A small subset of patients with supposedly nongenetically driven melanomas respond to molecularly targeted treatment with an MEK inhibitor, according to recent findings released today.
Two novel genetic fusions involving BRAF – PAPSS1-BRAF and TRIM24-BRAF – were present in 2 of 24 (8%) of pan-negative melanoma samples tested. Both BRAF fusions activate the MAPK signaling pathway, and tumors found harboring either genetic fusion were more sensitive to treatment with trametinib than with the BRAF inhibitor vemurafenib, reported Dr. Jeffrey A. Sosman, professor of medicine, director of the melanoma and tumor immunotherapy program, and co-leader of the VICC signal transduction and cell proliferation research program of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and his associates.
"About 35% of melanomas are, as of today, considered pan negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11," Dr. Sosman explained in a press release issued by the American Association of Cancer Research.
"Our data support the idea that pan-negative cancers are not truly pan negative," he added, noting the results are "important because they suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now."
Dr. Sosman and his associates have spent several years assessing pan-negative tumors for any potential genetic anomalies other than those already known that could offer targets for molecularly driven treatment. Their discovery of PAPSS1-BRAF came from examination of a sample from a 27-year-old woman with stage IIIC malignant melanoma involving almost all the axillary lymph nodes. Despite irradiation and experimental and standard immunotherapies, the patient progressed rapidly and died just 11 months after her diagnosis.
The patient’s sample had been genotyped using the FoundationOne assay, which examines more than 3,000 exons in 182 cancer-related genes and 37 introns and in 14 genes recurrently rearranged in cancer. The assay simultaneously looks for any single nucleotide variants, insertions, deletions, copy number changes, and selected genetic rearrangements.
They found a large genomic deletion in BRAF and a region on chromosome 7 suggesting that two genes were possibly fused together. Subsequent targeted RNA sequencing of complementary DNA identified PAPSS1-BRAF and further studies showed that it activated the MAPK signaling pathway and that this activation was more sensitive to inhibition with a MEK inhibitor than with a BRAF inhibition.
The team then evaluated a further 51 melanoma samples, of which the majority were supposedly pan negative – only eight had BRAF V600 changes and seven had other, non-V600 changes. TRIM24-BRAF was also identified and found to affect the MAPK signalling pathway and be more sensitive to MEK than BRAF inhibition.
The team also analyzed RNA, whole genome, and whole-exome sequencing data from an independent cutaneous dataset available from the Cancer Genome Atlas (TCGA) and found BRAF fusions in two of 49 of pan-negative melanoma cases researchers.
"Collectively, these data suggest that BRAF fusions exist in 4%-8% of pan-negative melanomas," the researchers reported. "Coupled with the fact that the transforming ability of multiple BRAF fusions has already been established, we believe enough evidence exists to raise awareness that BRAF fusions are present in this ‘pan-negative’ population."
This could have implications for clinical trials involving therapies that target the MAPK signaling pathway and explain why unexpected clinical responses are sometimes seen with MEK inhibitor therapy. The findings could also help clinicians select patients for MEK-directed therapy.
Dr. Sosman and associates conclude (Clin. Cancer Res. 2013 Dec. 17;19:6696-702): "BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors."