Analysis of BRAF, NRAS, cKIT, and EGFR alterations in melanoma lung metastases.

Abstract

e19033 Background: About 25% of pts will eventually develop lung metastases from primary melanoma. Activating mutations in BRAF, NRAS, CKIT and EGFR genes are involved in melanoma progression. Trials with drugs targeting oncogenic BRAF in melanoma have shown that a V600E mutation may identify a subgroup of pts with a high response rate. Methods: We analysedtheprevalence of BRAF, NRAS and CKIT mutations by direct sequencing and of EGFR copy number alterations by FISH, in pts affected by melanoma lung metastases, and explored their correlation with lung metastasis-free survival (LMFS) and post surgical progression-free survival (psPFS). Results: Over 10 years, 33 cases of pts with melanoma lung metastases were diagnosed at our institution, of which 22 underwent surgery with curative intent. The mean age was 64 years, and 19 (57.5%) were male. 51% carried a BRAF V600E mutation while 18% had a NRAS codon 61 mutation. The two events were mutually exclusive. No alterations were observed in exon 11 of the CKIT gene. FISH analysis indicated an EGFR low amplification in 3 cases and chromosome 7 polysomy in 13 cases. The presence of a BRAF V600E mutation was associated with a longer LMFS (median 6.1 vs 4.4 years, p<0.05), but it had no impact on psPFS (26.9 vs 29.6 months, p=0.6). NRAS mutations were associated with a reduction in both LMFS (3.7 years vs 4.7 years, p = 0.008) and, more significantly, in psPFS (12,5 months vs 41,1 months, p = 0.005; hazard ratio, 2.7). Conclusions: The frequency of mutations in BRAF (51%) and NRAS (18%) observed in lung metastatic melanomas was similar to the rates reported in other metastatic sites. BRAF mutations don't appear to be related with a more aggressive clinical course, while NRAS might be an independent negative prognostic factor after resection of melanoma lung metastases. The presence of BRAF mutations should be tested in melanoma lung metastases to identify the patients eligible for anti BRAF targeted therapy.