Lung Adenocarcinoma: Next Generation Sequencing and Outcome in Regional Community Oncology Setting

2021 ◽  
Author(s):  
Laura Skacel ◽  
Michael Babcock ◽  
Antoine Harb ◽  
Adam Curtis ◽  
Carter Liou ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Suppressor Gene ◽  
Smoking History ◽  
Published Data ◽  
Next Generation ◽  
Nccn Guidelines ◽  
Molecular Features ◽  
Generation Sequencing

Abstract PURPOSE: To analyze lung adenocarcinomas (LUAD) from a geographically unique population of rural Maine by next generation sequencing (NGS), correlate mutational findings with clinical features, patient outcomes and published data from other populations.METHODS: 210 consecutive LUADs diagnosed in 2017-2018 were analyzed for 50 oncogene/tumor suppressor gene hot spots by NGS. ALK, ROS-1, RET and MET were assessed by FISH, PD-L1 by immunohistochemistry. Findings were correlated with age, gender, smoking history, stage, overall (OS) and progression-free survival (PFS) and compared to pubished literature.RESULTS: The cohort included 113 (54%) women and 97 (46%) men, ages 33 to 91 (mean: 67.4 years), 52% active and 41% former smokers, 79 (38%) of advanced stage (stage IV). Most frequently detected mutations included TP53 (47.6%), KRAS (38.1%), EGFR (10%), STK11 (8.6%), BRAF (4.8%), MET (3.8%), ABL-1, ATM, CDKN2A, PIK3CA, (all 2.9%), RB-1 and NRAS (2.4%), APC, ERBB4, PTPN11, SMAD4, (all 1.9%), CTNNB1 and ERBB2 (both 1.4%). MET amplification occurred in 3.3%, RET and ALK/ROS-1 rearrangements in 1.4% and 0.5%, high PD-L1 expression in 35.2%. Treatment included surgery/radiation/adjuvant chemotherapy for stages I-II, definitive chemo/radiation therapy and immunotherapy for stage III, immunotherapy, chemo-immunotherapy, targeted therapy, palliative radiation for stage IV. At median of 26 months (minimum 21 month for surviving patients), OS/PFS were 44.3%/39.5%. Stage, male gender, TP53 mutation and KRAS/STK11 co-mutations correlated with adverse OS. In stages I-II, KRAS/TP53 co-mutation was unfavorable. CONCLUSION: NGS testing in a regional oncology setting identified established prognostic/therapeutic markers, as well as additional molecular features correlating with outcome. Our findings support prognostic stratification of LUAD based on the presence of gene mutations outside of the current NCCN guidelines: TP53, KRAS and STK11.

Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 500-500 ◽  
Author(s):  
Jianzhen Lin ◽  
Weiwei Shi ◽  
Songhui Zhao ◽  
Jinwei Hu ◽  
Zheng Hou ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Checkpoint Inhibitors ◽  
Clinical Stage ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Cancer Genes ◽  
Next Generation ◽  
Multikinase Inhibitor ◽  
Generation Sequencing

500 Background: Lenvatinib (Len) is a multikinase inhibitor targeting VEGFR 1-3, FGFR 1-4 and other kinases. Pembrolizumab (Pem) and nivolumab (Nivo) are antibodies inhibiting programmed cell death 1 (PD-1) and reactivate T-cell cytotoxic effect. Len plus PD-1 inhibitors have shown promising results in treating various solid tumors. The role of this combination in ICC is undefined. Methods: 14 ICC pts (median age 49 years, range 34-68; 7 males and 7 females) with treatment of enrolled in a single center, observational study of Len plus Pem/Nivo. Objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were measured according to RECIST 1.1. Next generation sequencing (NGS) with deep coverage on 450 cancer genes and whole exome sequencing were performed in 7 pts to detect all classes of genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Results: All 14 pts had > = 2 prior anticancer therapy with clinical stage IV. ORR was 21.4% with 3 pts achieved partial response (PR), DCR was 92.9% and clinical benefit rate (ORR + durable stable disease > = 5 months) was 64.3%. Median PFS was 5.9 months (95% CI: 4.2-6.2). The most common adverse events (AEs) included hypertension, aminotransferase elevation and fatigue. The grade-3 AEs were occurred at 14% while no grade-4 AE was observed. The most altered genes in the 7 sequenced tumors were IDH1 (3 pts), ARID1A (3 pts), PIK3CA (3 pts), TP53 (2 pts) and BAP1 (2 pts). 4 out of the 7 pts had high TMB ( > 12 mut/Mb) and all responded to Len plus Pem/Nivo with 2 PR. One pt with low TMB and FGFR2 mutation had a response of 27% decreased target lesion. Two low TMB pts were progressed, including one with FGFR2 rearrangement. A responder harbored a 399 bp deletion on MLH1, and was identified as MSI-H. More data will be presented. Conclusions: Our study preliminarily indicates that combining Len with PD-1 inhibitors results in promising efficacy in advanced ICC. High TMB from 450-gene NGS panel was strongly associated with a better therapeutic response.

scholarly journals Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with cancer

Cell Cycle ◽  
2015 ◽  
Vol 14 (11) ◽  
pp. 1730-1737 ◽  
Author(s):  
Maria Schwaederle ◽  
Gregory A Daniels ◽  
David E Piccioni ◽  
Santosh Kesari ◽  
Paul T Fanta ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Next Generation ◽  
Patients With Cancer ◽  
Poor Outcome ◽  
Generation Sequencing

scholarly journals Next-Generation Sequencing Reveals High Uncommon EGFR Mutations and Tumour Mutation Burden in a Subgroup of Lung Cancer Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Gang Guo ◽  
Gaofeng Li ◽  
Yinqiang Liu ◽  
Heng Li ◽  
Qi Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Next Generation Sequencing ◽  
Kinase Inhibitors ◽  
The Cancer Genome Atlas ◽  
Egfr Mutations ◽  
Next Generation ◽  
Molecular Features ◽  
Mutation Burden ◽  
Incidence And Mortality ◽  
Generation Sequencing

Xuanwei County in Southwest China shows the highest incidence and mortality rate of lung cancer in China. Although studies have reported distinct clinical characteristics of patients from Xuanwei, the molecular features of these patients with non-small cell lung cancer (NSCLC) remain unclear. Here, we comprehensively characterised such cases using next-generation sequencing (NGS). Formalin-fixed, paraffin-embedded tumour samples from 146 patients from Xuanwei with NSCLC were collected for an NGS-based target panel assay; their features were compared with those of reference Chinese and The Cancer Genome Atlas (TCGA) cohorts. Uncommon EGFR mutations, defined as mutations other than L858R, exon 19del, exon 20ins, and T790M, were the predominant type of EGFR mutations in the Xuanwei cohort. Patients harbouring uncommon EGFR mutations were more likely to have a family history of cancer (p = 0.048). A higher frequency of KRAS mutations and lower frequency of rearrangement alterations were observed in the Xuanwei cohort (p < 0.001). Patients from Xuanwei showed a significantly higher tumour mutation burden than the reference Chinese and TCGA cohorts (p < 0.001). Our data indicates that patients from Xuanwei with NSCLC harbouring G719X/S768I co-mutations may benefit from treatment with EGFR-tyrosine kinase inhibitors. Our comprehensive molecular profiling revealed unique genomic features of patients from Xuanwei with NSCLC, highlighting the potential for improvement in targeted therapy and immunotherapy.

A Streamlined and High-Throughput Error-Corrected Next-Generation Sequencing Method for Low Variant Allele Frequency Quantitation

2019 ◽  
Author(s):  
Page B McKinzie ◽  
Michelle E Bishop
Keyword(s):  
Next Generation Sequencing ◽  
Suppressor Gene ◽  
Tumor Formation ◽  
Read Length ◽  
Next Generation ◽  
Sequencing Method ◽  
Proportional Increase ◽  
Duplex Sequencing ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Quantifying mutant or variable allele frequencies (VAFs) of ≤10−3 using next-generation sequencing (NGS) has utility in both clinical and nonclinical settings. Two common approaches for quantifying VAFs using NGS are tagged single-strand sequencing and duplex sequencing. While duplex sequencing is reported to have sensitivity up to 10−8 VAF, it is not a quick, easy, or inexpensive method. We report a method for quantifying VAFs that are ≥10−4 that is as easy and quick for processing samples as standard sequencing kits, yet less expensive than the kits. The method was developed using PCR fragment-based VAFs of Kras codon 12 in log10 increments from 10−5 to 10−1, then applied and tested on native genomic DNA. For both sources of DNA, there is a proportional increase in the observed VAF to input VAF from 10−4 to 100% mutant samples. Variability of quantitation was evaluated within experimental replicates and shown to be consistent across sample preparations. The error at each successive base read was evaluated to determine if there is a limit of read length for quantitation of ≥10−4, and it was determined that read lengths up to 70 bases are reliable for quantitation. The method described here is adaptable to various oncogene or tumor suppressor gene targets, with the potential to implement multiplexing at the initial tagging step. While easy to perform manually, it is also suited for robotic handling and batch processing of samples, facilitating detection and quantitation of genetic carcinogenic biomarkers before tumor formation or in normal-appearing tissue.

Longitudinal monitoring by next generation sequencing of plasma cell-free DNA in ALK-rearranged non-small cell lung cancer (NSCLC) patients treated with ALK tyrosine kinase inhibitors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9603-9603 ◽  
Author(s):  
Minsuk Kwon ◽  
Bo Mi Ku ◽  
Sehhoon Park ◽  
Hyun Ae Jung ◽  
Jong-Mu Sun ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Next Generation ◽  
Resistance Mutations ◽  
Plasma Dna ◽  
Anaplastic Lymphoma ◽  
Free Plasma ◽  
Generation Sequencing

9603 Background: Patients with anaplastic lymphoma kinase-rearranged (ALK+) NSCLC inevitably acquire resistance to ALK inhibitors. We hypothesized that longitudinal monitoring of cell-free plasma DNA (cfDNA) next generation sequencing (NGS) could predict the response and resistance of TKI therapy in ALK+NSCLC Methods: Patients with ALK+ advanced NSCLC determined by standard tissue testing and planned for TKI therapy were prospectively recruited. Plasma was collected before therapy (n = 92), two months post-therapy (n = 58), and at progression (n = 35). Plasma DNA NGS analysis was done retrospectively by Guardant360. Results: From April 2015 to July 2019, 92 patients enrolled; 81 (88.0%) received ALK TKI as first-line (crizotinib, n = 59; alectinib, n = 22), 10 (10.9%) received TKI as second-line (alectinib, n = 6; crizotinib, n = 2; ceritinib, n = 1; brigatinib, n = 1), and 1 (1.1%) was treated in third-line (lorlatinib). At the cut-off date of January 28, 2020, 56 of 92 patients had disease progression. Circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%); among these were 43 ALK fusions (62.3%) and 1 ALK G1202R without fusion (1.4%). Fusions included EML4-ALK v1 (n = 19), EML4-ALK v3 (n = 14), CLTC-ALK (n = 1), TPM3-ALK (n = 1), GCC2-ALK/CLIP4-ALK (n = 1), and other EML4-ALK fusions (n = 7). Eight patients developed ALK resistance mutations after crizotinib therapy: L1196M (n = 5), G1269A (n = 1), G1202R (n = 1), and co-occurring F1174L, G1202R, and G1269A (n = 1). Two patients developed ALK resistance mutations after ceritinib: G1202R (n = 1), and co-occurring G1202R and T1151R (n = 1). The absence of detectable ctDNA at baseline was associated with longer progression-free survival (PFS; median 36.1 vs 11.6 months, HR 0.432, p = 0.004) and overall survival (OS; median not reached vs 27.9 months, HR 0.418, p = 0.034). Patients with clearance of ctDNA at two months (n = 29) had significantly longer PFS (median 25.4 vs 13.9 months, HR 0.343, p = 0.030) and OS (median not reached vs 25.7 months, HR 0.173, p = 0.035) than those without clearance (n = 22). Patients with co-occurring TP53 alterations and ALK fusions at baseline (n = 9) showed shorter PFS (median 7.0 vs 12.5 months, HR 3.596, p = 0.0154) than those without TP53 alterations (n = 35). Conclusions: NGS of cell-free plasma DNA is useful not only for the detection of ALK fusions and resistance mutations but also for assessing prognosis and monitoring the dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK TKI.

scholarly journals Targeted Next-Generation Sequencing Analysis for Recurrence in Early-Stage Lung Adenocarcinoma

2020 ◽  
Author(s):  
In Ae Kim ◽  
Jae Young Hur ◽  
Hee Joung Kim ◽  
Jung Hoon Park ◽  
Jae Joon Hwang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
Early Stage ◽  
Genetic Alterations ◽  
Smoking History ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Generation Sequencing

Abstract Background Despite surgical resection, early lung adenocarcinoma has a recurrence rate of 20–50%. No clear predictive markers for recurrence of early lung adenocarcinoma are available. Targeted next-generation sequencing (NGS) is rarely used to identify recurrence-related genes. We aimed to identify genetic alterations that can predict recurrence, by comparing the molecular profiles of patient groups with and without recurrence. Methods Tissues from 230 patients with resected stage I–II lung adenocarcinoma (median follow-up: 49 months) were analyzed via targeted NGS for 207 cancer-related genes. The recurrence-free survival according to the number and type of mutation was estimated using the Kaplan–Meier method. Independent predictive biomarkers related to recurrence were identified using the Cox proportional hazards model. Results Recurrence was observed in 64 patients (27.8%). In multivariate analysis adjusted for age, sex, smoking history, stage, surgical mode, and visceral pleural invasion, the CTNNB1 mutation and fusion genes (ALK, ROS1, RET) were negative prognostic factors for recurrence in early-stage lung adenocarcinoma (HR 4.47, p = 0.001; HR 2.73, p = 0.009). EGFR mutation was a favorable factor (HR 0.51, p = 0.016), but the CTNNB1/EGFR co-mutations were negative predictors (HR 19.2, p < 0.001). TP53 mutation was a negative predictor compared with EGFR mutation for recurrence (HR 5.24, p = 0.02). Conclusions: Targeted NGS can provide valuable information to predict recurrence and identify patients at high recurrence risk, facilitating selection of the treatment strategy among close monitoring and adjuvant-targeted therapy. Larger datasets are required to validate these findings.

scholarly journals PIK3CA and p53 Mutations by Next Generation Sequencing in Lymphoepithelioma-Like Carcinoma of the Endometrium

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Lucie Bienfait ◽  
Nicky D’Haene ◽  
Xavier Catteau ◽  
Jean-Christophe Noël
Keyword(s):  
Next Generation Sequencing ◽  
T Lymphocytes ◽  
Endometrial Carcinoma ◽  
Cytotoxic T Lymphocytes ◽  
Plasma Cells ◽  
P53 Gene ◽  
P53 Mutations ◽  
Next Generation ◽  
Molecular Features ◽  
Generation Sequencing

Lymphoepithelioma-like carcinoma of the endometrium is a very rare variant of endometrial carcinoma characterized by syncytial nests of pleomorphic epithelial cells and heavy infiltration of the stroma by lymphocytes (in particular CD8 cytotoxic T-lymphocytes) and plasma cells. Until now, only five cases have been characterized in this location. This report describes the clinicopathological and the molecular features of this unusual tumor. In particular, using the next generation sequencing (NGS) technique, we have demonstrated that this tumor could be associated with PIK3CA and p53 gene mutations. These data have not been reported to date and suggest that lymphoepithelioma-like carcinoma of the endometrium shares common molecular features with high grade endometrioid and serous-like endometrial carcinoma which are associated with poor outcome. Nevertheless, in endometrial lymphoepithelioma-like carcinoma, the alterations on cell cycle, apoptosis, and/or senescence secondary to p53 mutations could potentially be counterbalanced by the antitumoral response induced by CD8 cytotoxic T-lymphocytes numerous in these tumors.

Identifying large indels in targeted next generation sequencing assays for myeloid neoplasms: a cautionary tale of the ZRSR1 pseudogene

2017 ◽  
Vol 70 (12) ◽  
pp. 1069-1073 ◽  
Author(s):  
Isaac KS Ng ◽  
Christopher Ng ◽  
Jia Jin Low ◽  
Lily Chiu ◽  
Elaine Seah ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Clinical Diagnostics ◽  
Great Promise ◽  
Next Generation ◽  
Bioinformatics Pipeline ◽  
Targeted Next Generation Sequencing ◽  
Molecular Features ◽  
Myeloid Neoplasms ◽  
Large Indels ◽  
Generation Sequencing

Targeted next generation sequencing platforms have been increasingly utilised for identification of novel mutations in myeloid neoplasms, such as acute myeloid leukaemia (AML), and hold great promise for use in routine clinical diagnostics. In this study, we evaluated the utility of an open source variant caller in detecting large indels in a targeted sequencing of AML samples. While we found that this bioinformatics pipeline has the potential to accurately capture large indels (>20 bp) in patient samples, we highlighted the pitfall of a confounding ZRSR1 pseudogene that led to an erroneous ZRSR2 variant call. We further discuss possible clinical implications of the ZRSR1 pseudogene in myeloid neoplasms based on its molecular features. Knowledge of the confounding ZRSR1 pseudogene in ZRSR2 sequencing assays could be particularly important in AML diagnostics because the detection of ZRSR2 in AML patients is highly specific for an s-AML diagnosis.

Sign in / Sign up

Export Citation Format

Share Document