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Ref Type Journal Article
PMID (31515458)
Authors Yaeger R, Kotani D, Mondaca S, Parikh AR, Bando H, Van Seventer EE, Taniguchi H, Zhao H, Thant CN, de Stanchina E, Rosen N, Corcoran RB, Yoshino T, Yao Z, Ebi H
Title Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 25 23 2019 12 01 7089-7097 Clin Cancer Res
URL
Abstract Text 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.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).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).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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BRAF A33T missense no effect - predicted BRAF A33T does not lie within any known functional domains of the Braf protein (UniProt.org). A33T results in Erk pathway activation similar to wild-type Braf in cultured cells (PMID: 31515458), and therefore, is predicted to have no effect on Braf protein function.
BRAF L525R missense gain of function - predicted BRAF L525R lies within the protein kinase domain of the Braf protein (UniProt.org). L525R results in increased activation of Erk signaling in a dimer-dependent but RAS-independent manner (PMID: 31515458, PMID: 28972961), and therefore, is predicted to lead to a gain of Braf protein function.
BRAF R558Q missense loss of function - predicted BRAF R558Q lies within the protein kinase domain of the Braf protein (UniProt.org). R558Q results in moderate activation of Erk pathway signaling in a dimer and Ras-dependent manner in culture (PMID: 31515458), and therefore, is predicted to lead to a loss of Braf protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF N581S colorectal cancer not predictive Cetuximab + Fluorouracil + Irinotecan + Leucovorin Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with FOLFIRI as a first-line therapy resulted in a partial response with progression-free survival lasting 16 months in a patient with metastatic colorectal cancer harboring BRAF N581S (PMID: 31515458). 31515458
BRAF G469A colorectal cancer not predictive Cetuximab + Irinotecan Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with Camptosar (irinotecan) as a third-line therapy resulted in stable disease with a PFS of 3.5 months in a patient with metastatic colorectal cancer harboring BRAF G469A (PMID: 31515458). 31515458
BRAF L597R colorectal cancer not predictive Fluorouracil + Irinotecan + Leucovorin + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with FOLFIRI as a second-line therapy resulted in stable disease with a PFS of 16.5 months in a patient with metastatic colorectal cancer harboring BRAF L597R (PMID: 31515458). 31515458
BRAF N581I colorectal cancer not predictive Cetuximab + Irinotecan Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with Camptosar (irinotecan) as a first-line therapy resulted in stable disease with progression-free survival of 10.3 months in a patient with metastatic colorectal cancer harboring BRAF N581I (PMID: 31515458). 31515458
BRAF D594N colorectal cancer not predictive Irinotecan + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with Camptosar (irinotecan) as a third-line therapy resulted in partial responses with 14.9 and 14.7 months progression-free survival in two patients with metastatic colorectal cancer harboring BRAF D594N (PMID: 31515458). 31515458
BRAF D594G colorectal cancer not predictive Cetuximab + Irinotecan Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with Camptosar (irinotecan) as a third-line therapy resulted in stable disease in two patients with metastatic colorectal cancer harboring BRAF D594G, with progression-free survival of 2.2 and 6.6 months (PMID: 31515458). 31515458
BRAF G469A colorectal cancer not predictive Cetuximab + Fluorouracil + Irinotecan + Leucovorin Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with FOLFIRI as a third-line therapy resulted in stable disease with a PFS of 4.4 months in a patient with metastatic colorectal cancer harboring BRAF G469A (PMID: 31515458). 31515458
BRAF G469V colorectal cancer not predictive Fluorouracil + Leucovorin + Oxaliplatin + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with FOLFOX as a first-line therapy resulted in a partial response with progression-free survival of 18.9 months in a patient with metastatic colorectal cancer harboring BRAF G469V (PMID: 31515458). 31515458
BRAF G469V colorectal cancer not predictive Cetuximab + Irinotecan Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with Camptosar (irinotecan) as a third-line therapy resulted in stable disease with progression-free survival of 10.9 months in a patient with metastatic colorectal cancer harboring BRAF G469V (PMID: 31515458). 31515458
BRAF G469A colorectal cancer not predictive Irinotecan + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with Camptosar (irinotecan) as a third-line therapy resulted in stable disease with a PFS of 4.0 months in a patient with metastatic colorectal cancer harboring BRAF G469A (PMID: 31515458). 31515458
BRAF T599dup colorectal cancer predicted - resistant Fluorouracil + Leucovorin + Oxaliplatin + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with FOLFOX as a first-line therapy resulted in progressive disease in a patient with metastatic colorectal cancer harboring BRAF T599dup (PMID: 31515458). 31515458
BRAF F247L colorectal cancer not predictive Cetuximab + Fluorouracil + Irinotecan + Leucovorin Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with FOLFIRI as a third-line therapy resulted in a complete response with regression of the thoracic nodes and progression-free survival lasting 12.6 months in a patient with metastatic colorectal cancer harboring BRAF F247L (PMID: 31515458). 31515458
BRAF F595L colorectal cancer not predictive Fluorouracil + Leucovorin + Oxaliplatin + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with FOLFOX as a first-line therapy resulted in a partial response with progression-free survival of 10.2 months in a patient with metastatic colorectal cancer harboring BRAF F595L (PMID: 31515458). 31515458
BRAF K601E colorectal cancer predicted - resistant Panitumumab Case Reports/Case Series Actionable In a clinical study, Vectibix (panitumumab) treatment as a third-line therapy resulted in progressive disease in a metastatic colorectal cancer patient harboring BRAF K601E (PMID: 31515458). 31515458
BRAF G469A colorectal cancer not predictive Cetuximab Case Reports/Case Series Actionable In a clinical study, Erbitux (cetuximab) treatment as a third-line therapy resulted in stable disease with progression-free survival of 2.8 months in a patient with metastatic colorectal cancer harboring BRAF G469A (PMID: 31515458). 31515458
BRAF R558Q colorectal cancer not predictive Cetuximab + Irinotecan Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with Camptosar (irinotecan) as a fourth-line therapy resulted in a complete response with progression-free survival of 37.7 months in a patient with metastatic colorectal cancer harboring BRAF R558Q (PMID: 31515458). 31515458
BRAF D594G colorectal cancer not predictive Fluorouracil + Irinotecan + Leucovorin + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with FOLFIRI as a third-line therapy resulted in stable disease with progression-free survival of 2.6 months in a patient with metastatic colorectal cancer harboring BRAF D594G (PMID: 31515458). 31515458
BRAF class 2 colorectal cancer decreased response Panitumumab Clinical Study Actionable In a clinical study, colorectal cancer patients harboring class 2 BRAF mutations demonstrated a decreased response to treatment with the combination of either Erbitux (cetuximab) or Vectibix (panitumumab) plus chemotherapy compared to those with class 3 BRAF mutations, with a response rate of 8% (1/12) vs 50% (14/28) (P=0.02), respectively, in first, second, third or later-line setting and a response rate of 17% (1/6) vs 78% (7/9) (P=0.04), respectively, in the first or second-line setting (PMID: 31515458). 31515458
BRAF class 2 colorectal cancer decreased response Cetuximab Clinical Study Actionable In a clinical study, colorectal cancer patients harboring class 2 BRAF mutations demonstrated a decreased response to treatment with the combination of either Erbitux (cetuximab) or Vectibix (panitumumab) plus chemotherapy compared to those with class 3 BRAF mutations, with a response rate of 8% (1/12) vs 50% (14/28) (P=0.02), respectively, in first, second, third or later-line setting and a response rate of 17% (1/6) vs 78% (7/9) (P=0.04), respectively, in the first or second-line setting (PMID: 31515458). 31515458
BRAF L525R colorectal cancer not predictive Cetuximab Case Reports/Case Series Actionable In a clinical study, Erbitux (cetuximab) treatment as a third-line therapy resulted in stable disease with progression-free survival of 4 months in a patient with metastatic colorectal cancer harboring BRAF L525R (PMID: 31515458). 31515458
BRAF D594G colorectal cancer not predictive Fluorouracil + Leucovorin + Oxaliplatin + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with FOLFOX as a first-line therapy resulted in two partial responses with progression-free survival of 8.3 and 2.8 months and stable disease with progression-free survival of 7.0 months in patients with metastatic colorectal cancer harboring BRAF D594G (PMID: 31515458). 31515458
BRAF D594G colorectal cancer not predictive Irinotecan + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with Camptosar (irinotecan) as a third-line therapy resulted in one patient with a partial response with 6.7 months progression-free survival (PFS) and two with stable disease with PFS of 1.8 and 2.3 months in patients with metastatic colorectal cancer harboring BRAF D594G (PMID: 31515458). 31515458
BRAF T599dup colorectal cancer resistant Cetuximab Preclinical - Pdx Actionable In preclinical study, a colorectal cancer patient-derived xenograft (PDX) model harboring BRAF T599dup was resistant to Erbitux (cetuximab) treatment (PMID: 31515458). 31515458
BRAF G466E colorectal cancer not predictive Irinotecan + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with Camptosar (irinotecan) resulted in a partial response in two patients with metastatic colorectal cancer harboring BRAF G466E, each with a progression-free survival of 8.3 months (PMID: 31515458). 31515458
BRAF K601E colorectal cancer resistant Cetuximab Preclinical - Pdx Actionable In preclinical study, a colorectal patient-derived xenograft (PDX) model harboring BRAF K601E was resistant to Erbitux (cetuximab) treatment (PMID: 31515458). 31515458
BRAF N581T colorectal cancer not predictive Fluorouracil + Leucovorin + Oxaliplatin + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with FOLFOX as a first-line therapy resulted in a partial response with progression-free survival lasting 1.4 months in a patient with metastatic colorectal cancer harboring BRAF N581T (PMID: 31515458). 31515458
BRAF D594N colorectal cancer not predictive Cetuximab Preclinical - Pdx Actionable In a preclinical study, Erbitux (cetuximab) treatment inhibited tumor growth in a colorectal cancer patient-derived xenograft (PDX) model harboring BRAF D594N (PMID: 31515458). 31515458
BRAF G466V colorectal cancer not predictive Irinotecan + Panitumumab Case Reports/Case Series Actionable In a clinical study, the combination of Vectibix (panitumumab) with Camptosar (irinotecan) as a third-line therapy resulted in a partial response with 6.1 months progression-free survival in a patient with metastatic colorectal cancer harboring BRAF G466V (PMID: 31515458). 31515458
BRAF D594G colorectal cancer not predictive Cetuximab + Fluorouracil + Irinotecan + Leucovorin Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with FOLFIRI resulted in one partial response with progression-free survival (PFS) of 3.2 months, and two with stable disease with PFS of 3.7 and 3.6 months in patients with metastatic colorectal cancer harboring BRAF D594G who had been previously treated with two lines of therapy (PMID: 31515458). 31515458
BRAF L485F colorectal cancer not predictive Cetuximab + Irinotecan Case Reports/Case Series Actionable In a clinical study, the combination of Erbitux (cetuximab) with Camptosar (irinotecan) as a third-line therapy resulted in stable disease with progression-free survival of 6.3 months in a patient with metastatic colorectal cancer harboring BRAF L485F (PMID: 31515458). 31515458