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Cited by 174Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsHER2/EGFR in Cancer Research

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

Open access
Kim, Youjin, Lee, Boram, Shim, Joon Ho, Lee, Se-Hoon, Park, Woong-Yang, Choi, Yoon-La, Sun, Jong-Mu, Ahn, Jin Seok +2 more·2019·Journal of Thoracic Oncology
DOI 10.1016/j.jtho.2018.10.150
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Abstract

Introduction: EGFR‐mutant NSCLC displays diverse outcomes to tyrosine kinase inhibitor (TKI) treatment. Because co‐occurring genomic alterations might describe different biological subsets of patients with this cancer, exploring co‐occurring genomic alterations that impact patients’ outcomes using a comprehensive gene panel is potentially important. Methods: This retrospective cohort study was conducted with the panel‐sequencing data acquired from January 2014 to May 2017, and clinical outcome data collected until February 2018. This study includes all eligible patients who possess panel‐sequencing data before treatment with first‐/second‐generation EGFR‐TKIs (cohort 1) or third‐generation EGFR‐TKIs following initial EGFR‐TKI failure (cohort 2). Results: Seventy‐five patients (mean [SD] age, 58.5 [11.0] years; 68.0% women) were included in cohort 1, and 82 patients (mean [SD] age, 57.3 [9.1] years; 67.1% women) were included in cohort 2. In cohort 1, alterations in TP53 were independently associated with worse progression‐free survival (PFS) (hazard ratio [HR]: 2.02; 95% confidence interval [CI]: 1.04–3.93; p = 0.038) in multivariate analysis. In cohort 2, TP53 mutation was associated with significantly worse PFS (8.9 versus 12.8 months; p = 0.029). RB1 mutation was significantly associated with worse (median PFS, 1.9 versus 11.7 months; p < 0.001). PTEN mutation was associated with significantly worse PFS (2.6 versus 10.3 months; p = 0.001). MDM2 amplification was associated with worse PFS (6.6 versus 10.4 months; p = 0.025). In cohort 2, multivariate analysis revealed that alterations in TP53 (HR: 2.23; 95% CI: 1.16–4.29; p = 0.017), RB1 (HR: 5.62; 95% CI: 1.96–16.13; p = 0.001), PTEN (HR: 5.84; 95% CI: 1.56–21.85; p = 0.009), and MDM2 (HR: 2.46; 95% CI: 1.02–5.94; p = 0.046) were independently associated with worse PFS. Conclusions: Co‐occurring genomic alterations detected by panel sequencing are associated with the clinical outcomes of EGFR‐TKI treatment in NSCLC.

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Crossref · 10.1016/j.jtho.2018.10.150

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 20 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In cohort 2 multivariate analysis, RB1 alteration was independently associated with worse progression-free survival (HR 5.62, 95% CI 1.96-16.13, p=0.001).

    “RB1 (HR: 5.62; 95% CI: 1.96-16.13;p ¼ 0.001)”
    Quote in the paperSubstantial claim
  • Findingown data

    In cohort 1, TP53 mutation showed a trend toward shorter progression-free survival than wild-type TP53 (median 12.5 vs 14.7 months, p=0.087).

    “The TP53 mutation was associated with a trend toward a shorter PFS as compared with wild-type TP53 (median PFS, 12.5 [95% confidence interval (CI): 11.1-13.9versus 14.7 [95% CI: 7.2-22.2]months; p ¼ 0.087).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In cohort 2, PTEN mutation was associated with worse overall survival (median 13.2 vs 24.3 months, p=0.005).

    “PTEN mutation was found in three (3.7%)patients and predictive of significantly shorter PFS (median PFS, 2.6 [95% CI: .4-5.2] versus 10.3 [95% CI: 7.4-13.2]months; p ¼ 0.001) (Fig. 3C and Supplementary Fig. 2C) and worse OS (median OS, 13.2 [95% CI: 4.9-26.5]versus 24.3 [95% CI: 21.1-27.5]months; p ¼ 0.005)”
    Quote in the paperSubstantial claim
  • Findingown data

    In cohort 2, PI3K pathway alteration was associated with shorter progression-free survival (median 4.9 vs 10.8 months, p=0.008).

    “and the PI3K pathway (n ¼ 10; median PFS, 4.9 [95% CI: 0-11.6]versus 10.8 [95% CI: 8.2-13.4]months; p ¼ 0.008; median OS, 11.3 [95% CI: 4.9-NR] versus 24.5 [95% CI: 21.9-NR] months; p < 0.001)”
    Quote in the paperSubstantial claim
  • Findingown data

    In cohort 2 multivariate analysis, PTEN alteration was independently associated with worse progression-free survival (HR 5.84, 95% CI 1.56-21.85, p=0.009).

    “PTEN (HR: 5.84; 95% CI: 1.56-21.85;p ¼ 0.009)”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 7

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cell-free DNA analysis has demonstrated clinical utility and high concordance with tissue-based genomic testing.

    “Recently, cell-free DNA analysis has shown significant clinical utility and high concordance with tissue-based genomic testing.[27][28][29]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27][28][29]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Patients treated with different EGFR-TKIs of differing clinical efficacy were included.

    “patients treated with different EGFR-TKI of different clinical efficacy are included”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Prior work has suggested that TP53 mutations and cell-cycle gene alterations may contribute to poor therapeutic response.

    “Previous studies suggested a potential role of TP53 mutations and alterations in cell-cycle genes in poor therapeutic response.[10][11][12]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10][11][12]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RB1 mutation has been reported to be associated with poor prognosis.

    “however, RB1 mutation is reportedly associated with poor prognosis, which is consistent with our results.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Burke, 2005, Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non–small cell lung carcinoma, Clin Cancer Res source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Variant detection, annotation, and filtering used a previously described pipeline, and only variants predicted to have functional impact were selected to avoid false positives from germline variants and multiple comparisons.

    “Variant detection, annotation, and filtering were performed using a previously described pipeline.14 To avoid false-positive results caused by insignificant germline variants and multiple comparisons, only variants predicted to have functional impact were selected.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Lee, 2018, Landscape of actionable genetic alterations profiled from 1,071 tumor samples in Korean cancer patients, Cancer Res Treat

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study accrued patients from a single center.

    “we used a single center of accrual”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Comprehensive tissue-based panel sequencing may be advantageous for understanding genetic mechanisms of tumor progression and therapeutic resistance.

    “Therefore, comprehensive analysis of genomic alterations in tumor tissues via high-throughput panel sequencing can be advantageous to understand the genetic mechanisms associated with tumor progression and therapeutic resistance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A prior report found that high PTEN expression improves survival in patients with EGFR-activating mutations.

    “A previous report showed that high expression of PTEN increases survival in patients with and EGFR-activating mutation.24”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Endoh, 2006, PTEN and PIK3CA expression is associated with prolonged survival after gefitinib treatment in EGFR-mutated lung cancer patients, J Thorac Oncol

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In advanced EGFR-mutant NSCLC, EGFR-TKIs such as gefitinib, erlotinib, and afatinib yield higher survival than standard chemotherapy.

    “In advanced cases of NSCLC with the presence of EGFR mutations, treatment with EGFR-tyrosine kinase inhibitors (TKIs; e.g., gefitinib, erlotinib, and afatinib) has resulted in higher survival rates as compared with standard chemotherapy.[1][2][3]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1][2][3]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    RB1 regulates cell cycle progression, and its loss participates in NSCLC small-cell transformation.

    “RB1 is an important regulator of cell cycle progression, and its loss is involved in the small-cell transformation of NSCLC.21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Niederst, 2015, RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The findings support the idea that driver mutations alone do not determine therapeutic response and that comprehensive genome sequencing is important for EGFR-mutant patients.

    “This observation supports the concept that it is not just major driver mutations that affect therapeutic response and clinical outcomes and highlights the importance of conducting comprehensive genome sequencing in patients harboring an EGFR mutation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Co-occurring genetic alterations may contribute to resistance and help explain the wide variation in patient outcomes.

    “Co-occurring genetic alterations might play a role in resistance mechanisms and could potentially explain the marked diversity of individual patient outcomes.8,9”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Hong, 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 source

      Not checked in the free run.

    • cites [9] Blakely, 2017, Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers, Nat Genet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    About 20% to 30% of patients show no objective response to EGFR-TKIs.

    “Furthermore, approximately 20% to 30% of patients do not exhibit objective responses to EGFR-TKIs.[1][2][3]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1][2][3]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    EGFR-mutant tumors show substantial inter- and intratumoral heterogeneity, and their co-occurring mutations influence TKI clinical efficacy.

    “EGFRmutated tumors have significant inter-and intratumor heterogeneity along with various co-occurring mutations that determine the clinical efficacy of TKIs in EGFRmutated NSCLC patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductnone given

    The generalizability of the findings must be considered.

    “the generalizability of our study findings must be considered.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    This study is a comprehensive analysis of co-occurring genomic alterations and their predictive value for EGFR-TKI clinical benefit in NSCLC.

    “Our study represents a comprehensive analysis of cooccurring genomic alterations to assess their predictive efficacy of the clinical benefits of EGFR-TKI treatment in NSCLC.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Data collection received Samsung Medical Center IRB/Privacy Board approval, and all patients gave written informed consent for genetic analysis.

    “Data collection was approved by the Samsung Medical Center Institutional Review Board/ Privacy Board (approval number: 2012-0795), and all patients provided written informed consent for the genetic analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All tumor specimens were reviewed by pathologists to determine viable tumor percentage and adequacy for sequencing.

    “All tumor specimens were reviewed by pathologists to determine the percentage of viable tumor and its adequacy for sequencing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Patients who received upfront third-generation TKI were excluded because their NGS data were not included.

    “NGS data on patients who received upfront third-generation TKI were excluded from this study”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The retrospective database limited investigation of other potential bias sources.

    “the use of a retrospective database limited our ability to investigate other sources of potential bias”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Third-generation EGFR-TKIs such as osimertinib, rociletinib, and olmutinib show strong efficacy against T790M-positive resistant NSCLC.

    “Recently, third-generation EGFR-TKIs (EGFR-TKI 3rd ), such as osimertinib, rociletinib, and olmutinib, have displayed remarkable efficacy against T790M-related resistance mutation-positive NSCLC.[4][5][6]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4][5][6]

      Not checked in the free run.

21 of 21

  • The paper relies on this without support.

    PTEN suppresses tumors by inhibiting PI3K pathway activation.

    “PTEN acts as a tumor suppressor by inhibiting PI3K pathway activation.”

  • The paper relies on this without support.

    The PI3K pathway lies downstream of EGFR signaling.

    “Given that the PI3K pathway is downstream of the EGFR-signaling pathway”

  • The paper relies on this without support.

    High-throughput sequencing analysis can systematically detect clinically meaningful genetic alterations and identify patients likely to respond to targeted agents.

    “Statistical analysis of high-throughput sequencing data enables systematic detection of clinically meaningful genetic alterations, making it possible to identify patients potentially sensitive to targeted agents.”

  • The paper relies on this without support.

    NGS results from pre-treatment tumor samples represent the genomic state relevant to subsequent EGFR-TKI response.

    “Cohort 1 included patients with NGS results obtained before treatment with first-/second-generation EGFR-TKIs”

  • The paper relies on this without support.

    PFS is a valid measure of clinical benefit from EGFR-TKI treatment.

    “Progression-free survival (PFS) and overall survival (OS) were measured from the first day of treatment with EGFR-TKI to tumor progression and death, respectively.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy.

    “In keeping with a more complex genomic landscape and a larger burden of clonal or sub-clonal co-drivers, multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy72, 73, 111–116.”

    From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [116]

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Authors
Kim, Y., Lee, B., Shim, J. H., Lee, S.-H., Park, W.-Y., Choi, Y.-L., Sun, J.-M., Ahn, J. S., Ahn, M.-J., & Park, K.
Affiliations
Samsung Medical Center (KR)
Corresponding author
Lee, Se-Hoon
ORCID
Venue
Journal of Thoracic Oncology
Publisher
Elsevier BV
Published
2019-02
Volume
14
Issue
2
Pages
193-202
ISSN
1556-0864 (ISSN-L)
DOI
10.1016/j.jtho.2018.10.150
OpenAlex
W2898978171
Semantic Scholar
b57daf65e62ec5edcc28cca0e0804fbf0e125eab
Cited by
174
References
33
Citations by year
2026: 12 · 2025: 24 · 2024: 18 · 2023: 29 · 2022: 24 · 2021: 22 · 2020: 32 · 2019: 13
FWCI
12.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Thoracic Oncology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministry of Trade, Industry and Energy
  • National Research Foundation of Korea
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords
EGFR-mutant non-small cell lung cancer, tyrosine kinase inhibitors, anti-EGFR therapy, TP53 mutation, RB1 mutation, PTEN mutation, MDM2 amplification, progression-free survival, treatment resistance, predictive biomarkers, third-generation EGFR-TKI, comprehensive genomic profiling, molecular subtypes, prognostic factors
MeSH terms
Progression-Free Survival, Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, DNA, Neoplasm, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Retrospective Studies, Signal Transduction, Survival Rate, Tumor Suppressor Protein p53, Sequence Analysis, DNA, Ubiquitin-Protein Ligases, Protein Kinase Inhibitors, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-mdm2, Retinoblastoma Binding Proteins, High-Throughput Nucleotide Sequencing, ErbB Receptors

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