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@ARTICLE{deBortoli:278343,
      author       = {T. de Bortoli and M. Benary and P. Horak$^*$ and M. Lamping
                      and S. Stintzing$^*$ and I. Tinhofer$^*$ and S. Leyvraz and
                      R. Schäfer$^*$ and F. Klauschen$^*$ and U. Keller$^*$ and
                      A. Stenzinger$^*$ and S. Fröhling$^*$ and R. Kurzrock and
                      U. Keilholz$^*$ and D. T. Rieke$^*$ and I. Jelas},
      title        = {{T}umour mutational burden and survival with molecularly
                      matched therapy.},
      journal      = {European journal of cancer},
      volume       = {190},
      issn         = {0014-2964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-01600},
      pages        = {112925},
      year         = {2023},
      abstract     = {The impact of tumour mutational burden (TMB) on outcome
                      with molecularly matched therapy is unknown. Higher TMB
                      could predict resistance to molecularly matched therapy
                      through co-occurring driver mutations.One hundred and four
                      patients with advanced cancers underwent molecular profiling
                      in the DKTK-MASTER program. Fifty-five patients received
                      systemic therapy excluding immunotherapy. Patients with
                      molecularly matched (n = 35) or non-molecularly informed
                      therapy (n = 20) were analysed for TMB and survival. Results
                      were validated in an independent cohort of patients
                      receiving molecularly matched (n = 68) or non-molecularly
                      informed therapy (n = 40). Co-occurring driver mutations and
                      TMB were analysed in the exploratory cohort and The Cancer
                      Genome Atlas (TCGA) datasets.Patients were stratified by the
                      median TMB of 1.67 mutations per Megabase (mut/Mb) of 35
                      patients receiving molecularly matched therapy into TMB-high
                      or TMB-low groups. Median overall survival (4 months $[95\%$
                      CI, 3.3-7.6] versus 12.8 months $[95\%$ CI, 10-not reached],
                      p < 0.001) and progression-free survival (1.8 months $[95\%$
                      CI, 1.1-3.7] versus 7.9 months $[95\%$ CI, 2.8-17.0], p =
                      0.003) were significantly shorter in the TMB-high group
                      compared to the TMB-low group. In the validation cohort,
                      shorter OS and PFS were identified in the TMB-high group
                      (TMB cut-off of 4 mut/Mb) treated with molecularly matched
                      therapy. No differences were observed in patients receiving
                      non-molecularly informed systemic therapy. A significant
                      correlation between co-occurring driver mutations and TMB (n
                      = 104, r = 0.78 $[95\%$ CI, 0.68-0.85], p < 0.001) was found
                      in the exploratory cohort as well as the majority (24/33) of
                      TCGA studies.A high TMB was associated with unfavourable
                      outcome in patients receiving molecularly matched therapy,
                      indicating untargeted resistance pathways. Therefore, TMB
                      should be further investigated as a predictive biomarker in
                      precision oncology programs.},
      keywords     = {Molecular tumour board (Other) / Personalised therapy
                      (Other) / Precision oncology (Other) / Tumour mutational
                      burden (Other)},
      cin          = {B340 / BE01 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B340-20160331 / I:(DE-He78)BE01-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37544709},
      doi          = {10.1016/j.ejca.2023.05.013},
      url          = {https://inrepo02.dkfz.de/record/278343},
}