Here, we combined the advantages of targeted PCR analysis with a more comprehensive Next Generation Sequencing (NGS) analysis including 1,114 cosmic mutations testing five cancer genes relevant in melanoma biology (BRAF, NRAS, KRAS, EGFR, and PIK3CA) on cell-free DNA from blood plasma samples obtained from melanoma patients receiving gold standard immunotherapy (anti-CTLA4-Antibody, anti-PD1-Antibody). The gene discussed is PIK3CA; the disease is cancer.