-cancer treatment were enrolled. TQ-B3139 was administered orally from 50mg~100mg qd and 200, 300, 400, 500, 600 and 800mg bid, using a PK-guided modified Fibonacci 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles, dose limited toxicities (DLTs) was observed at first cycle. Dose-expansion phase started at dose level which objective response occurs. Treatment was continued until disease progression, death or unacceptable toxicity. Results: Between July 2017 and May 2019, totally 63 patients (59 ALK+, 4 ROS1+) were enrolled. Sixteen patients had prior ALK inhibitor therapy (11 Crizotinib, 5 Ensartinib), and 23 (36.5%) with baseline brain metastasis. Totally, 62 (98.4%) patients experienced treatment-related adverse events (TRAEs), grade 3-4 TRAEs were observed in 21 (33.3%) patients. One DLT occurred in the 800mg bid dose cohort (grade 3 nausea and vomiting). Top 3 common TRAEs were nausea (all grade 87.3%; grade 3-4 3.2%), diarrhea (84.1%, 6.4%), transaminase elevation (65.1%, 4.8%). AUC and Ctrough at steady state increased proportionally from 200mg to 600mg bid. Absorption saturation was observed in 800mg bid. Base on the safety and PK results, PR2D was decided at 600mg bid. Overall ORR was 73.0% (2 CR, 44 PR); DCR was 85.7% (8 SD). Objective response was observed from dose level 200mg bid cohort, ORR and DCR at ≥200mg bid was 78.0% and 89.8%. For ALK TKI-naïve and -resistant patients, the ORR was 78.7% (37/47) and 56.3% (9/16) respectively. For patients with measurable baseline brain metastasis, the ORR for brain lesions was 80.0% (8/10). At data cut-off (23 Jan 2020), 32 events (50.8%) occurred, the median PFS for all patients was 12.1 months (95%CI 8.5-15.6), for patients at ≥200mg bid dose was 12.2 months. The median PFS was not reached for -naive patients (6 months PFS rate 74.5%, 95%CI 68.1-80.9), and 5.6months (95%CI 1.6-9.5) for ALK TKI-resistant patients. Conclusions: TQ-B3139 was well tolerated in Chinese NSCLC patients with high antitumor activity. RP2D was established at 600mg bid. A randomized phase III trial of TQ-B3139 versus Crizotinib in advanced ALK-TKI naïve NSCLC patients is underway. Clinical trial information: NCT03099330 .

Characterization of MET exon 14 skipping in Chinese non-small cell lung cancer (NSCLC) patients.

e21525 Background: MET exon 14 skipping ( METex14) has been identified as a precise biomarker for MET-targeted therapy. Most METex14 alterations occur in patients (pts) with non-small cell lung cancer (NSCLC). Here, we present the clinical, pathological, and genomic characteristics of Chinese NSCLC pts harboring METex14. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and matched blood samples from 3433 pts were collected from December 2017 to January 2019 for a 450 cancer gene targeted next-generation sequencing (NGS) panel. Genomic alterations (GAs) including single nucleotide variations, short and long insertions/deletions (Indels), copy number variations, and gene rearrangements were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: A total of 35 (1.0%) pts harbored the GAs predicted to cause METex14, which was lower than that of the Western population (3%), and comparable to data in previously reported Chinese NSCLC pts. METex14 mutation rates were 10.5% in sarcomatoid carcinoma, 1.5% in adenosquamous carcinoma and 1.0% in adenocarcinoma. The median age of pts with METex14 was 65 years (range 46-85) and 46% were female. Compared with wild-type (WT) pts, those harboring METex14 were significantly associated with older age (median age: 65 vs. 60 years, respectively, p = 0.005) and earlier stage (stage I &amp; II ratio: 67.7% vs 42.0%, respectively, p &lt; 0.0001). METex14 alterations included 17 samples (48.6%) that were base substitutions located on the non-coding adjacent splice acceptor (1), donors (7), and other splice acceptors (9), and 18 (48.6%) Indels located on the non-coding adjacent splice acceptors (8), donor (1), other splice acceptor (1), and exon/intron junctions (7). MDM2, FRS2, and CDK4 amplification was observed in 22.9%, 20.0%, and 17.1%, respectively, of pts with METex14, which was significantly higher than in WT pts (P &lt; 0.001). Concurrent EGFR mutations were rarely observed with METex14 compared with WT pts (8.6% vs. 51.7%, respectively, p &lt; 0.0001). Concurrent MET amplification was identified in 3 samples with METex14, and no other driver genes were found. Conclusions: METex14 occurred in 1.0% of Chinese NSCLC pts and showed a significantly higher prevalence in sarcomatoid carcinoma. METex14 observed in pts with NSCLC were associated with increased concurrent MDM2, FRS2, and CDK4 amplification and decreased EGFR mutation, suggesting that METex14 acts as a driving oncogenic factor in NSCLC.

Genomic correlates and classification of PD-L1 status in non-small cell lung cancer.

e21578 Background: Programmed cell death 1 (PD-L1) is the first FDA-approved predictive biomarker for non-small cell lung cancer (NSCLC) patients treated with PD-(L)1 blockade therapy. Herein, we aim to identify potential anti-PD-L1 treatment-related biomarkers through evaluating the correlation between the PD-L1 expression level, clinical characteristics, and the mutational profile of a large Chinese NSCLC cohort. Methods: Genomic profiling of tumor biopsies from a total of 808 Chinese NSCLC patients, including 651 adenocarcinomas (ADCs) and 157 squamous cell carcinomas (SCCs), was performed using next-generation sequencing by targeting 425 cancer-relevant genes. Immunohistochemical analysis was used to evaluate PD-L1 protein expression using PD-L1 antibodies including DAKO 22C3 ( N= 695) and DAKO 28-8 ( N= 113), respectively. Results: The PD-L1 positive ( &gt; 1%) rate was 49.2% in ADCs and 52.9% in SCCs, respectively. PD-L1 expression (22C3) was associated with the male gender( p&lt; 0.01) and lymph node metastasis ( p= 0.048) in ADCs but not in SCC patients. PD-L1 expression (22C3) was inversely correlated with KRAS wildtype ( p&lt; 0.001) and EGFR exon 19 deletion( p&lt; 0.01) in ADC, while it was negatively associated with TP53 oncogenic mutations ( p= 0.049) in SCC. Copy number variation analysis revealed that MDM2 amplification ( p= 0.027), 1q gain ( p= 0.012), and 5q deletion ( p&lt; 0.01) negatively correlated with PD-L1 expression, whereas PD-L1 and PD-L2 amplification ( p&lt; 0.001 and p&lt; 0.0001) were positively associated with PD-L1 expression in ADCs. In SCCs, PD-L1 expression (22C3) was negatively associated with copy number gain in EGFR ( p= 0.040), MDM2 ( p= 0.044), 14q ( p= 0.032), and 20q ( p= 0.026), along with PTPRD loss (p = 0.015) and 19p deletion (p = 0.025). However, it was positively associated with 9p amplification ( p&lt; 0.01) and 13q deletion ( p= 0.019). Plus, KIF5B- RET ( p= 0.006) appeared to be inversely related to the PD-L1 expression levels (22C3) in ADCs alone. In addition, these predicted biomarkers were used to delineate the receiver operating characteristic (ROC) calculation to discriminate between PD-L1 low and high (22C3, 50%) with an AUC score of 0.779. Lastly, PD-L1 expression (28-8) did not show significant correlation with any detected oncogenic mutations, but negatively correlated with NKX2-1 gain ( p= 0.0379) and 9q deletion ( p= 0.0379) in ADCs. Conclusions: This study revealed the correlation between PD-L1 protein expression, clinical features, and mutational traits in NSCLC patients, and provided a classifier for PD-L1 expression prediction.

Neoantigen screening identifies EGFR L858R mutation immunogenicity in 1862 Chinese NSCLC patients.

e21512 Background: Therapeutic vaccines targeting mutation-derived neoantigens prime T-cell responses and deliver long-term clinical benefit to patients. Last year we reported EGFR L858R mutation could be a possible target for individual-independent vaccine in 799 Chinese patients with non-small cell lung cancer (NSCLC). Here we verified the findings and explored possible immunological mechanisms in a larger sample size of 1862 Chinese NSCLC. Peripheral blood or normal tissue was used as control. Methods: DNA sequencing data was acquired using our targeted 1021-gene panel and HLA-I genotyping was determined based on DNA sequencing by OptiType v1.0. The peptide-HLA binding affinity was predicted with netMHCpan v4.0. Neoantigen was identified if the IC50 MT &lt; 500 nM and IC50 WT &gt; 500 nM, furthermore, IC50 MT &lt; 50 nM was considered as strong-binders. Results: EGFR (50.05%) was the most prevalent mutated gene, with 22.61% and 13.16% harboring L858R mutations and E746_A750del respectively. HLA typing showed HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. The combination of EGFR L858R and HLA-A*33:03 had both relatively strongest binding affinity (IC50 MT = 22.9 nM and IC50 WT = 12734.0 nM, 2.93%) and highest shared frequency (2.93%). In terms of mechanism, we examined 7 of 1862 (0.37%) B2M gene mutation and 1092 of 1731 (63.1%) HLA-I LOH (loss of heterozygosity) in our population, but didn’t see any statistical difference between L858R subtype and other position mutations in EGFR. We also calculated 26 immune cell types’ signature scores from Chinese CHOICE study and found L858R subtype was associated with elevated level of pDC (KW-test p = 0.02) and lower level of neutrophils signature(KW-test p = 0.07) compared with exon 19 deletion and other uncommon mutations of EGFR. Conclusions: (1) Targeting EGFR L858R mutation in patients with HLA-A*33:03 allele appeared to be valuable for the neoantigen-based vaccine designed for Chinese NSCLC patients. (2) The specific immunogenicity of L858R seemed to be little influenced by B2M mutation and HLA-I LOH which were important factors for neoantigen presentation. (3) High pDC and low neutrophils infiltration might contribute to the inhibitive microenvironment associated with L858R mutation.

Real-world mutational profiling of Chinese non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) uncommon mutations acquired resistant to icotinib using next generation sequencing: A multicenter study.

e21557 Background: Just like classical EGFR mutations, EGFR uncommon mutations non-small cell lung cancer (NSCLC) will still have acquired resistant problem to icotinib. The mechanism of icotinib resistance in such uncommon EGFR mutant patients has also risen to be a difficult question in lung cancer research. In order to explore the resistance mechanism in EGFR uncommon mutant NSCLC patients treated by icotinib, it is necessary to first identify the resistant gene profiles and clinic-pathologic characteristics of those patients. As far as we know that there is no large cohort of EGFR uncommon mutant NSCLC study in evaluating the efficacy and resistant genomic profiling of icotinib. Methods: We screened 3279 patients with NSCLC for EGFR uncommon mutations. Among them, 106 patients received icotinib treatment, and a total of 69 patients with stage IIIb-IV EGFR uncommon mutations NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to icotinib, in including formalin-fixed paraffin-embedded (FFPE) samples, serum samples and serous effusions. We used targeted next-generation sequencing to detect genes status of patients. Results: Among 69 patients treated with icotinib, 69.57% (48/69) developed acquired resistance, and 30.43% (21/69) had primary resistance. Using the specimens at the baseline, there were 39(81.25%) patients with EGFR T790M (including 7 patients with EGFR T790M, 32 patients with EGFR T790M plus EGFR amplification), 3(36.25%) patients with EGFR amplification, 1(2.08%) patient with BRAF mutation, 1(2.08%) patient with PIK3CA mutation, 1(2.08%) patient with CTNNB1 mutation, 1(2.08%) patient with ALK fusion, 1(2.08%) patient with ROS1 fusion, and 1(2.08%) patient with unknown status. Conclusions: EGFR T790M, EGFR amplification, BRAF mutation, PI3K-AKT-mTOR signaling pathway (PIK3CA mutations), CTNNB1 mutation, ALK fusion or ROS1 fusion might contribute to molecular mechanisms of acquired resistance to icotinib in EGFR uncommon mutations NSCLC. Our study uncovered EGFR uncommon mutational profiles of NSCLC patients with icotinib resistance with potential therapeutic implications.

Characters of germline mutations in Chinese non-small cell lung cancer patients.

e13542 Background: Environment factors are associated with lung cancer occurrence. Genetic susceptibility to lung cancer remains unclear. This study assessed germline mutations in Chinese non-small-cell lung cancer (NSCLC) patients. Methods: 506 FFPE samples were collected from 469 patients pathologically confirmed as lung adenocarcinoma. A 508-gene panel including 63 hereditary cancer genes was applied to detect mutations on MGI-seq 2000. Raw data was processed and analyzed. Variation pathogenicity was categorized following ACMG 2015 guideline. Results: 21 patients (4%) carried (likely) pathogenic (P or LP) mutations in 15 cancer predisposition genes. 11 germline variations included MUTYH (1/21), BLM (1/21), BRIP1(2/21), RAD50(1/21), PMS1(1/21), TP53(1/21), BRCA2(1/2), PALB2(1/21), NF1(1/21), CDH1(1/21) and MRE11A (1/21) genes. Nine likely pathogenic mutations were identified in MRE11A, RAD51C, RAD50, ATR, BRCA2, BLM, PMS1 and VHL genes. These mutations are involved in homologous recombination repair, mismatch repair, Fanconi anemia, and Li-Fraumeni syndrome. Germline mutations were commonly occurred in females (female vs Male: 13 vs 7) without statistical significance. No significant correlations of age of onset and TMB were observed between NSCLC patients with germline wild type and mutation. Other clinical characters like histology and clinical stage presented similar results. Somatic mutations with high frequency like EGFR, KRAS were distributed equally in patients with both germline mutation positive and negative. Conclusions: In this study, there is no significant correlation of germline susceptibility gene mutations with clinical and genetic characters of NSCLC patients. Further investigation on germline genetic aberrations of NSCLC is definitely needed to clarify germline impact on the etiology of NSCLC. [Table: see text]

TP53 fusions with next-generation sequencing (NGS) in Chinese non-small cell lung cancer (NSCLC): A multicenter study.

e21742 Background: Currently, with the advances in detection techniques, such as next generation sequencing (NGS), more and more rare or atypical TP53 fusions had been identified. Such as TP53-PSMD14, the importance of EGFR signaling in the pathogenesis of lung cancer and the efficacy of EGFR-TKI treatment had been demonstrated. The aim of this study was to evaluate the prevalence of TP53 fusions in Chinese NSCLC populations, which had not been reported earlier, and to describe targeting potential in Chinese NSCLC populations. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. A total of 2743 patients with NSCLC were screened by using next-generation sequencing (NGS)-based 381 genes panel assay for detecting TP53 fusions. Results: Of this entire cohort, just four (0.15%) patients were identified with a TP53 fusion, including DNAH2-TP53 (1), TP53-MPDU1 (1), TP53-FXR2 (1), TP53-VEZF1 (1). Of the TP53 fusion NSCLC patients, 50.00% were detected in female patients. Biopsies were obtained from primary lung tumor (25.00%) and metastatic sites (75.00%). Overall TMB in the TP53 fusion was high, which had more than 20 mut/Mb. Of the TP53 fusion NSCLC, two cases (50.00%) featured EGFR SV alterations. Conclusions: The frequency of TP53 fusions in Chinese populations with NSCLC is extremely rare (0.17%). TP53 fusions may reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions or exon 21 L858R.

APC fusions analysis in Chinese non-small cell lung cancer (NSCLC) using comprehensive NGS panel: A multicenter study.

e21086 Background: Currently, with the advances in detection techniques, such as next generation sequencing (NGS), more and more rare or atypical APC fusions had been identified. Such as APC-MCC, the importance of Wnt signaling in the pathogenesis of lung cancer and the efficacy of EGFR-TKI treatment had been demonstrated. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. To determine the frequency of the APC fusions in NSCLC and other tumors, we analyzed data from 2743 clinical NSCLC cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort, just two (0.07%) patients were identified with a APC fusion, including APC-MCC (1), APC-MRPL13 (1). The genes most frequently co-altered in patients with APC fusions were TP53 (100.00%), CCND1 (50.00%), ESR1 (50.00%), TNN (50.00%), MAP2K2 (50.00%) and POM121L12 (50.00%). Overall TMB in the APC fusions was low (median 2.16 mut/Mb). For treatments, both patients chose chemotherapy based on pemetrexed for first line, and a case example of advanced APC fusion NSCLC patients responding to anlotinib was actively being sought thru our database. Conclusions: The frequency of APC fusions in Chinese populations with NSCLC is extremely rare (0.08%). NGS can identify novel fusions and increase the list of actionable variants for patients. More patients can benefit from targeted treatment. In addition, for short-or long-term responses to TKI treatment, we can use the NGS assay to explore differential gene expression in the future.

Clinical characteristics and treatment outcomes of 65 patients with BRAF-mutated non-small cell lung cancer (NSCLC).

e21745 Background: BRAF mutations are infrequently seen in non-small cell lung cancer (NSCLC) in Chinese population. We aimed to investigate the clinicopathologic characteristics and treatment outcomes of Chinese patients with NSCLC harboring BRAF mutations. Methods: We conducted a retrospective multicenter study in China of patients with NSCLC harboring BRAF mutations between Jan 2017 and Jul 2019. Results: A total of 65 patients treated in 22 centers were included, 54 harbored BRAF-V600E mutation and 11 had non-V600E mutations, including K601E, G469S, G469V, G469A, G596R, G466R and T599dup. No significant difference in age or gender was found between BRAF-V600E and non-V600E cases, while the majority of patients with non-V600E mutations were smokers (81.8%). Of the 18 patients with early-stage disease at diagnosis and underwent a resection, the median disease-free survival (DFS) was 43.2 months, 18.7 months and 10.1 months of stage I, II and IIIA patients (P = 0.07), respectively. In 46 patients with advanced-stage disease at data cutoff, disease control rate (DCR) and progression-free survival (PFS) of first-line anti-BRAF targeted therapy was superior than chemotherapy in patients harboring BRAF-V600E mutation (DCR, 100.0% vs. 70.0%, P = 0.027; median PFS, 9.8 months vs. 5.4 months, P = 0.149). Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, the median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8 months, 5.8 months and 6.0 months, respectively (P = 0.970). Median PFS were similar between V600E and non-V600E patients (5.4 months vs. 5.4 months, P = 0.825) to first-line chemotherapy. Nine patients were treated with checkpoint inhibitors, DCR and median PFS were 62.5% and 3.0 months (95%CI 2.9, 3.1), respectively. Conclusions: Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study.[Table: see text]

The Genomic Characteristics of ALK Fusion Positive Tumors in Chinese NSCLC Patients.

Anaplastic lymphoma kinase (ALK) fusion events account for ~3–7% genetic alterations in patients with non-small cell lung cancer (NSCLC). In this study, we identified the ALK fusion patterns and a novel ALK fusion partner in 44 ALK positive NSCLC patients using a customized HapOncoCDx panel, and identified ALK fusion partners. The most common partner is EML4, forming the variant 1 (v1, E13:A20, 18/44), variant 2 (v2, E20:A20, 5/44), and variant 3 (v3, E6:A20, 13/44). Moreover, we detected a new ALK fusion partner HMBOX1. At the mutation level, TP53 is the most frequently mutated gene (24%), followed by ALK (12%) and STED2 (12%). The median tumor mutation burden (TMB) of these samples is 2.29 mutations/Mb, ranging from 0.76 mut/Mb to 16.79 muts/Mb. We further elaborately portrayed the TP53 mutation sites on the peptide sequence of the encoded protein by lollipop. The mutational signature and copy number alterations (CNAs) of the samples were also analyzed. The CNA events were found in 13 (13/44) patients, and the most commonly amplified genes were MDM2 (n = 4/13) and TERT (n = 4/13). Together, these results may guide personalized clinical management of patients with ALK fusion in the era of precision medicine.

Clinical Characteristics and Treatment Outcomes of 65 Patients With BRAF-Mutated Non-small Cell Lung Cancer.

BRAF mutation is an oncogenic driver gene in non-small cell lung cancer (NSCLC) with low frequency. The data of patients with NSCLC harboring BRAF mutations is rare. We conducted a retrospective multicenter study in Chinese patients with NSCLC harboring BRAF mutations between Jan 2017 and Jul 2019. A total of 65 patients treated in 22 centers were included, 54 harbored BRAF-V600E mutation and 11 had non-V600E mutations, including K601E, G469S, G469V, G469A, G596R, G466R, and T599dup. Of 18 patients with early-stage disease at diagnosis and underwent a resection, the median disease-free survival (DFS) was 43.2, 18.7, and 10.1 months of stage I, II, and IIIA patients, respectively. In 46 patients with advanced-stage disease at data cutoff, disease control rate (DCR), and progression-free survival (PFS) of first-line anti-BRAF targeted therapy was superior than chemotherapy in patients harboring BRAF-V600E mutation (DCR, 100.0 vs. 70.0%, P = 0.027; median PFS, 9.8 vs. 5.4 months, P = 0.149). Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8, 5.8, and 6.0 months, respectively (P = 0.970). Median PFS were similar between V600E and non-V600E patients (5.4 vs. 5.4 months, P = 0.825) to first-line chemotherapy. Nine patients were treated with checkpoint inhibitors, with median PFS of 3.0 months. Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study.

ATM gene polymorphisms are associated with poor prognosis of non-small cell lung cancer receiving radiation therapy.

We investigated the prognostic significance of ataxia telangiectasia mutated (ATM) single nucleotide polymorphisms (SNPs) in 720 Han Chinese non-small cell lung cancer (NSCLC) patients who underwent radiation or chemoradiation therapy. Kaplan-Meier survival curves showed that overall survival (OS) and disease-free survival (DFS) rates were significantly associated with two ATM SNPs, rs664143 and rs189037. Patients with the rs664143 GA or AA genotype had poorer DFS (hazard ratio (HR) = 1.40, 95% confidence interval (CI) = 1.05–1.86, P = 0.021) and OS (HR = 1.28, 95%CI = 1.12–1.78, P = 0.040) than those with the rs664143 GG phenotype. Patients with the rs189037 AG/GG genotypes had poorer prognoses than those with the rs189037 AA genotype (AG/GG vs. AA: DFS, HR = 1.44, 95%CI = 1.06–1.95, P=0.019; OS, HR = 1.16, 95%CI = 1.16–1.17–2.21, P=0.004). These results were confirmed by subgroup analysis based on clinical factors such as smoking, histology, tumor stage, treatment, and radiation dose, all of which were significantly associated with DFS and OS rates in NSCLC patients. These findings show that ATM rs664143 and rs189037 variants determine prognosis in NSCLC patients that have undergone radiation or chemoradiation therapies.

Relationship between intestinal flora structure and metabolite analysis and immunotherapy efficacy in Chinese NSCLC patients.

BackgroundMany immune checkpoint inhibitors (ICIs) have been approved in China to treat non‐small cell lung cancer (NSCLC). However, in the long term, less than 20% of patients benefit from ICIs. To maximize the benefit for NSCLC patients, it is necessary to guide the choice of immunotherapy through biomarkers. Recent studies have shown that gut microbiota can affect tumor response to immunotherapy and might be a potential predictive biomarker. This study analyzed the relationship between intestinal flora structure and metabolomic characteristics in NSCLC and the efficacy of ICIs.MethodsProspective analysis of samples from 63 patients with advanced NSCLC who attended the Department of Respiratory Medicine of the Peking Union Medical College Hospital from March 2018 to June 2019, and were prescribed programmed cell death 1 (PD‐1) inhibitors, was carried out. The follow‐up deadline was 31 December 2019. Stool samples were collected from all patients before the start of immunotherapy. DNA was extracted from all samples and libraries were constructed. This was followed by sequencing using the Illumina sequencing platform, and results were studied using a biological information data analysis process. We divided the data into two groups based on progression‐free survival (PFS) ≥ six months and PFS < six months.ResultsThe median PFS was 7.0 months, not reaching the median overall survival (OS). We obtained 373.5 G of original sequencing data. The phyla Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria accounted for most of the bacterial communities in the stool samples studied. Compared with the PFS < six‐month group, the patients in the PFS ≥ six‐month group had significantly higher β‐diversity in the intestinal microbiome at the baseline level. There were also differences in composition between the two groups. Samples in the PFS ≥ six‐month group were rich in Parabacteroides and Methanobrevibacter, while those in the PFS < six‐month group were rich in Veillonella, Selenomonadales, and Negativicutes. The KO, COG, and CAZy databases were used to study functional group protein families, yielding 390 (KO), 264 (COG), and 859 (CAZy) functional group abundances, with significant differences between the two groups. Bacterial metabolites analysis suggested significant differences in the metabolic potential of methanol and methane between the two groups.ConclusionsWe found a close correlation between intestinal microbiome β‐diversity and anti‐PD‐1 immunotherapy response in Chinese patients with advanced NSCLC. The intestinal flora composition, functional group protein family, and KEGG metabolism also differed between the two groups. Differences in pathways and flora metabolites were also noted.

Target-based genomic profiling of ctDNA from Chinese non-small cell lung cancer patients: a result of real-world data.

Approximately 30% of NSCLC patients cannot obtain tissue sample or sufficient tissue sample for molecular subtyping. Cell-free circulating tumor DNA (ctDNA) in plasma is a potential alternative specimen type to assess genomic variants in patients with non-small cell lung cancer (NSCLC). The purpose of this study was to identify the genomic alteration profile of ctDNA in real-world Chinese NSCLC patients. A total of 325 subjects with pathological diagnosis of NSCLC were enrolled. 10ml Peripheral blood was collected in streck tube, and ctDNA NGS analysis was carried out using an Ampliseq-based 11-gene panel. 295 out of 325 patients (90.8%) had detected ctDNA results. In 62.1% (183/295) of these cases, at least one genomic alterations was detected. Frequency altered genes were EGFR (27.8%), TP53 (22.7%), KRAS (21.36%), and PIK3CA (4.75%). EGFR mutation was associated with female, younger age (< 65years), and adenocarcinoma. The most common mutations in EGFR were L858R (39.4%), exon19 deletions (31.73%), and T790M (18.3%); G13S was the most common alterations in KRAS. TP53 mutation was most occurred in exon7 and exon8. TP53 mutation was significantly more common in patients with history of radiochemotherapy/chemotherapy therapy, and T790M was mainly found in patients with TKIs treatments. Co-existence EGFR mutation with KRAS and different multiple gene co-mutation panels were detected. In Chinese NSCLC patients, EGFR mutation was significantly associated with female, younger age (< 65years), and adenocarcinoma. Genomic profiles of NSCLC were associated with the treatment history; TP53 mutation was significantly more frequent in the patients with history of radiochemotherapy/chemotherapy therapy. Various multiple genes co-mutation panels, especially EGFR and KRAS co-mutation, were observed in the ctDNA of Chinese NSCLC patients.

EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study

ObjectivesTo describe the treatment patterns and outcomes of Chinese non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations in real-world as EGFR ex20ins consist of a diverse group of mutations with limited information on the clinical outcome of these patients treated with chemotherapy or EGFR tyrosine kinase inhibitors (TKIs). Materials and methodsReal-world treatment outcomes of Chinese NSCLC patients harboring EGFR ex20ins were retrospectively analyzed based on medical records at different institutions and detailed web-based patient questionnaires. ResultsBetween March 17, 2018 and December 20, 2018, 165 advanced EGFR ex20ins NSCLC patients treated in 99 hospitals from 26 different regions in China were analyzed. Thirty-nine different molecular variants of EGFR ex20ins were identified with V769_D770insASV being the most common (23.0 %). Central nervous system (CNS) metastasis occurred in 23.0 % of patients at the time of baseline diagnosis. Median progression-free survival (PFS) was significantly longer in patients who received first-line platinum-based chemotherapy (6.4 m; 95 % CI: 5.7–7.1) than all-generation EGFR TKIs (2.9 m; 95 %CI: 1.5–4.3; P < 0.001) or 1st-generation EGFR TKIs (2.0 m; 95 %CI: 0.2–3.8; P < 0.001). Median PFS was numerically longer in patients who received second-line chemotherapy (4.0 m; 95 %CI: 3.2–4.8) than those received second-line EGFR TKIs (2.0 m; 95 %CI: 1.1–2.9; P = 0.342). Patients with CNS metastasis had numerically shorter median PFS than those without CNS metastasis when treated with 1st-line chemotherapy (3.6 m; 95 %CI: 0–8.0 vs. 6.5 m; 95 %CI: 4.9–8.1; P = 0.645) or 1st-line EGFR TKIs (2.0 m; 95 %CI: 0.8–3.2 vs. 2.9 m; 95 %CI: 2.1–3.7; P = 0.058). ConclusionChemotherapy is superior to current approved EGFR TKIs as 1st- or 2nd-line treatment of EGFR ex20ins mutations. CNS metastasis conferred numerically shorter PFS with chemotherapy or EGFR TKIs treatment. Targeted agent against EGFR ex20ins with CNS activity is urgently needed.