22 Sep Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors
MedicalResearch.com Interview with:
Darren R. Feldman, MD
Memorial Sloan Kettering Cancer Center
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: There is limited knowledge as to why a minority of patients with advanced germ cell tumors are resistant to chemotherapy while the majority achieve complete responses. Patients with cisplatin-resistant disease require intensive salvage treatment and are at high risk of dying from their disease. We sought to determine whether certain genomic alterations within tumors might be associated with cisplatin-resistance in GCT. We also wanted to identify the spectrum of genomic alterations in this population which might represent novel targets for existing or new drug development in this disease.
MedicalResearch.com: What are the main findings?
Response: The main findings were that mutations or deletions in TP53 were exclusive to patients with cisplatin-resistant GCT and were found in a high proportion (72%) of patients with primary mediastinal nonseminoma. This may explain why this disease is more difficult to cure than testicular nonseminoma and primary mediastinal seminoma. There was also a trend toward more frequent amplifications of MDM2 within cisplatin-resistant tumors and combined MDM2-TP53 alterations were found in 24% of cisplatin-resistant tumors vs. only 3% of cisplatin-sensitive tumors. The combination of TP53/MDM2 alterations was associated with adverse progression-free survival independent of the current clinically-based International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic model. Finally, potentially targetable alterations were identified in slightly more than half of patients with cisplatin-resistant GCT.
MedicalResearch.com: What should readers take away from your report?
1) TP53 alterations and MDM2 amplifications within GCT are associated with resistance to cisplatin-based chemotherapy.
2) TP53 alterations were found in the majority of patients with primary mediastinal nonseminoma, possibly providing a biological explanation for why these are the most difficult GCT to cure with chemotherapy.
3) TP53/MDM2 alterations are associated with poor progression-free survival independent of the IGCCCG risk classification suggesting that genomic profiling could improve upon the existing prognostic model.
4) Targetable alterations are present in about half of patients with cisplatin-resistant disease. Therefore, there is the potential for targeted therapy use in the management of patients with refractory GCT and genomic profiling may benefit patients in both identifying an appropriate target and in enhancing prognostication.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Although we identified alterations in genes in the TP53-MDM2 pathway to be strongly associated with cisplatin-resistance, these alterations were found in only 23% of resistant patients. The etiology of cisplatin-resistance in the remaining cases is unclear. Future research evaluating epigenetic alterations in the TP53-MDM2 pathway and other unrelated pathways will be important to determine the mechanism of resistance in the majority of patients.
MedicalResearch.com: Is there anything else you would like to add?
Response: An intact TP53-MDM2 pathway appears to be present in the majority of patients with GCT and is possibly important to the exquisite cisplatin-sensitivity of this disease. However, 20-30% of those with advanced disease will be resistant to first-line cisplatin-based chemotherapy. Nearly one quarter of these cisplatin-resistant patients can be explained by alterations in the TP53-MDM2 pathway. Additional explanations for cisplatin-resistance in patients with tumors harboring an intact TP53/MDM2 pathway should be investigated in future research
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September 19, 2016JCO687798JCO
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