Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA.
Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Hum Pathol. 2018 Dec;82:206-214. doi: 10.1016/j.humpath.2018.08.002. Epub 2018 Aug 16.
Despite the efficacy of BRAF-targeted and PD-L1-related immune therapies in tackling metastatic melanoma, a significant number of patients exhibit resistance. Given this, the objective of the current study was to ascertain concordance of somatic mutations in BRAF/NRAS/TERT and immunohistochemical PD-L1 and CD8 in matched primary cutaneous and metastatic melanoma. A total of 43 archival paired samples with sufficient material for genetic and immunohistochemical analyses met the criteria for inclusion in the study. Immunohistochemistry was performed for PD-L1 and CD8 and direct-DNA Sanger sequencing for BRAF/NRAS/TERT promoter mutational analyses. Agreement between paired samples was assessed using Cohen κ. Poor concordance among primary and corresponding metastases was noted in BRAF (9/42 cases discordant, κ = 0.49; 95% confidence interval [CI], 0.21-0.77; P = .0013), TERT promoter mutations (13/41 cases discordant, κ = 0.33; 95% CI, 0.04-0.62; P = .033), tumoral PD-L1 immunoexpression (9/43 cases discordant, κ = 0.39; 95% CI, 0.07-0.72; P = .0099), and immunoexpression of CD8 T lymphocytes (12/43 cases discordant, κ = 0.44; 95% CI, 0.19-0.69; P = .002). Although NRAS1 and NRAS2 were highly concordant (42/43 and 39/43 cases, respectively), discordant NRAS2 mutational status was associated with a median time to metastasis of 90 versus 455 days for pairs with concordant status (P = .07). Although limited by sample size, our findings suggest that consideration be given to mutational analysis of metastatic tissue rather than the primary to guide BRAF-targeted therapy and question the roles of TERT promoter mutations and PD-L1 as predictive biomarkers in malignant melanoma.
尽管 BRAF 靶向和 PD-L1 相关免疫疗法在治疗转移性黑色素瘤方面具有疗效，但仍有相当数量的患者表现出耐药性。鉴于此，本研究的目的是确定 BRAF/NRAS/TERT 体细胞突变和免疫组化 PD-L1 和 CD8 在匹配的原发性皮肤和转移性黑色素瘤中的一致性。共有 43 例存档的配对样本，其组织学材料足以进行遗传和免疫组化分析，符合纳入研究的标准。对 PD-L1 和 CD8 进行免疫组化，对 BRAF/NRAS/TERT 启动子突变进行直接 DNA Sanger 测序。使用 Cohen κ 评估配对样本之间的一致性。在 BRAF（9/42 例不一致，κ=0.49；95%置信区间[CI]，0.21-0.77；P=0.0013）、TERT 启动子突变（13/41 例不一致，κ=0.33；95%CI，0.04-0.62；P=0.033）、肿瘤 PD-L1 免疫表达（9/43 例不一致，κ=0.39；95%CI，0.07-0.72；P=0.0099）和 CD8 T 淋巴细胞免疫表达（12/43 例不一致，κ=0.44；95%CI，0.19-0.69；P=0.002）方面，原发性和相应转移瘤之间的一致性较差。虽然 NRAS1 和 NRAS2 高度一致（分别为 42/43 和 39/43 例），但不一致的 NRAS2 突变状态与具有一致状态的配对中位转移时间为 90 天与 455 天相关（P=0.07）。尽管受到样本量的限制，但我们的研究结果表明，在指导 BRAF 靶向治疗时，应考虑对转移组织进行突变分析，而不是对原发性组织进行突变分析，并质疑 TERT 启动子突变和 PD-L1 作为恶性黑色素瘤预测生物标志物的作用。
