Melanoma Institute Australia and The University of Sydney, Sydney, New South Wales, Australia.
School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales, Australia.
Clin Cancer Res. 2019 Feb 15;25(4):1272-1279. doi: 10.1158/1078-0432.CCR-18-1680. Epub 2019 Jan 10.
V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to ±. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy.
Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with ± underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti-PD-1 immunotherapy was examined.
Baseline tissue and clinical outcome with ± were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, -31% vs. -52%, = 0.154) and shorter progression-free survival (PFS; median, 5.7 vs. 7.1 months, = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in and tumor-suppressor genes. In patients treated with anti-PD-1, V600K ( = 19) had superior outcomes than V600E ( = 84), including response rate (53% vs. 29%, = 0.059), PFS (median, 19 vs. 2.7 months, = 0.049), and overall survival (20.4 vs. 11.7 months, = 0.081).
V600K melanomas appear to benefit less from ± than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.
V600E 和 V600K 黑色素瘤具有不同的临床病理特征，且 V600K 对 ± 的反应似乎较差。我们研究了产生这种现象的机制，并探讨了基因型是否会影响免疫治疗的反应。
对接受 ± 治疗的患者的预处理福尔马林固定石蜡包埋肿瘤进行基因表达谱分析和 DNA 测序。使用癌症基因组图谱（TCGA）数据验证分子结果。对接受抗 PD-1 免疫治疗的 V600E/K 患者的独立队列进行了检查。
对 93 例患者（78 例 V600E，15 例 V600K）的基线组织和临床结果进行了 ± 的研究。V600K 患者的肿瘤消退程度（中位数，-31%对-52%， = 0.154）和无进展生存期（PFS；中位数，5.7 对 7.1 个月， = 0.15）均低于 V600E。V600K 黑色素瘤的 ERK 通路反馈调节子双特异性磷酸酶 6 的表达较低，这一结果通过 TCGA 数据得到了证实（116 例 V600E，17 例 V600K）。通路分析显示，与 V600E 相比，V600K 的 ERK 表达较低，PI3K-AKT 基因表达较高。V600K 中观察到更高的突变负荷， 和肿瘤抑制基因的突变比例更高。在接受抗 PD-1 治疗的患者中，V600K（ = 19）的治疗效果优于 V600E（ = 84），包括缓解率（53%对 29%， = 0.059）、PFS（中位数，19 对 2.7 个月， = 0.049）和总生存期（20.4 对 11.7 个月， = 0.081）。
V600K 黑色素瘤对 ± 的反应似乎不如 V600E，可能是由于对 ERK 通路激活的依赖性较小，而对替代途径的依赖性较大。相比之下，这些黑色素瘤具有更高的突变负荷，对免疫治疗的反应更好。
