Tumor mutational burden and response to programmed cell death protein 1 inhibitors in a case series of patients with metastatic desmoplastic melanoma
Authors: Lise Boussemart, Adrienne Johnson, Alexa B. Schrock, Sumanta K. Pal, Garrett M. Frampton, David Fabrizio, Zachary Chalmers, Michal Lotem, Geoffrey Gibney, Jeffery Russell, Bartosz Chmielowski, Jeffrey S. Ross, Phil J. Stephens, Vincent A. Miller, Siraj M. Ali
Journal: Journal of the American Academy of Dermatology (2018)

To the Editor: Desmoplastic melanomas (4% of melanomas) are characterized by spindled melanocytes, collagenous or desmoplastic stroma, and an intense inflammatory response.1Quinn M.J. Crotty K.A. Thompson J.F. Coates A.S. O'Brien C.J. McCarthy W.H. Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients.Cancer. 1998; 83: 1128-1135Crossref PubMed Scopus (259) Google Scholar Desmoplastic melanomas carry a high mutation burden compared generally with other cancers.2Shain A.H. Garrido M. Botton T. et al.Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway.Nat Genet. 2015; 47: 1194-1199Crossref PubMed Scopus (165) Google Scholar Programmed cell death 1 protein (PD-1) inhibitors have been granted Food and Drug Administration approval for advanced melanoma as first-line therapy.3Robert C. Schachter J. Long G.V. et al.Pembrolizumab versus Ipilimumab in advanced melanoma.N Engl J Med. 2015; 372: 2521-2532Crossref PubMed Scopus (4074) Google Scholar In addition, a high mutation burden has been demonstrated as an effective predictor of response to checkpoint inhibitors, likely due to the increased neoepitope generation and cytotoxic T-cell activation. In this study, we examined 12 desmoplastic melanomas by using comprehensive genomic profiling and assessed tumor mutational burden (TMB) and response to PD-1 inhibitors during clinical care. DNA was extracted from 40-μm–thick paraffin-embedded sections, and comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >650x for 236 or 315 genes plus the introns from 19 or 28 genes frequently involved in cancer. TMB was determined on up to 1.14 Mb of sequenced DNA by using an estimation algorithm that extrapolates to the genome as a whole.4Chalmers Z.R. Connelly C.F. Fabrizio D. et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.Genome Med. 2017; 9: 34Crossref PubMed Scopus (1808) Google Scholar Comprehensive genomic profiling was performed on 1240 melanoma cases, including 12 desmoplastic melanomas. A mean of 54 (range 8-128) variants/sample, which were likely somatic on the basis of allele frequency, were detected in desmoplastic samples, and a mean of 22 variants/sample were predicted to be somatic in nondesmoplastic melanomas (Mann-Whitney-Wilcoxon, P value = .001). The average TMB in desmoplastic melanomas was 77 mutations/Mb, compared with 35 mutations/Mb across the remaining 1228 melanomas (Fig 1). In 10 of 12 samples, C>T and G>A mutations made up >80% of the base substitutions, indicating a ultraviolet light–related mutational signature. TP53 was the most frequently mutated gene (9/12 cases). Alterations in neurofibromin (NF) genes were frequent, with NF1 altered in 6 of 12 cases and NF2 altered in 2 of 12 cases, consistent with previous studies.2Shain A.H. Garrido M. Botton T. et al.Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway.Nat Genet. 2015; 47: 1194-1199Crossref PubMed Scopus (165) Google Scholar Two cases lacking NF1 or NF2 mutations had NRAS-activating mutations. Other frequently mutated genes included cyclin-dependent kinase inhibitor 2A (6/12) and AT-rich interactive domain–containing protein 2 (5/12). All desmoplastic cases were BRAF wildtype. Of 9 patients with clinical treatment history available, 6 received a PD-1 inhibitor, and 5 of 5 with available response data had stable disease or better, including 2 with ongoing partial responses (Table I). Four of these patients also received prior treatment with ipilimumab, but none of them responded.Table IAvailable demographic information, treatment history, and response to immunotherapy in cases of desmoplastic melanoma analyzed using CGPCase no.Age, ySexTissue of origin for CGP testingPrevious immunotherapyBest response to immunotherapy174MSkinNonePembrolizumab, PR, 6 mon, ongoing280MSoft tissueNoneNone351MSkin4 doses ipilimumab, PDPembrolizumab, PR, 11 mon470MSkin4 doses ipilimumab, PDPembrolizumab, SD, 11 mon, ongoing556MLung8 doses of high-dose IL-2, PRPembrolizumab (no data available)654MSkinNoneNone781MSkin2 doses ipilimumab, PDPembrolizumab, SD, 2 mon, ongoing829MUnknownInterferon and ipilimumab, PDNivolumab, PR, ongoing958MSkinNoneNone1078MSkinUnknownUnknown1167FSoft tissueUnknownUnknown1262MSkinUnknownUnknownCGP, Comprehensive genomic profiling; IL, interleukin; PD, progressive disease; PR, partial response; SD, stable disease. Open table in a new tab CGP, Comprehensive genomic profiling; IL, interleukin; PD, progressive disease; PR, partial response; SD, stable disease. Our study is limited by our small number of desmoplastic melanomas and even fewer with clinical information, but a multi-institutional study in 60 patients with advanced desmoplastic melanoma treated with varied PD-1 ligand pathway inhibitors showed a 6-month progression-free survival rate of 77% and 1-year overall survival rate of 80%.5Eroglu Z. Zaretsky J.M. Hu-Lieskovan S. et al.High response rate to PD-1 blockade in desmoplastic melanomas.Nature. 2018; 553: 347-350Crossref PubMed Scopus (186) Google Scholar The correlation between TMB and response to PD-1 blockade has been reasonably established in the context of many cancer types, including conventional melanoma, nonsmall cell lung cancer, and others, while ultraviolet radiation has been shown to increase the somatic mutation rate in melanomas. The cases we have highlighted confirm that desmoplastic melanomas might respond well to PD-1 inhibitors.