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Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Dec 01; Vol. 25 (23), pp. 7089-7097. Date of Electronic Publication: 2019 Sep 12. - Publication Year :
- 2019
-
Abstract
- Purpose: While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy.<br />Experimental Design: We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3).<br />Results: Forty patients with oncogenic non-V600 BRAF-mutant mCRC received anti-EGFR antibody treatment [ n = 12 (30%) class 2 and n = 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P = 0.02). Specifically, in first- or second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded ( P = 0.04). In third- or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded ( P = 0.14).<br />Conclusions: Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment. See related commentary by Fontana and Valeri, p. 6896 .<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Animals
Colorectal Neoplasms drug therapy
Colorectal Neoplasms genetics
ErbB Receptors antagonists & inhibitors
Female
Humans
Male
Mice, Inbred NOD
Mice, SCID
Prognosis
Prospective Studies
Protein Kinase Inhibitors therapeutic use
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Cetuximab therapeutic use
Colorectal Neoplasms pathology
Molecular Targeted Therapy
Mutation
Proto-Oncogene Proteins B-raf genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 25
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 31515458
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-19-2004