Clinical activity of the <scp>MEK</scp> inhibitor trametinib in metastatic melanoma containing <i><scp>BRAF</scp></i> kinase fusion

Menzies, Alexander M.; Yeh, Iwei; Botton, Thomas; Bastian, Boris C.; Scolyer, Richard A.; Long, Georgina V.

doi:10.1111/pcmr.12388

Cited by 77 publications

(57 citation statements)

References 12 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This previously unresectable tumor was removed with clean surgical margins, and without any of the 16 recovered lymph nodes involved with melanoma. Similarly, in a recent study, significant clinical activity was demonstrated when trametinib was used in the treatment of a patient with metastatic melanoma harboring a BRAF fusion …”

Section: Resultsmentioning

confidence: 77%

The distribution of BRAF gene fusions in solid tumors and response to targeted therapy

Ross¹,

Wang²,

Chmielecki³

et al. 2015

Intl Journal of Cancer

263

245

View full text Add to dashboard Cite

Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in‐frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5′ fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall‐cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs. nonpilocytic gliomas (1%; p < 0.0001), Spitzoid (75%) vs. nonSpitzoid melanomas (1%; p = 0.0001), acinar (67%) vs. nonacinar pancreatic cancers (<1%; p < 0.0001) and papillary (3%) vs. nonpapillary thyroid cancers (0%; p < 0.03). Clinical responses to trametinib and sorafenib are presented. In conclusion, BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms, but enriched in Spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers.

show abstract

Section: Resultsmentioning

confidence: 77%

The distribution of BRAF gene fusions in solid tumors and response to targeted therapy

Ross¹,

Wang²,

Chmielecki³

et al. 2015

Intl Journal of Cancer

263

245

View full text Add to dashboard Cite

show abstract

“…21,22,27,30–32 The identification of BRAF fusions in MIFS may also offer new potential therapeutic options for clinically protracted cases. In pilocytic astrocytoma with BRAF fusions, the slow growing and low-grade nature of the tumor has been attributed to oncogene-induced senescence (OIS).…”

Section: Discussionmentioning

confidence: 99%

Recurrent BRAF Gene Rearrangements in Myxoinflammatory Fibroblastic Sarcomas, but Not Hemosiderotic Fibrolipomatous Tumors

Kao

Ranucci

Zhang

et al. 2017

American Journal of Surgical Pathology

View full text Add to dashboard Cite

Myxoinflammatory fibroblastic sarcoma (MIFS) is a low grade soft tissue sarcoma with a predilection for acral sites, being associated with a high rate of local recurrence but very infrequent distant metastases. Although a t(1;10) translocation resulting in TGFBR3-MGEA5 fusion has been reported as a recurrent genetic event in MIFS, this abnormality is seen only in a subset of cases. As no studies to date have investigated the spectrum of alternative genetic alterations in TGFBR3-MGEA5 fusion negative MIFS, we undertook a genetic analysis of this particular cohort for further molecular classification. Triggered by an index case occurring in the finger of a 37 year-old female and harboring a novel TOM1L2-BRAF fusion by targeted RNA sequencing we investigated potential recurrent BRAF abnormalities by screening a large group of 19 TGFBR3-MGEA5 fusion negative MIFS by FISH. There were 6 (32%) additional MIFS with BRAF genetic abnormalities, including 5 gene rearrangements and one showing BRAF amplification. Interestingly, VGLL3 amplification, a recurrent genetic abnormality coexisting with t(1;10) in some MIFS, was also detected by FISH in 4/6 (67%) BRAF-rearranged MIFS, but not in the BRAF-amplified case. Up-regulated VGLL3 mRNA expression was also demonstrated in the index case by RNAseq. The 7 BRAF-rearranged/amplified MIFS arose in the fingers (n=3), and 1 each in wrist, forearm, foot, and knee, of adult patients (36–74 years; M:F=4:3). The histological spectrum ranged from predominantly solid growth of plump histiocytoid to epithelioid tumor cells with focal myxoid change to a predominantly myxoid background with scattered tumor cells. Varying degree of inflammatory infiltrates and large tumor cells with virocyte-like macronucleoli were observed in most cases. Immunohistochemical stains of phosphorylated ERK, a downstream effector of BRAF activation, were positive in all 4 cases tested (2 diffuse strong, 2 focal strong). Unlike t(1;10), BRAF rearrangements were only found in MIFS but not in 6 hemosiderotic fibrolipomatous tumor (HFLT) lacking TGFBR3-MGEA5 fusions (including 2 pure HFLT, 2 hybrid HFLT-MIFS, and 2 associated with pleomorphic hyalinizing angiectatic tumors).

show abstract

“…sorafenib) have been reported in patients and using in vitro models. 61–63 We are currently conducting a clinical trial of trametinib in patients with non-V600 BRAF mutations. In addition, one arm of the NCI MATCH study is testing trametinib in this same population across cancer types.…”

Section: Specific Mutationsmentioning

confidence: 99%

Melanoma: What do all the mutations mean?

Davis

Johnson

Sosman

et al. 2018

Cancer

138

111

View full text Add to dashboard Cite

Melanoma is one of the most highly mutated malignancies, largely as a function of its generation through ultraviolet light and other mutational processes. The wide array of mutations in both "driver" and "passenger" genes can present a confusing array of data for practitioners, particularly within the context of the recent revolutions in targeted and immune therapy. Although mutations in BRAF V600 clearly confer sensitivity to BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors, the clinical implications of most other mutations are less often discussed and understood. In this review, we provide an overview of the high-frequency genomic alterations and their prognostic and therapeutic relevance in melanoma.

show abstract

Clinical activity of the MEK inhibitor trametinib in metastatic melanoma containing BRAF kinase fusion

Cited by 77 publications

References 12 publications

The distribution of BRAF gene fusions in solid tumors and response to targeted therapy

The distribution of BRAF gene fusions in solid tumors and response to targeted therapy

Recurrent BRAF Gene Rearrangements in Myxoinflammatory Fibroblastic Sarcomas, but Not Hemosiderotic Fibrolipomatous Tumors

Melanoma: What do all the mutations mean?

Contact Info

Product

Resources

About