• What is BRAF?
  • BRAF in Thyroid Cancer
  • BRAF c.1799T>A (V600E)
  • Clinical Trials

BRAF

BRAF belongs to a family of serine-threonine protein kinases that includes ARAF, BRAF, and CRAF (RAF1). RAF kinases are central mediators in the MAP kinase signaling cascade and exert their effect predominantly through phosphorylation and activation of MEK. This occurs following the dimerization (hetero- or homo-) of the RAF molecules. As part of the MAP kinase pathway, RAF is involved in many cellular processes, including cell proliferation, differentiation, and transcriptional regulation.

Mutant BRAF has been implicated in the pathogenesis of several cancers, including melanoma, non-small cell lung cancer, colorectal cancer, papillary thyroid cancer, and ovarian cancer (Davies et al. 2002). Mutant BRAF has been observed in these cancers as well as glioma and gastrointestinal stromal tumor (GIST).

mapk-pk13.png

Figure 1. Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. BRAF. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/braf/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

BRAF in Thyroid Cancer

Somatic mutations in BRAF have been found in 40–45% of papillary thyroid cancer (Kimura et al. 2003; Cohen et al. 2003; Ciampi et al. 2005). BRAF mutations are also found in anaplastic thyroid cancer (30–40%) and poorly differentiated tumors (20–40%; Namba et al. 2003; Nikiforova et al. 2003; Begum et al. 2004; Xing 2005; Ricarte-Filho et al. 2009).

The most prevalent BRAF mutations detected in thyroid cancers are missense mutations which introduce an amino acid substitution at valine 600. The vast majority (98%) of BRAF mutations are V600E (valine to glutamic acid). The result of these mutations is enhanced BRAF kinase activity and increased phosphorylation of downstream targets, particularly MEK (Wan et al. 2004).

The AKAP9-BRAF rearrangement is another mechanism of BRAF activation in thyroid cancers. This translocation, which fuses the first 8 exons of the A-kinase anchor protein 9 (AKAP9) gene with the C-terminal region (exons 9–18) of BRAF, is found in up to 11% of tumors associated with radiation exposure but in less than 1% of sporadic tumors (Ciampi et al. 2005; Fusco, Viglietto, and Santoro 2005).

Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D.

Suggested Citation: Espinosa, A., J. Gilbert. 2015. BRAF in Thyroid Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/braf/ (Updated June 18).

Last Updated: June 18, 2015

BRAF c.1799T>A (V600E) Mutation in Thyroid Cancer

Properties
Location of mutation Kinase domain (exon 15)
Frequency of BRAF mutations in papillary thyroid cancer 40–45% (Ciampi et al. 2005; Cohen et al. 2003; Kimura et al. 2003)
Frequency of BRAF mutations in follicular thyroid cancer 1.3% (COSMIC)
Frequency of BRAF mutations in poorly differentiated thyroid cancer 20–40% (Nikiforova et al. 2003; Ricarte-Filho et al. 2009)
Frequency of BRAF mutations in anaplastic thyroid cancer 30–40% (Begum et al. 2004; Nikiforova et al. 2003; Ricarte-Filho et al. 2009)
Frequency of V600E mutation among BRAF-mutated papillary thyroid cancers 99.7% (COSMIC)
Frequency of V600E mutation among BRAF-mutated follicular thyroid cancers 75% (COSMIC)
Frequency of V600E mutation among BRAF-mutated poorly differentiated carcinomas 100% (COSMIC)
Frequency of V600E mutation among BRAF-mutated anaplastic thyroid cancers 98% (COSMIC)​
Implications for Targeted Therapeutics
Response to non-specific BRAF inhibitors Variable responsea
Response to mutant-specific BRAF-inhibitors Unknown​ at this timeb

The V600E mutation results in an amino acid substitution at position 600 in BRAF, from a valine (V) to a glutamic acid (E). This mutation occurs within the activation segment of the kinase domain (Figure 1). Mutant BRAF proteins have increased kinase activity and are transforming in vitro (Davies et al. 2002).

a Sorafenib (BAY43-9006) is a multi-targeted kinase inhibitor with activity against VEGFR 1 and 2, KIT, and RET as well as wild type BRAF. In phase II trials, the drug demonstrated partial response rates of 15–25% and stable disease in 34 to 87.5% of patients with differentiated or medullary thyroid cancers. Progression free survivals ranged from 14.5 to 18.4 months (Gupta-Abramson et al. 2008; Kloos et al. 2009; Lam et al. 2009; Hoftijzer et al. 2009). Another multi-targeted kinase inhibitor, XL281, has demonstrated similar results (see Table 1).

b Vemurafenib (PLX4032) is an orally available inhibitor of mutated BRAF (V600E). In a phase I trial, patients with metastatic melanoma whose tumors harbored a BRAF V600E mutation displayed an 81% response rate to vemurafenib (Flaherty et al. 2010). Vemurafenib was FDA-approved in 2011 for use in BRAF V600E-mutated melanoma. Three patients with BRAF V600E positive thyroid cancers displayed stable disease on vemurafenib (Flaherty et al. 2009).


Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status # Patients in Study Response Rate PFS (months) OS (months unless otherwise indicated)
Kloos et al. 2009 Phase II 1st line or greater Sorafenib 14 BRAF V600E
3 K601E
33 PTC (of these, 28 were included in the response assessments) without previous chemotherapy 15% 15 23 (Kaplan-Meier estimate of median OS)
8 PTC with previous chemotherapy 13% 10 (Kaplan-Meier estimate of median PFS) 37.5 (Kaplan-Meier estimate of median OS)
BRAF, HRAS, and NRAS wild type 11 HTC or FTC 0% 4.5 (Kaplan-Meier estimate of median PFS) 24.2 (Kaplan-Meier estimate of median OS)
4 ATC 0%
Hoftijzer et al. 2009 Phase II 1st line or greater Sorafenib 9 BRAF V600E
1 BRAF V600E + PIK3CA mutation
2 NRAS mutations
1 KRAS mutation
32 DTC 25% 13.3
Flaherty et al. 2009 Phase I Vemurafenib BRAF V600E 3 Progression-free 4-7 months after treatment initiation
Schwartz et al. 2009a, 2009b Phase I 1st line or greater XL281 2 BRAF V600E mutations
1 BRAF wild type
5 mutation status unknown
7 DTC 0% > 12 weeks 43% alive at time of analysis
2 BRAF V600E mutations 2 DTC 0% > 12 weeks 50% alive at time of analysis
placebo Not measured 73 5% 5.9 44% alive at time of analysis
24 PTC 5.9
40 follicular or poorly differentiated 5.6
NOTES: ATC = anaplastic thyroid cancer, DTC = differentiated thyroid cancer, FTC = follicular thyroid cancer, OS = overall survival, PFS = progression-free survival, PTC = papillary thyroid cancer.


braf-v600e.png

Figure 1.
Schematic of BRAF V600E mutation. Functional domains of BRAF are depicted. CR1: conserved regions 1. CR2: conserved region 2.

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Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D., James Fagin, M.D.

Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2015. BRAF c.1799T>A (V600E) Mutation in Thyroid Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/braf/54/ (Updated March 6).

Last Updated: March 6, 2015

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