PLoS ONE (Jan 2020)

Assessment of clinical outcomes with immune checkpoint inhibitor therapy in melanoma patients with CDKN2A and TP53 pathogenic mutations.

  • Thomas T DeLeon,
  • Daniel R Almquist,
  • Benjamin R Kipp,
  • Blake T Langlais,
  • Aaron Mangold,
  • Jennifer L Winters,
  • Heidi E Kosiorek,
  • Richard W Joseph,
  • Roxana S Dronca,
  • Matthew S Block,
  • Robert R McWilliams,
  • Lisa A Kottschade,
  • Kandelaria M Rumilla,
  • Jesse S Voss,
  • Mahesh Seetharam,
  • Aleksandar Sekulic,
  • Svetomir N Markovic,
  • Alan H Bryce

DOI
https://doi.org/10.1371/journal.pone.0230306
Journal volume & issue
Vol. 15, no. 3
p. e0230306

Abstract

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BACKGROUND:CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors. METHODS:All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (QuadWT). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and QuadWT. RESULTS:A total of 102 patients were included in this study of which 14 had mutations of CDKN2A (CDKN2Amut), 21 had TP53 mutations (TP53mut), and 12 were QuadWT. TP53mut, CDKN2Amut and QuadWT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2Amut cohort and a trend towards worsened median TTP in the QuadWT cohort. CONCLUSION:Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used.