Tumour mutational burden and survival with molecularly matched therapy

Item Type:	Article
Title:	Tumour mutational burden and survival with molecularly matched therapy
Creators Name:	de Bortoli, T. and Benary, M. and Horak, P. and Lamping, M. and Stintzing, S. and Tinhofer, I. and Leyvraz, S. and Schäfer, R. and Klauschen, F. and Keller, U. and Stenzinger, A. and Fröhling, S. and Kurzrock, R. and Keilholz, U. and Rieke, D.T. and Jelas, I.
Abstract:	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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:	Precision Oncology, Personalised Therapy, Molecular Tumour Board, Tumour Mutational Burden
Source:	European Journal of Cancer
ISSN:	0959-8049
Publisher:	Elsevier
Volume:	190
Page Range:	112925
Date:	September 2023
Official Publication:	https://doi.org/10.1016/j.ejca.2023.05.013
PubMed:	View item in PubMed

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