Effects of tumor mutational burden and gene alterations associated with radiation response on outcomes of postoperative radiation therapy in non-small cell lung cancer Journal Article

Authors: Shaverdian, N.; Shepherd, A. F.; Li, X.; Offin, M.; Lengel, H. B.; Gelblum, D. Y.; Wu, A. J.; Simone, C. B. 2nd; Rimner, A.; Jones, D. R.; Chaft, J. E.; Riaz, N.; Gomez, D. R.
Article Title: Effects of tumor mutational burden and gene alterations associated with radiation response on outcomes of postoperative radiation therapy in non-small cell lung cancer
Abstract: Purpose: Postoperative radiation therapy (PORT) in resected non-small cell lung cancer (NSCLC) improves locoregional outcomes, but recent randomized data do not support its unselected use. We assessed if tumor mutational burden (TMB) and mutations in genes associated with radiation sensitivity can select patients for PORT. Methods and Materials: Patients with resected NSCLC treated with and without PORT who underwent tumor genomic profiling were examined. The incidence of locoregional failures (LRFs) in patients with deleterious mutations in DNA damage response and repair (DDR) genes and genes associated with radiation resistance (KEAP1/NFE2L2/STK11/PIK3CA) were investigated. Cox modeling and receiver operating characteristic curve (ROC) analysis assessed the relationship between TMB and locoregional control (LRC). Results: Eighty-nine patients with NSCLC treated with PORT were analyzed, with a 2-year LRF rate of 19% (95% confidence interval, 10%-27%). Among patients treated with PORT, those with mutations in radiation resistance genes (n = 16 [18%]) had significantly more LRFs than patients without mutations (2-year LRF rate: 60% vs 11%; P < .001). On multivariate analysis, radiation-resistance mutations were associated with LRF after PORT (hazard ratio, 7.42; P < .001). Patients with mutations identified in DDR genes (n = 15 [17%]) had significantly improved LRC (P = .048) and no LRF events after PORT. On multivariate analysis, a higher TMB was associated with improved LRC after PORT (hazard ratio, 0.86; P = .01), and TMB was associated with PORT outcomes (area under ROC curve, 0.67-0.77). These genomic markers were not similarly associated with LRF in patients not treated with PORT. Conclusions: The data suggest that patients with radiation-resistance gene alterations may derive minimal benefit from PORT, whereas patients with high TMB and/or alterations in DDR genes may benefit from PORT and be suited for future precision-RT strategies. Prospective studies are necessary to validate these findings. © 2022 Elsevier Inc.
Keywords: genetics; mutation; prospective study; prospective studies; metabolism; genes; carcinoma, non-small-cell lung; lung neoplasms; radiotherapy; patient monitoring; tumor marker; lung tumor; radiation effects; tumors; genomics; dna damage response; locoregional control; multi variate analysis; multivariant analysis; biological organs; diseases; non small cell lung cancer; damage repair; hazards; failure rate; transcription factor nrf2; postoperative radiation therapy; radiation resistance; kelch like ech associated protein 1; humans; human; biomarkers, tumor; nf-e2-related factor 2; resistance genes; kelch-like ech-associated protein 1
Journal Title: International Journal of Radiation Oncology, Biology, Physics
Volume: 113
Issue: 2
ISSN: 0360-3016
Publisher: Elsevier Inc.  
Date Published: 2022-06-01
Start Page: 335
End Page: 344
Language: English
DOI: 10.1016/j.ijrobp.2022.02.014
PUBMED: 35157996
PROVIDER: scopus
Notes: Article -- Export Date: 1 June 2022 -- Source: Scopus
Citation Impact
MSK Authors
  1. Daphna Y Gelblum
    154 Gelblum
  2. Nadeem Riaz
    332 Riaz
  3. Daniel R Gomez
    114 Gomez
  4. Jamie Erin Chaft
    210 Chaft
  5. Andreas Rimner
    416 Rimner
  6. Abraham Jing-Ching Wu
    313 Wu
  7. David Randolph Jones
    300 Jones
  8. Michael David Offin
    112 Offin
  9. Charles Brian Simone
    74 Simone
  10. Xingzhe Li
    12 Li
  11. Harry Benjamin Lengel
    3 Lengel