BRAF Gene and Melanoma: Back to the Future
Abstract
:1. Introduction
2. BRAF Gene Biology
3. BRAF Mutations in Melanoma: Epidemiology and Clinic-Pathological Correlations
3.1. BRAF V600 Mutations
3.2. BRAF Non-V600 Mutations
3.3. BRAF Fusions
4. BRAF Mutational Assessment: State of Art of Companion Diagnostic and Laboratory-Developed Tests
4.1. Immunohistochemistry
4.2. Sanger Sequencing
4.3. Pyrosequencing
4.4. Real-Time PCR
4.5. Next-Generation Sequencing
5. BRAF Mutations as Pharmacological Targets in Melanoma
5.1. Dabrafenib Plus Trametinib (COMBI-d and COMBI-v)
5.2. Vemurafenib Plus Cobimetinib (coBRIM)
5.3. Encorafenib Plus Binimetinib (COLUMBUS)
5.4. Pembrolizumab and Nivolumab in Monotherapy
5.5. Ipilimumab Plus Nivolumab
5.6. Adjuvant Therapies
6. From the Past to the Future of BRAF-Mutant Melanoma Treatment
6.1. Combining Immunotherapy with BRAF and MEK Inhibitors
6.2. MAPK Pathway
6.3. PI3K/AKT/mTOR Pathway and PTEN
6.4. Cell Cycle Regulation
6.5. Genomic Instability
6.6. Epigenetics
6.7. Angiogenesis
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Mutation | Frequency (among BRAF V600 Mutations) | DFS | PFS (with TT) | TMB | Response to ICIs |
---|---|---|---|---|---|
V600E | 70–88% | Longer | Longer | Lower | Good |
V600K | 10–20% | Shorter | Shorter | Higher | Better |
Phase 3 Clinical Trial | % of BRAF V600-Mutant Patients | Experimental Arm | Standard Arm | Primary Endpoint in BRAF V600-Mutant Patients | Reference |
---|---|---|---|---|---|
COMBI-d | 100% | D + T | D | PFS: 9.3 months vs. 8.8 months (p = 0.03) | [59] |
COMBI-v | 100% | D + T | V | 1-year OS: 72% vs. 65% (p = 0.005) | [60] |
coBRIM | 100% | V + C | V | PFS: 9.9 months vs. 6.2 months (p < 0.001) | [63,64] |
COLUMBUS | 100% | E + B | V | PFS: 14.9 months vs. 7.3 months (p < 0.0001) | [66,67] |
KEYNOTE-006 | 36.2% | P | I | HR for PFS: 0.44–0.87 | [4,69] |
CheckMate 067 | 31% | N + I | I | 5-year OS: 60% vs. 30% | [70,71] |
Phase 3 Clinical Trial | % of BRAF V600-Mutant Patients | Stage (AJCC VII Edition) | Experimental Arm | Standard Arm | Primary Endpoint in BRAF V600-Mutant Patients | Reference |
---|---|---|---|---|---|---|
BRIM-8 | 100% | IIC-IIIB | V | placebo | RFS: 23.1 months vs. 15.4 months (p = 0.026) | [74] |
COMBI-AD | 100% | III | D+T | placebo | 4-year RFS: 54% vs. 38% | [73,75] |
CheckMate-238 | 42.1% | IIIB-IV | N | I | HR for 2-year RFS: 0.79 | [81] |
KEYNOTE-054 | 43.3% | III | P | placebo | HR for 1-year RFS: 0.59 | [80] |
Pathway/Cancer Hallmark | Molecular Target | Drugs under Investigation | Phase of Development | Reference (or NCT Number) |
---|---|---|---|---|
MAPK | ERK1/2 | MK-8353 | Phase 1 trial | NCT01358331 |
Ulixertinib | Phase 1trial | NCT01781429 | ||
PI3K-AKT-mTOR | PI3K | GSK2636771 | Phase 1/2 trial | [115] |
Buparlisib | Phase 2 trial | [116] | ||
AKT | Uprosertib | Phase 1 trial | [118] | |
MK2206 | Phase 2 trial | NCT01519427 | ||
Cell cycle regulation | CDK4/6 | LY2835219 | Preclinical data | [126] |
Voruciclib | Phase 1 trial | [127] | ||
Ribociclib | Phase 1b/2 trial | [128] | ||
Phase 2 trial | [116] | |||
Palbociclib | Preclinical data | [129] | ||
DNA repair | PARP | Rucaparib | Phase 2 trial | [142] |
Veliparib | Preclinical data | [145] | ||
Phase 2 trial | [143] | |||
Niraparib | Phase 2 trial | NCT03925350 | ||
Olaparib | Phase 2 trial | NCT04633902 | ||
Epigenetic regulation | HDAC | Vorinostat | Phase 1/2 trial | NCT02836548 |
EZH2 | Tazemetostat | Phase 1/2 trial | NCT04557956 | |
Angiogenesis | VEGF-A | Bevacizumab | Phase 2 trial | NCT04356729 |
Phase 2 trial | NCT02681549 | |||
VEGFR, PDGFR | Lenvatinib | Phase 2 trial | NCT01136967 | |
VEGFR, AXL, MET | Cabozantinib | Phase 2 trial | NCT04091750 | |
Phase 1b/2 trial | NCT03957551 |
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Ottaviano, M.; Giunta, E.F.; Tortora, M.; Curvietto, M.; Attademo, L.; Bosso, D.; Cardalesi, C.; Rosanova, M.; De Placido, P.; Pietroluongo, E.; et al. BRAF Gene and Melanoma: Back to the Future. Int. J. Mol. Sci. 2021, 22, 3474. https://doi.org/10.3390/ijms22073474
Ottaviano M, Giunta EF, Tortora M, Curvietto M, Attademo L, Bosso D, Cardalesi C, Rosanova M, De Placido P, Pietroluongo E, et al. BRAF Gene and Melanoma: Back to the Future. International Journal of Molecular Sciences. 2021; 22(7):3474. https://doi.org/10.3390/ijms22073474
Chicago/Turabian StyleOttaviano, Margaret, Emilio Francesco Giunta, Marianna Tortora, Marcello Curvietto, Laura Attademo, Davide Bosso, Cinzia Cardalesi, Mario Rosanova, Pietro De Placido, Erica Pietroluongo, and et al. 2021. "BRAF Gene and Melanoma: Back to the Future" International Journal of Molecular Sciences 22, no. 7: 3474. https://doi.org/10.3390/ijms22073474