Research Papers:
Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic
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Abstract
Vikas Dembla1, Neeta Somaiah2, Pedro Barata3, Kenneth Hess4, Siqing Fu1, Filip Janku1, Daniel D. Karp1, Aung Naing1, Sarina Anne Piha-Paul1, Vivek Subbiah1, Apostolia M. Tsimberidou1, Kenna Shaw5, Funda Meric-Bernstam1 and David S. Hong1
1Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3Department of Solid Tumors, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
4Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
5Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Correspondence to:
David S. Hong, email: [email protected]
Keywords: MDM2 amplification; phase I trials; solid tumors; TP53 mutation; CDK4 amplification
Received: January 04, 2018 Accepted: August 20, 2018 Published: September 04, 2018
ABSTRACT
Background: TP53 is the most commonly mutated gene in cancer and codes for the best studied tumor suppressor, p53. MDM2 is involved in the negative regulation of p53 and itself serves as an oncogene, reported to be overexpressed in several cancer tumor types. In this retrospective study, we assessed the occurrence of MDM2 amplification among patients with various types of cancers and its association with clinical factors, other genetic aberrations, and response to targeted therapy in a phase I clinical trial setting.
Methods: Samples from patients with advanced solid tumors who had been referred to the MD Anderson phase I clinical trials program between January 2011 and January 2016 were collected and analyzed for MDM2 amplification using FoundationOne’s genomic profiling assay. Patients whose tumors expressed MDM2 amplification were compared to those with tumors of the same histologic types without MDM2 amplification.
Results: We tested tumors from 523 patients, of which 23 (4.4%) had MDM2 amplification. The highest prevalence of MDM2 amplification was in sarcoma (57%), breast cancer (13%) and bladder cancer (9%). Six patients with liposarcoma were treated on phase I protocol with an MDM2 inhibitor. The most common molecular aberrations co-occurring with MDM2 amplification was CDK4 amplification (70%). TP53 mutation was also detected in 7 patients (30%).
Conclusion: MDM2 amplification was most commonly associated with liposarcoma. Concomitant alterations in additional genes such as CDK4 amplification and TP53 mutations, along with variable responses to targeted therapies including MDM2 inhibitors, suggest that further combinational studies are needed to target this population.
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