Tumour mutational burden predicts resistance to EGFR/BRAF blockade in BRAF-mutated microsatellite stable metastatic colorectal cancer.

To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF-mutated and microsatellite stable (MSS) metastatic colorectal cancer. In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression. Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6-20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3-7.29] versus 3 [IQR, 1.26-3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07-4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02-4.81, P = 0.044). Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF-mutated mCRC deserves prospective validation.

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Déclaration de conflit d'intérêts

Conflict of interest statement Filippo Pietrantonio received honoraria for speakers bureau from Servier, research grants from BMS and honoraria for advisory boards/speakers bureau from Roche, Amgen, Merck-Serono, Lilly, Sanofi, Bayer and Servier. Elena Élez reports personal fees from Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, ArrayBiopharma, Sanofi. Chiara Cremolini reports personal fees from Roche, Amgen, Bayer, and Servier; research funding from Merck Serono; and a consulting or advisory role with Roche, Bayer, Amgen. Matteo Fassan reports a consulting or advisory role with Astellas Pharma, GlaxoSmithKline, Diaceutics, and Roche; research funding from Astellas Pharma, QED Therapeutics, and Macrophage Pharma. Sara Lonardi received honoraria for Speakers Bureau, Consulting or Advisory Role from Amgen, Merck Serono, Lilly, Astra Zeneca, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Servier, MSD, Roche, Pierre-Fabre, GSK and Research Funding (to Institution) from Amgen, Merck Serono, Bayer, Roche, Lilly, Astra Zeneca, Bristol-Myers Squibb. All remaining authors have declared no conflicts of interest. This Study was partially funded by a grant from Ministero della Salute, Bando della Ricerca Finalizzata 2019, Project Number GR-2019-12368903, CUP code J99C21000260001.