Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-02-2020 | NSCLC | Original Article – Clinical Oncology

Co-occurring genetic alterations and primary EGFR T790M mutations detected by NGS in pre-TKI-treated NSCLCs

Authors: Yuan Tang, Nanying Che, Yang Yu, Yun Gao, Huaiyin Shi, Qin Feng, Bing Wei, Liheng Ma, Min Gao, Jie Ma, Dongmei Lin

Published in: Journal of Cancer Research and Clinical Oncology | Issue 2/2020

Abstract

Introduction

Next-generation sequencing (NGS)-based assays to understand various mutations and co-occurrence of genomic alterations in non-small cell lung cancer (NSCLC) have enabled understanding of treatment impact on clinical outcomes.

Methods

This retrospective study was conducted in 1353 formalin-fixed paraffin-embedded (FFPE) tissues from surgically resected, pre-TKI-treated NSCLC patients with identified gene alterations. Genomic DNA and RNA extraction was followed by NGS library preparation and sequencing using the Ion Ampliseq Colon and Lung Cancer Gene Panel V2 and the AmpliSeq RNA Lung Cancer Research Fusion Panel.

Results

A total of 2328 alterations in 25 genes were detected from the 1293 patients. DNA mutations and RNA fusions co-occurred in 27 patients with TP53 being the most common co-occurring DNA mutation (43.8%) with concurrent ALK fusions. Analysis of the 975 patients with EGFR mutations revealed that the incidence of dual EGFR L858R/T790M mutations was higher compared to EGFR 19del/T790M, and the mean allele fraction (MAF) of T790M was lower compared to 19del in dual EGFR 19del/T790M patients.

Conclusion

NSCLC patients represented genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways. This diverse mutational profile may have key clinical and research implications for understanding the variability of treatment outcome in pre-TKI-treated NSCLC population. The differences in the MAF of EGFR T790M may determine different responses to TKI therapy in patients harboring dual mutations.

Available only for authorised users

Ahn MJ et al (2019) Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer 125:892–901. https://doi.org/10.1002/cncr.31891 CrossRefPubMed

Akamatsu H et al (2018) Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non-small-cell lung cancer: AURA3 trial. Cancer Sci 109:1930–1938. https://doi.org/10.1111/cas.13623 CrossRefPubMedPubMedCentral

Blakely CM et al (2017) Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet 49:1693–1704. https://doi.org/10.1038/ng.3990 CrossRefPubMedPubMedCentral

Butler KS, Young MY, Li Z, Elespuru RK, Wood SC (2016) Performance characteristics of the AmpliSeq cancer hotspot panel v2 in combination with the ion torrent next generation sequencing personal genome machine. Regul Toxicol Pharmacol 74:178–186. https://doi.org/10.1016/j.yrtph.2015.09.011 CrossRefPubMed

Cai W et al (2015) Intratumoral heterogeneity of ALK-rearranged and ALK/EGFR coaltered lung adenocarcinoma. J Clin Oncol 33:3701–3709. https://doi.org/10.1200/JCO.2014.58.8293 CrossRefPubMedPubMedCentral

Canale M et al (2017) Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. Clin Cancer Res 23:2195–2202. https://doi.org/10.1158/1078-0432.CCR-16-0966 CrossRefPubMed

Chen LY et al (2016) Coexistence of EGFR T790M mutation and common activating mutations in pretreatment non-small cell lung cancer: a systematic review and meta-analysis. Lung Cancer 94:46–53. https://doi.org/10.1016/j.lungcan.2016.01.019 CrossRefPubMed

Ding PN et al (2019) Plasma next generation sequencing and droplet digital PCR-based detection of epidermal growth factor receptor (EGFR) mutations in patients with advanced lung cancer treated with subsequent-line osimertinib. Thorac Cancer 10:1879–1884. https://doi.org/10.1111/1759-7714.13154 CrossRefPubMedPubMedCentral

Drilon A et al (2015) Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res 21:3631–3639. https://doi.org/10.1158/1078-0432.CCR-14-2683 CrossRefPubMedPubMedCentral

Fan J, Dai X, Nie X (2018) Concomitant epidermal growth factor receptor mutation and EML4-alk fusion in a patient with multifocal lung adenocarcinomas. J Thorac Oncol 13:e45–e48. https://doi.org/10.1016/j.jtho.2017.11.130 CrossRefPubMed

Godin-Heymann N et al (2007) Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer Res 67:7319–7326. https://doi.org/10.1158/0008-5472.CAN-06-4625 CrossRefPubMedPubMedCentral

Grasso C et al (2015) Assessing copy number alterations in targeted, amplicon-based next-generation sequencing data. J Mol Diagn 17:53–63. https://doi.org/10.1016/j.jmoldx.2014.09.008 CrossRefPubMedPubMedCentral

Gregorc V, Lazzari C, Karachaliou N, Rosell R, Santarpia M (2018) Osimertinib in untreated epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer. Transl Lung Cancer Res 7:S165–S170. https://doi.org/10.21037/tlcr.2018.03.19 CrossRefPubMedPubMedCentral

Hirsch FR, Suda K, Wiens J, Bunn PA Jr (2016) New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet 388:1012–1024. https://doi.org/10.1016/S0140-6736(16)31473-8 CrossRefPubMed

Hong S, Gao F, Fu S, Wang Y, Fang W, Huang Y, Zhang L (2018) Concomitant genetic alterations with response to treatment and epidermal growth factor receptor tyrosine kinase inhibitors in patients with EGFR-mutant advanced non-small cell lung cancer. JAMA Oncol 4:739–742. https://doi.org/10.1001/jamaoncol.2018.0049 CrossRefPubMedPubMedCentral

Inukai M et al (2006) Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 66:7854–7858. https://doi.org/10.1158/0008-5472.CAN-06-1951 CrossRefPubMed

Jurgens J, Engel-Riedel W, Stoelben E, Schildgen V, Schildgen O, Brockmann M (2016) The (Con-) fusion in ALK diagnostics: when food and drug administration-approved algorithms fail. J Clin Oncol 34:1961–1962. https://doi.org/10.1200/JCO.2015.65.4871 CrossRefPubMed

Ke EE, Wu YL (2016) Afatinib in the first-line treatment of epidermal-growth-factor-receptor mutation-positive non-small cell lung cancer: a review of the clinical evidence. Ther Adv Respir Dis 10:256–264. https://doi.org/10.1177/1753465816634545 CrossRefPubMedPubMedCentral

Lee CK et al (2015) Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in egfr-mutant lung cancer: a meta-analysis. J Clin Oncol 33:1958–1965. https://doi.org/10.1200/JCO.2014.58.1736 CrossRefPubMed

Liang H et al (2018) The alteration of T790M between 19 del and L858R in NSCLC in the course of EGFR-TKIs therapy: a literature-based pooled analysis. J Thorac Dis 10:2311–2320. https://doi.org/10.21037/jtd.2018.03.150 CrossRefPubMedPubMedCentral

Lim SM et al (2016) Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium). Oncotarget 7:36311–36320. https://doi.org/10.18632/oncotarget.8904 CrossRefPubMedPubMedCentral

Liu Y, Sun L, Xiong ZC, Sun X, Zhang SL, Ma JT, Han CB (2017) Meta-analysis of the impact of de novo and acquired EGFR T790M mutations on the prognosis of patients with non-small cell lung cancer receiving EGFR-TKIs. Onco Targets Ther 10:2267–2279. https://doi.org/10.2147/OTT.S133082 CrossRefPubMedPubMedCentral

Lusebrink J, Pieper M, Tillmann RL, Brockmann M, Schildgen O, Schildgen V (2018a) Detailed overview on the mutations detected by and the sensitivity of the GeneReader NGS sequencing platform. Data Brief 18:1962–1966. https://doi.org/10.1016/j.dib.2018.04.114 CrossRefPubMedPubMedCentral

Lusebrink J, Pieper M, Tillmann RL, Brockmann M, Schildgen O, Schildgen V (2018b) Pre-clinical validation of a next generation sequencing testing panel. Exp Mol Pathol 104:170–174. https://doi.org/10.1016/j.yexmp.2018.04.001 CrossRefPubMed

Mok TS et al (2017) Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 376:629–640. https://doi.org/10.1056/NEJMoa1612674 CrossRefPubMed

Oxnard GR et al (2018) Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol 4:1527–1534. https://doi.org/10.1001/jamaoncol.2018.2969 CrossRefPubMed

Peng M, Weng YM, Liu HL, Yang GF, Yao Y, Han G, Song QB (2018) Clinical characteristics and survival outcomes for non-small-cell lung cancer patients with epidermal growth factor receptor double mutations. Biomed Res Int 2018:7181368. https://doi.org/10.1155/2018/7181368 CrossRefPubMedPubMedCentral

Recondo G, Facchinetti F, Olaussen KA, Besse B, Friboulet L (2018) Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat Rev Clin Oncol 15:694–708. https://doi.org/10.1038/s41571-018-0081-4 CrossRefPubMed

Rosell R et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239–246. https://doi.org/10.1016/S1470-2045(11)70393-X CrossRefPubMed

Schildgen V, Schildgen O (2018) The lonely driver or the orchestra of mutations? How next generation sequencing datasets contradict the concept of single driver checkpoint mutations in solid tumours—NSCLC as a scholarly example. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2018.11.005 CrossRefPubMed

Soejima K, Yasuda H, Hirano T (2017) Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer. Expert Rev Clin Pharmacol 10:31–38. https://doi.org/10.1080/17512433.2017.1265446 CrossRefPubMed

Su KY et al (2012) Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol 30:433–440. https://doi.org/10.1200/JCO.2011.38.3224 CrossRefPubMed

Suda K, Mitsudomi T (2014) Successes and limitations of targeted cancer therapy in lung cancer Prog. Tumor Res 41:62–77. https://doi.org/10.1159/000355902 CrossRef

Vollbrecht C, Lehmann A, Lenze D, Hummel M (2018) Validation and comparison of two NGS assays for the detection of EGFR T790M resistance mutation in liquid biopsies of NSCLC patients. Oncotarget 9:18529–18539. https://doi.org/10.18632/oncotarget.24908 CrossRefPubMedPubMedCentral

Wang WX et al (2018) TP53 mutations predict for poor survival in ALK rearrangement lung adenocarcinoma patients treated with crizotinib. J Thorac Dis 10:2991–2998. https://doi.org/10.21037/jtd.2018.04.98 CrossRefPubMedPubMedCentral

Watanabe M et al (2015) Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res 21:3552–3560. https://doi.org/10.1158/1078-0432.CCR-14-2151 CrossRefPubMed

Wu YL et al (2014) Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15:213–222. https://doi.org/10.1016/S1470-2045(13)70604-1 CrossRefPubMed

Xu T et al (2017) Cross-platform comparison of four leading technologies for detecting EGFR mutations in circulating tumor DNA from non-small cell lung carcinoma patient plasma. Theranostics 7:1437–1446. https://doi.org/10.7150/thno.16558 CrossRefPubMedPubMedCentral

Yang JC et al (2015) Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 16:141–151. https://doi.org/10.1016/S1470-2045(14)71173-8 CrossRefPubMed

Ye X et al (2013) High T790M detection rate in TKI-naive NSCLC with EGFR sensitive mutation: truth or artifact? J Thorac Oncol 8:1118–1120. https://doi.org/10.1097/JTO.0b013e31829f691f CrossRefPubMed

Youssef O, Knuuttila A, Piirila P, Bohling T, Sarhadi V, Knuutila S (2018) Hotspot mutations detectable by next-generation sequencing in exhaled breath condensates from patients with lung cancer. Anticancer Res 38:5627–5634. https://doi.org/10.21873/anticanres.12897 CrossRefPubMed

Yu HA et al (2018) Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin Cancer Res 24:3108–3118. https://doi.org/10.1158/1078-0432.CCR-17-2961 CrossRefPubMedPubMedCentral

Zhang Y et al (2014) Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis. PLoS One 9:e107161. https://doi.org/10.1371/journal.pone.0107161 CrossRefPubMedPubMedCentral

Zhang B et al (2018) Coexistence of sensitive and resistant epidermal growth factor receptor (EGFR) mutations in pretreatment non-small cell lung cancer (NSCLC) patients: First or third generation tyrosine kinase inhibitors (TKIs)? Lung Cancer 117:27–31. https://doi.org/10.1016/j.lungcan.2018.01.006 CrossRefPubMed

Zheng G et al (2016) Test feasibility of next-generation sequencing assays in clinical mutation detection of small biopsy and fine needle aspiration specimens. Am J Clin Pathol 145:696–702. https://doi.org/10.1093/ajcp/aqw043 CrossRefPubMedPubMedCentral

Title: Co-occurring genetic alterations and primary EGFR T790M mutations detected by NGS in pre-TKI-treated NSCLCs
Authors: Yuan Tang
Nanying Che
Yang Yu
Yun Gao
Huaiyin Shi
Qin Feng
Bing Wei
Liheng Ma
Min Gao
Jie Ma
Dongmei Lin
Publication date: 01-02-2020
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Lung Cancer
Fluorescence in Situ Hybridization
Lung Cancer
Tyrosine Kinase Inhibitors
NSCLC
Lung Cancer
Tyrosine Kinase Inhibitors
Published in: Journal of Cancer Research and Clinical Oncology / Issue 2/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-03065-0

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Co-occurring genetic alterations and primary EGFR T790M mutations detected by NGS in pre-TKI-treated NSCLCs

Abstract

Introduction

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2020

Treatment of refractory germ-cell tumours with single-agent cabazitaxel: a German Testicular Cancer Study Group case series

Prostate specific membrane antigen (PSMA) in urothelial cell carcinoma (UCC) is associated with tumor grading and staging

Impact of clinical complete response on treatment outcomes in patients with locally advanced HPV-negative oropharyngeal squamous cell carcinoma

Prolonged time to treatment initiation in advanced pancreatic cancer patients has no major effect on treatment outcome: a retrospective cohort study controlled for lead time bias and waiting time paradox

Crosstalk of estrogen receptors and Wnt/β-catenin signaling in endometrial cancer

Clinical impact of first-line bevacizumab plus chemotherapy in metastatic colorectal cancer of mucinous histology: a multicenter, retrospective analysis on 685 patients

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page