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Published on: February 25, 2020
The Predictive Value of MAP2K1/2 Mutations on Efficiency of Immunotherapy in Melanoma
Ting Ye1, Jie-Ying Zhang1, Xin-Yi Liu2
1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Background:
MAP2K1/2 genes are mutated in approximately 8% of melanoma patients; however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. This study focused on the correlation between MAP2K1/2 gene mutations and the treatment response.
Methods:
Six metastatic melanoma clinical cohorts treated with immune checkpoint inhibitors [anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) or anti-programmed cell death-1 (PD-1)] were recruited in this study. RNA expression profiling results from each of these six cohorts and the Cancer Genome Atlas (TCGA) melanoma cohort were analysed to explore the mechanism related to immune activation.
Results:
Compared to patients with wild-type MAP2K1/2, those with MAP2K1/2 mutations in an independent anti-CTLA-4-treated cohort had higher objective response rates, longer progression-free survival, and longer overall survival (OS). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the OS. However, there was no correlation between MAP2K1/2 mutations and OS in the anti-PD-1-treated cohort. Subgroup Cox regression analysis suggested that patients with MAP2K1/2 mutations received fewer benefits from anti-PD-1 monotherapy than from anti-CTLA-4 treatment. Furthermore, transcriptome profiling analysis revealed that melanoma tumours with MAP2K mutation was enriched in CD8+ T cells, B cells, and neutrophil cells, also expressed high levels of CD33 and IL10, implying a potential mechanism underlying the benefit of melanoma patients with MAP2K1/2 mutations from anti-CTLA-4 treatment.
Conclusions:
MAP2K1/2 mutations were identified as an independent predictive factor for anti-CTLA-4 therapy in melanoma patients. Anti-CTLA-4 treatment might be more effective than anti-PD-1 therapy for patients with MAP2K1/2-mutated melanoma.
Insights
MAP2K1/2 gene mutations predict better response to anti-CTLA-4 immunotherapy in melanoma patients. These mutations did not correlate with anti-PD-1 therapy outcomes, suggesting anti-CTLA-4 may be more effective for MAP2K1/2-mutated melanoma.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Genomics
Background:
- MAP2K1/2 gene mutations occur in ~8% of melanoma patients.
- The impact of MAP2K1/2 alterations on immunotherapy efficacy remains unclear.
- This study investigates the link between MAP2K1/2 mutations and melanoma treatment response.
Purpose of the Study:
- To determine if MAP2K1/2 gene mutations influence the effectiveness of immune checkpoint inhibitors in melanoma.
- To compare the efficacy of anti-CTLA-4 and anti-PD-1 therapies in melanoma patients with MAP2K1/2 mutations.
Main Methods:
- Analysis of six metastatic melanoma cohorts treated with anti-CTLA-4 or anti-PD-1.
- RNA expression profiling from clinical cohorts and The Cancer Genome Atlas (TCGA).
- Exploration of immune activation mechanisms through transcriptome profiling.
Main Results:
- MAP2K1/2 mutations correlated with higher response rates and improved survival with anti-CTLA-4 therapy.
- No significant correlation between MAP2K1/2 mutations and survival was observed with anti-PD-1 therapy.
- Melanoma tumors with MAP2K mutations showed enrichment in immune cells (CD8+ T, B, neutrophils) and specific markers (CD33, IL10).
Conclusions:
- MAP2K1/2 mutations are an independent predictive factor for anti-CTLA-4 therapy response in melanoma.
- Anti-CTLA-4 therapy may offer superior efficacy compared to anti-PD-1 therapy for MAP2K1/2-mutated melanoma patients.
