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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Neuroendocrine Science
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1364021

Genomic Signature for Oligometastatic Disease in Non-Small Cell Lung Cancer Patients with Brain Metastases

Provisionally accepted
Ariel R. Choi Ariel R. Choi 1*Ralph B. D'Agostino Jr Ralph B. D'Agostino Jr 2*Michael K. Farris Michael K. Farris 1*Mohammed Abdulhaleem Mohammed Abdulhaleem 3*John Hunting John Hunting 3Yue Wang Yue Wang 4Margaret Smith Margaret Smith 4Jimmy Ruiz Jimmy Ruiz 3Thomas W. Lycan Thomas W. Lycan 3*William J. Petty William J. Petty 3*Christina Cramer Christina Cramer 1Stephen B. Tatter Stephen B. Tatter 5*Adrian Laxton Adrian Laxton 5Jaclyn J. White Jaclyn J. White 5*Wencheng Li Wencheng Li 6*Jing Su Jing Su 7*Christopher Whitlow Christopher Whitlow 8*Fei Xing Fei Xing 4Michael D. Chan Michael D. Chan 1*
  • 1 Department of Radiation Oncology, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, United States
  • 2 Department of Biostatistics and Data Sciences, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, United States
  • 3 Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, United States
  • 4 Department of Cancer Biology, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, United States
  • 5 Department of Neurosurgery, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, United States
  • 6 Department of Pathology, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, United States
  • 7 Department of Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health, Indiana University, Purdue University Indianapolis, Indianapolis, Indiana, United States
  • 8 Department of Radiology, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, United States

The final, formatted version of the article will be published soon.

    Purpose/Objective(s): Biomarkers for extracranial oligometastatic disease remain elusive and few studies have attempted to correlate genomic data to the presence of true oligometastatic disease. Methods: Patients with non-small cell lung cancer (NSCLC) and brain metastases were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based comprehensive genomic profiling (Guardant Health) was available. Extracranial oligometastatic disease was defined as patients having ≤5 non-brain metastases without diffuse involvement of a single organ. Widespread disease was any spread beyond oligometastatic. Fisher's exact tests were used to screen for mutations statistically associated (p<0.1) with either oligometastatic or widespread extracranial disease. A risk score for the likelihood of oligometastatic disease was generated and correlated to the likelihood of having oligometastatic disease vs widespread disease. For oligometastatic patients, a competing risk analysis was done to assess for cumulative incidence of oligometastatic progression. Cox regression was used to determine association between oligometastatic risk score and oligoprogression. Results: 130 patients met study criteria and were included in the analysis. 51 patients (39%) had extracranial oligometastatic disease. Genetic mutations included in the Guardant panel that were associated (p<0.1) with the presence of oligometastatic disease included ATM, JAK2, MAP2K2, and NTRK1, while ARID1A and CCNE1 were associated with widespread disease. Patients with a positive, neutral and negative risk score for oligometastatic disease had a 78%, 41% and 11.5% likelihood of having oligometastatic disease, respectively (p<0.0001). Overall survival for patients with positive, neutral and negative risk scores for oligometastatic disease was 86% vs 82% vs 64% at 6 months (p=0.2). Oligometastatic risk score was significantly associated with the likelihood of oligoprogression based on the Wald chi-square test. Patients with positive, neutral and negative risk scores for oligometastatic disease had a cumulative incidence of oligometastatic progression of 77% vs 35% vs 33% at 6 months (p=0.03). Conclusions: Elucidation of a genomic signature for extracranial oligometastatic disease derived from non-invasive liquid biopsy appears feasible for NSCLC patients. Patients with this signature exhibited higher rates of early oligoprogression. External validation could lead to a biomarker that has the potential to direct local therapies in oligometastatic patients.

    Keywords: NSCLC - lung adenocarcinoma - EGFR - ALK - BRAF - KRAS - RET - MET - PD-L1 - ROS1, Genomic study, Metastatic NSCLC, Oligometastatic disease, brain metastases

    Received: 04 Jan 2024; Accepted: 28 Aug 2024.

    Copyright: © 2024 Choi, D'Agostino Jr, Farris, Abdulhaleem, Hunting, Wang, Smith, Ruiz, Lycan, Petty, Cramer, Tatter, Laxton, White, Li, Su, Whitlow, Xing and Chan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Ariel R. Choi, Department of Radiation Oncology, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    Ralph B. D'Agostino Jr, Department of Biostatistics and Data Sciences, School of Medicine, Wake Forest University, Winston-Salem, 27101, North Carolina, United States
    Michael K. Farris, Department of Radiation Oncology, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    Mohammed Abdulhaleem, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    Thomas W. Lycan, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    William J. Petty, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    Stephen B. Tatter, Department of Neurosurgery, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    Jaclyn J. White, Department of Neurosurgery, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    Wencheng Li, Department of Pathology, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    Jing Su, Department of Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health, Indiana University, Purdue University Indianapolis, Indianapolis, IN 46202-2872, Indiana, United States
    Christopher Whitlow, Department of Radiology, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States
    Michael D. Chan, Department of Radiation Oncology, School of Medicine, Wake Forest University, Winston-Salem, 27157, North Carolina, United States

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