Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC

Kim, Youjin; Lee, Boram; Shim, Joon Ho; Lee, Se‐Hoon; Park, Woong-Yang; Choi, Yoon‐La; Sun, Jong‐Mu; Ahn, Jin Seok; Ahn, Myung‐Ju; Park, Keunchil

doi:10.1016/j.jtho.2018.10.150

Cited by 106 publications

(116 citation statements)

References 29 publications

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“…From a biological perspective, cooccurrence of driver alterations clearly does occur [17,18,19,20], and appears to be a requirement for carcinogenesis, as evidenced by the insufficiency of BRAF and RAS hotspot mutations to transform benign colon polyps and nevi into invasive carcinoma [21,22]. However, statistical approaches to identifying cooccurrence have given mixed results.…”

Section: Introductionmentioning

confidence: 99%

Identifying Modules of Cooperating Cancer Drivers

Klein

Cannataro

Townsend

et al. 2020

Preprint

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AbstractIdentifying cooperating modules of driver alterations can provide biological insights to cancer causation and would advance the development of effective personalized treatments. We present Cancer Rule-Set Optimization (CRSO) for inferring the combinations of alterations that cooperate to drive tumor formation in individual patients. Application to 19 TCGA cancer types found a mean of 11 core driver combinations per cancer, comprising 2-6 alterations per combination, and accounting for a mean of 70% of samples per cancer. CRSO departs from methods based on statistical cooccurrence, which we demonstrate is a suboptimal criterion for investigating driver cooperation. CRSO identified well-studied driver combinations that were not detected by other approaches and nominated novel combinations that correlate with clinical outcomes in multiple cancer types. Novel synergies were identified in NRAS-mutant melanomas that may be therapeutically relevant. Core driver combinations involving NFE2L2 mutations were identified in four cancer types, supporting the therapeutic potential of NRF2 pathway inhibition. CRSO is available at https://github.com/mikekleinsgit/CRSO/.

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Section: Introductionmentioning

confidence: 99%

Identifying Modules of Cooperating Cancer Drivers

Klein

Cannataro

Townsend

et al. 2020

Preprint

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“…306 articles were excluded for duplicates. Following a title/abstract screening and a full text reviewing by all the authors, 15 studies [26][27][28][29][34][35][41][42][43][44][45][46][47][48][49] were included for final analysis.…”

Section: Study Identification and Selectionmentioning

confidence: 99%

“…Totally, 475 patients were TP53-positive cases and 867 were TP53-wild type cases. Among all patients included, 1049 in 11 studies [26][27][28][29][34][35][41][42][43][44][45][46][47][48][49] harbored EGFR active mutations (mainly EGFR Exon19 deletions and Exon 21 L858R mutations) and received EGFR-TKIs therapy (first generation EGFR-TKIs---gefitinib, erlotinib; second generation EGFR-TKIs---afatinib, dacomitinib; third generation EGFR-TKIs--osimertinib, olmutinib). Four studies with 293 patients investigated the impact of TP53 mutational status on outcome of patients with activating ALK rearrangements (mainly EML4-ALK fusions) receiving ALK-TKIs therapy (first generation ALK-TKIs----crizotinib; next generation ALK-TKIs---ceritinib, alectinib, brigatinib, ect), percent of TP53 concurrent mutations in ALK-rearranged advanced NSCLC in these four studies ranged from 23.44%-60%.…”

Section: Characteristics Of the Included Studiesmentioning

confidence: 99%

“…Percent of TP53 concurrent mutations in EGFR-mutated advanced NSCLC in these 11 studies ranged from 25.91%-60%. In terms of the pathology type of tumor, 9 studies focused on ADC only or over 96% of patients included were ADC patients [29,34,39,42,49]; the remaining 6 studies included patients with all NSCLC types (adenocarcinoma, squamous carcinoma, adeno-squamous carcinoma, neuroendocrine carcinoma, poorly differentiated carcinoma, ect) [26,27,28,35,42,43]. When it comes to treatment lines, 379 out of 1049 patients in 5 studies received first line treatment of first-or second-generation EGFR-TKIs [27,35,41,42,43]; the remaining 670 patients received EGFR-TKIs treatment in all lines setting (postoperative adjuvant treatment, first line treatment, second line treatment and other conditions).…”

Section: Characteristics Of the Included Studiesmentioning

confidence: 99%

“…Notably, patients in study by Youjin Kim et al [42] were divided in two independent groups according to different EGFR TKIs treatments: group1, 1st/2nd-generation EGFR TKIs (first-line treatment); group 2, 3rd-generation EGFR-TKIs following initial EGFR-TKIs failure (second-line treatment). Similarly, patients in study by Kron A et al [45] were also grouped based on types of ALK-TKIs therapy-patients with first generation ALK-TKIs or next generation ALK-TKIs (ceritinib/alectinib/brigatinib).…”

Section: Characteristics Of the Included Studiesmentioning

confidence: 99%

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Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

Qin

Hou

et al. 2020

Preprint

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Background The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)-or anaplastic lymphoma kinase (ALK)-mutated advanced non-smallcell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments.Methods Eligible studies were identified by searching the online databases PubMed, Embase, Medline,The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients.This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. ResultsIn total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR=1.88, 95%CI:1.59-2.23, p<0.001, I2=0.0%, P=0.792) and overall survival (OS) (HR=1.92, 95%CI: 1.55-2.38, p<0.001, I2=0.0%, P=0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P<0.001, I2=0.0%, P=0.473; pooled HR for OS:1.94, 95% CI 1.36-2.76, P<0.001, I2=0.0%, P=0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study.Conclusions This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced

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Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non–Small Cell Lung Cancer in Patients With Brain Metastases

Hou

et al. 2023

JAMA Netw Open

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ImportanceUse of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear.ObjectiveTo investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases.Design, Setting, and ParticipantsThis open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled.InterventionsThe eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone.Main Outcomes and MeasuresThe primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed.ResultsA total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P &lt; .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3; 95% CI, 14.4-18.2 months vs 9.5; 95% CI, 8.3-10.8 months; P &lt; .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0%; 95% CI, 77.0%-93.0% vs 63.0%; 95% CI, 52.2%-73.7%; P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable.Conclusions and RelevanceIn this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients.Trial RegistrationClinicalTrials.gov Identifier: NCT01951469

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Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC

Cited by 106 publications

References 29 publications

Identifying Modules of Cooperating Cancer Drivers

Identifying Modules of Cooperating Cancer Drivers

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non–Small Cell Lung Cancer in Patients With Brain Metastases

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