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PURPOSE: A significant proportion of patients with locoregional (stage III) cutaneous melanoma recur despite adjuvant systemic therapy. Staging criteria and surgical nodal management have changed since the trials were completed. Data assessing the effect of systemic therapy compared to surveillance are limited, and factors associated with recurrence are unclear. We assessed the efficacy of adjuvant systemic therapy in real-world patients and assessed whether baseline genomic characteristics could prognosticate or predict benefit from therapy.METHODS: We collected demographic, histopathologic, clinical, and genomic data for patients diagnosed with stage III cutaneous melanoma. Outcomes of interest were recurrence-free survival (RFS) and distant-metastasis-free survival (DMFS). Survival analysis was performed using the Kaplan-Meier method with log-rank analysis. Univariate and multivariate analyses were performed using a Cox regression analysis.RESULTS: Two hundred and fifteen patients were included, of which 65 and 76 were treated with BRAF/MEK inhibitors (BRAFi/MEKi) and anti-PD1 adjuvant systemic therapy respectively. Seventy four underwent active surveillance. Both adjuvant therapies reduced the hazard of recurrence when compared to patients undergoing active surveillance: anti-PD1 HR: 0.32 (p < 0.01) and BRAFi/MEKi HR: 0.39 (p = 0.03). Anti-PD1-treated patients with a BRAF V600 mutation had a shorter RFS than patients with BRAF WT melanoma (p < 0.01); this was validated in external data where the presence of a BRAF V600 mutation was associated with an increased hazard recurrence (HR: 2.1, p = 0.025).CONCLUSION: Adjuvant systemic therapy improved RFS in our cohort. We found that BRAF V600 mutation was associated with a worse RFS for adjuvant anti-PD1 monotherapy. The effect of BRAF mutation on the response to anti-PD1 therefore may be considered when choosing between adjuvant anti-PD1 and BRAFi/MEKi for patients with BRAF V600 mutant melanoma.