Study Finds TP53 and MDM2 Alterations Linked to Cisplatin Resistance in Advanced Germ Cell Tumors
In a study reported in the Journal of Clinical Oncology, Bagrodia et al found that alterations in TP53 and MDM2 were associated with cisplatin resistance and poorer outcome in patients with advanced germ cell tumors. Actionable alterations were found in a high proportion of cases of cisplatin resistance.
Study Details
In the study, whole-exome or targeted sequencing of cisplatin-sensitive and cisplatin-resistant germ cell tumors was performed on 180 tumors from men treated at Memorial Sloan Kettering Cancer Center who had received a cisplatin-containing chemotherapy regimen.
TP53 and MDM2 Alterations
TP53 alterations were found exclusively in cisplatin-resistant tumors and were highly prevalent among primary mediastinal nonseminomas (13 of 18, 72%). Overall, TP53 mutations/deletions alone (17 of 104 [16.3%] vs 0 of 76 [0%], P < .001) and in combination with MDM2 amplifications (25 of 104 [24.0%] vs 2 of 76 [2.6%], P < .001) were significantly more common in resistant vs sensitive tumors.
TP53/MDM2 alterations were more common in patients in the International Germ Cell Cancer Collaborative Group poor-risk group vs intermediate- and good-risk groups (32.2% vs 7.1% vs 6.5%, P < .001). On multivariate analysis including the International Germ Cell Cancer Collaborative Group risk model, TP53/MDM2 alteration was an independent predictor of disease progression after first-line cisplatin-based chemotherapy (hazard ratio = 1.83, P = .016).
Actionable Alterations
A total of 75 potentially actionable alterations were found in 57 of 104 patients (55%) with cisplatin-resistant disease, including 9 novel RAC1 mutations. Other actionable mutations included 20 hotspot mutations in KIT in 19 patients, alterations in CBL (a negative regulator of KIT) in 7 additional tumors, and 24 tumors with mutually exclusive PI3K pathway mutations.
The investigators concluded: “In [germ cell tumor], TP53 and MDM2 alterations were associated with cisplatin resistance and inferior outcomes, independent of the [International Germ Cell Cancer Collaborative Group] model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this tumor subtype. A substantial portion of cisplatin-resistant [germ cell tumors] harbor actionable alterations, which might respond to targeted therapies. Genomic profiling of patients with advanced [germ cell tumors] could improve current risk stratification and identify novel therapeutic approaches for patients with cisplatin-resistant disease.”
The study was supported by the Cycle for Survival, Society of Memorial Sloan Kettering, a National Institutes of Health/National Cancer Institute Cancer Center support grant, the STARR Foundation, the Sidney Kimmel Center for Prostate and Urologic Cancers, the Urology Care Foundation/SUO Research Scholars Program, and the Marie-José and Henry R. Kravis Center for Molecular Oncology.
Darren R. Feldman, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
