The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Tumour mutational burden predicts resistance to EGFR/BRAF blockade in BRAF-mutated microsatellite stable metastatic colorectal cancer
Abstract
Aim 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. Experimental design 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. Results 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). Conclusion 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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Preclinical studies show that the reactivation of the MAPK pathway is a key mechanism underlying acquired resistance to BRAF inhibitors.
“Preclinical studies show that the reactivation of the MAPK pathway is a key mechanism underlying acquired resistance to BRAF inhibitors [38,39].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [39]
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Geisen, M. E., Tessmann, J. W., Kelson, C. O., He, D., Wang, C., Faisal, A. S. M., Beswick, E. J., Baca, Y., Rock, S., Kolesar, J. M., et al. (2026) · Neoplasia · doi:10.1016/j.neo.2026.101283
“Preclinical studies show that the reactivation of the MAPK pathway is a key mechanism underlying acquired resistance to BRAF inhibitors [38,39].”
Metadata
- Authors
- Randon, G., Intini, R., Cremolini, C., Elez, E., Overman, M. J., Lee, J., Manca, P., Bergamo, F., Pagani, F., Antista, M., Angerilli, V., Ros Montaña, F. J., Lavacchi, D., Boccaccino, A., Fucà, G., Brich, S., Cattaneo, L., Fassan, M., Pietrantonio, F., & Lonardi, S.
- Affiliations
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Istituto Oncologico Veneto (IT)
- University of Pisa (IT)
- The University of Texas MD Anderson Cancer Center (US)
- Samsung Medical Center (KR)
- University of Padua (IT)
- Azienda Ospedaliero-Universitaria Careggi (IT)
- Azienda Ospedaliera Universitaria Pisana (IT)
- Corresponding author
- Pietrantonio, Filippo
- ORCID
- Venue
- European Journal of Cancer
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 161
- Pages
- 90-98
- ISSN
- 0959-8049 (ISSN-L)
- OpenAlex
- W4200501736
- Cited by
- 24
- References
- 4
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 10 · 2023: 3 · 2022: 7
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- European Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- microsatellite stable, metastatic colorectal cancer, targeted therapy resistance, PTEN loss, progression-free survival
- MeSH terms
- Aged, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Colorectal Neoplasms, Case-Control Studies, Tumor Burden, Proto-Oncogene Proteins B-raf, Microsatellite Instability
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