Actionable alterations are present in many patients with cisplatin-resistant germ cell tumors (GCT).
Major finding: Actionable alterations are present in many patients with cisplatin-resistant germ cell tumors (GCT).
Clinical relevance: Alterations in the p53 pathway are associated with a poor prognosis in patients with advanced GCTs.
Impact: Genomic profiling of patients with GCT may guide risk stratification and targeted therapy development.
The majority of patients with metastatic germ cell tumors (GCT) are cured with cisplatin-based chemotherapy, but 20% to 30% of patients develop cisplatin resistance. To identify genomic alterations that may contribute to the development of cisplatin resistance, Bagrodia and colleagues performed whole-exome sequencing on a discovery cohort of 19 GCTs, 10 of which were resistant to cisplatin. Few recurrent alterations were identified, but five cisplatin-resistant tumors had p53 pathway alterations, including two patients with TP53 alterations and three with focal amplifications of MDM2, whereas no cisplatin-sensitive tumors harbored TP53 or MDM2 alterations. These alterations were further validated in a cohort of 161 patients with GCT that included 102 samples obtained prior to cisplatin treatment and 64 cisplatin-resistant samples from metastatic lesions. Alterations in TP53, including 14 hotspot mutations and 1 deletion, were found exclusively in cisplatin-resistant patient samples. An additional 7 tumors, 5 of which were cisplatin-resistant, contained MDM2 amplifications that were mutually exclusive with TP53 alterations. Patients with alterations in TP53 or MDM2 had a reduced progression-free survival, and TP53/MDM2 alterations were an independent predictor of disease progression after cisplatin-based chemotherapy. TP53 alterations were identified in 72% of patients with primary mediastinal nonseminoma, which may explain their inferior outcomes. Moreover, amplification of MYCN, which regulates TP53 and MDM2 transcription, was observed in 5 patients with cisplatin-resistant TP53/MDM2 wild-type tumors. Overall, potentially targetable alterations were identified in 57 of 104 patients (55%), including mutations in KIT in 19 patients and the KIT negative regulator CBL in 7 additional tumors, amplifications of KDR in 4 patients, RAS/ERK pathway mutations in 33 patients, and PI3K pathway mutations in 24 patients. The identification of TP53 alterations exclusively in cisplatin-resistant GCTs suggests that genomic profiling may be used to stratify patients according to risk, and the prevalence of actionable mutations may allow for targeted treatments based on the genomic profiles in patients with metastatic cisplatin-resistant GCT.
Bagrodia A, Lee BH, Lee W, Cha EK, Sfakianos JP, Iyer G, et al. Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors. J Clin Oncol 2016 Sep 19 [Epub ahead of print].
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