Personalized Medicine and Imaging Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Purpose: A previous study noted frequent B-RAF mutations among European patients with cisplatinresistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among patients with GCT at our center. Experimental Design: Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and resistance. Tumor DNA was extracted and subjected to Sequenom analysis to detect hotspot alterations in FGFR3, AKT1, PIK3CA, KRAS,HRAS,NRAS, and BRAFwith Sanger sequencing for confirmation. Nine GCT cell lines with varying degrees of cisplatin sensitivity and resistance were also assayed by Sequenom. Results: Seventy (24 cisplatin-sensitive; 46 cisplatin-resistant) of 75 patients had tumors with sufficient quality DNA to perform Sequenom. Nineteen mutations were detected among 16 (23%) patients but no BRAFmutations were identified. Similarly, none of the cell lines harbored BRAFmutations. FGFR3was the most frequentmutation, identified in 13%of both sensitive and resistant samples. All othermutations were exclusive to resistant cases (3 KRAS, 3 AKT1, 3 PIK3CA, and 1 HRAS). Conclusions: BRAF mutations are rare in American patients with GCT, including those with cisplatin resistance. However, other potentially targetable mutations occur in more than 25% of cisplatin-resistant patients. FGFR3, AKT1, and PIK3CA mutations are all reported for the first time in GCT. Whereas FGFR3 mutations occurred with equal frequency in both sensitive and resistant GCTs, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors. Clin Cancer Res; 20(14); 3712–20. 2014