Tumour mutational burden and survival with molecularly matched therapy

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Item Type:	Article
Title:	Tumour mutational burden and survival with molecularly matched therapy
Creators Name:	de Bortoli, T., Benary, M., Horak, P., Lamping, M., Stintzing, S., Tinhofer, I., Leyvraz, S., Schäfer, R., Klauschen, F., Keller, U., Stenzinger, A., Fröhling, S., Kurzrock, R., Keilholz, U., 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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