The predictive value of MAP2K1/2 mutations for efficiency of immunotherapy in melanoma.
The predictive value of MAP2K1/2 mutations for efficiency of immunotherapy in melanoma.
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MAP2K1/2 突变对黑色素瘤免疫治疗效率的预测价值。
DOI：
10.1200/jco.2021.39.15_suppl.e21587
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发表时间：
2021-05
影响因子：
45.3
通讯作者：
Jing Chen
中科院分区：
文献类型：
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作者：
Ting Ye;Jieying Zhang;Xinyi Liu;Mengmei Yang;Yuhan Zhou;Siyue Yuan;Yaoxu Chen;Chan Gao;Mengli Huang;Chengzhi Ye;Jing Chen
E21587背景：针对免疫检查点受体的免疫疗法已成为恶性黑色素瘤全身治疗选择的基石。对这些免疫疗法的反应可能与驱动程序突变有关。在约10%的黑色素瘤中，MAP2K1/2基因发生突变，然而，MAP2K1/2基因突变对免疫治疗效果的影响尚不清楚。方法：选择ICIS治疗的6个转移性黑色素瘤临床队列，研究免疫治疗的临床疗效与MAP2K1/2突变的关系。生存分析是在接受两种ICB药物的队列中进行的，即抗CTLA-4或抗PD-1。来自这些队列和TCGA黑色素瘤队列的RNA表达谱被用来探索与免疫激活相关的潜在机制。结果：在接受抗CTLA-4治疗的独立队列中，我们发现MAP2K1/2突变预测高客观缓解率(17.6%vs 1.3%，p=0.0185)和长期无进展生存期[中位OS，49.2月vs 8.3个月；风险比(HR)=0.37；95%CI，0.15~0.91；p=0.0307]和总生存期(中位PFS，19.4个月vs 2.8个月；HR=0.2；95%可信区间，P=0.0262)。这一预测价值在合并抗CTLA-4治疗的队列中得到了进一步验证(中位OS为49.3个月对22.0个月；HR=0.44；95%CI为0.22-0.91；p=0.0255)。然而，在接受抗PD-1治疗的队列(n=285)中，未观察到MAP2K1/2突变与总生存率之间的相关性。亚组COX回归分析显示，MAP2K基因突变患者从抗PD-1单一治疗中获益少于抗CTLA-4治疗(中位数OS，27.0个月对49.3个月；HR=3.26；95%CI，1.18~9.02；P=0.0225)，这与整个人群的结果相反。此外，转录组分析显示，MAP2K突变的肿瘤富含CD8+T细胞、B细胞和中性粒细胞，并表达高水平的CD33和IL10，这可能是MAP2K1/2突变的黑色素瘤患者从抗CTLA-4治疗中受益更多的潜在机制。结论：我们将MAP2K1/2基因突变作为黑色素瘤患者抗CTLA-4治疗的独立预测因素，发现携带MAP2K1/2突变的患者接受抗CTLA-4治疗可能比抗PD-1治疗更有效。
e21587 Background: Immunotherapies targeting immune checkpoint receptors have become the cornerstone of systemic treatment options for malignant melanoma. The response to these immunotherapies may correlate with driver mutations. MAP2K1/2 genes are mutated in approximately 10% of melanomas, however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. Methods: Six metastatic melanoma clinical cohorts treated with ICIs were included to investigate the association between clinical efficacy of immunotherapy and MAP2K1/2 mutations. Survival analyses were conducted in cohorts receiving two kinds of ICB agents, namely anti-CTLA-4 or anti-PD-1. RNA expression profiling from these cohorts and from the TCGA melanoma cohort were used to explore the potential mechanism related to immune activation. Results: In an independent anti-CTLA-4-treated cohort (n = 110), we found that MAP2K1/2 mutations are predictive of high objective response rate (17.6% vs 1.3%, p = 0.0185) and long progression-free survival [median OS, 49.2 months vs 8.3 months; hazard ratio (HR) = 0.37; 95% CI, 0.15–0.91; p = 0.0307] and overall survival (median PFS, 19.4 months vs 2.8 months; HR = 0.2; 95% CI, 0.05–0.83; p = 0.0262). This predictive value was further validated in a pooled anti-CTLA-4-treated cohort (n = 235) in terms of overall survival (median OS, 49.3 months vs 22.0 months; HR = 0.44; 95% CI, 0.22–0.91; p = 0.0255). However, no correlation between MAP2K1/2 mutations and overall survival was observed in the anti-PD-1-treated cohort (n = 285). Subgroup Cox regression analysis indicated that MAP2K-mutated patients receive less benefit from the anti-PD-1 monotherapy than from the anti-CTLA-4 treatment (median OS, 27.0 months vs 49.3 months; HR = 3.26; 95% CI, 1.18–9.02; p = 0.0225), which was contrary to the result obtained for the total population. Furthermore, transcriptome profiling analysis revealed that MAP2K-mutated tumors are enriched in CD8+ T cells, B cells, and neutrophil cells and also express high levels of CD33 and IL10, which might be the underlying mechanism for melanoma patients with MAP2K1/2-mutated benefit more from anti-CTLA-4 treatment. Conclusions: We identified mutations in MAP2K1/2 genes as the independent predictive factors for anti-CTLA-4 therapy in melanoma patients and found that anti-CTLA-4 treatment in patient harbouring MAP2K1/2 mutations might be more effective than the anti-PD-1 therapy.