Tumour mutational burden and survival with molecularly matched therapy

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...

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Published in:European journal of cancer (1990) 2023-09, Vol.190, p.112925-112925, Article 112925
Main Authors: de Bortoli, Till, Benary, Manuela, Horak, Peter, Lamping, Mario, Stintzing, Sebastian, Tinhofer, Ingeborg, Leyvraz, Serge, Schäfer, Reinhold, Klauschen, Frederick, Keller, Ulrich, Stenzinger, Albrecht, Fröhling, Stefan, Kurzrock, Razelle, Keilholz, Ulrich, Rieke, Damian T, Jelas, Ivan
Format: Article
Language:English
Subjects:
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Humans
Immunotherapy - methods
Mutation
Neoplasms - drug therapy
Neoplasms - genetics
Precision Medicine
Progression-Free Survival
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container_title European journal of cancer (1990)
container_volume 190
creator de Bortoli, Till
Benary, Manuela
Horak, Peter
Lamping, Mario
Stintzing, Sebastian
Tinhofer, Ingeborg
Leyvraz, Serge
Schäfer, Reinhold
Klauschen, Frederick
Keller, Ulrich
Stenzinger, Albrecht
Fröhling, Stefan
Kurzrock, Razelle
Keilholz, Ulrich
Rieke, Damian T
Jelas, Ivan
description 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 
doi_str_mv 10.1016/j.ejca.2023.05.013
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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 &lt; 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 &lt; 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. 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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. 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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 &lt; 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 &lt; 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. 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subjects Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Humans
Immunotherapy - methods
Mutation
Neoplasms - drug therapy
Neoplasms - genetics
Precision Medicine
Progression-Free Survival
title Tumour mutational burden and survival with molecularly matched therapy
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