Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic

Abstract

BackgroundTP53 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.MethodsSamples 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.ResultsWe 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%).ConclusionMDM2 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.

Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma

“…In the advanced setting, patients with DDLPS have universally poor outcomes with limited available therapies and a lack of validated biomarkers either for prognosis or for chemotherapy selection . MDM2 amplifications represent a unique phenomenon in cancer biology with its resultant product inhibiting the tumor‐suppressor functions of p53 . Although amplification of MDM2 in DDLPS is well established as a diagnostic tool, the variability and clinical ramifications of the degree of MDM2 amplification is yet to be thoroughly understood.…”

Personalized Cancer Therapy Prioritization Based on Driver Alteration Co-occurrence Patterns

“…LGW813 (an IAP inhibitor), and TAS266 (a DR5 agonist) DCO networks, we find links between MDM2 and CDK4, which are frequently co-altered as part of the same amplicon in the 12q chromosomal region [19,20]. Indeed, their hypothetical cooperation has triggered the use of CDK4/6 inhibitors as potentiators of MDM2 antagonists [20], which are currently being tested to treat liposarcoma in clinical trials (NCT02343172 and NCT01692496).…”

“…A total of 276 PDXs were treated in at least one of the 53 treatment groups considered, each treatment being tested in 29 to 246 animals, with a median of 43 (IQR: . We could obtain the molecular profile for 187 of them, which had been treated with a median of 18 (IQR: [14][15][16][17][18][19][20] drugs. The final dataset consisted on 3,127 experiments performed on 187 PDXs and 53 treatment responses, across 5 tumor types: BRCA (breast cancer, n=38), CM (cutaneous melanoma, n=32), COREAD (colorectal carcinoma, n=51), NSCLC (non-small cell lung carcinoma, n=27), PAAD (pancreatic adenocarcinoma, n=38), and 1 PDX without tumor type annotation).…”

“…However, most tumors do not present a single actionable mutation but have co-occurring driver alterations that might simultaneously alter key players of signaling pathways connected by cross-talk and feedback mechanisms [15,16]. There are many documented cases of functionally relevant co-occurring oncogenic mutations, such as the concomitant inactivation of TP53 and RB1 [17], co-deletion of CDKN2A and CDKN2B [18], co-amplification of MDM2 and CDK4 [19,20], 1p/19q co-deletion in glioma [21], MYC amplification and TP53 mutations [22] or activating alterations in KRAS and BRAF [5]. At pathway level, the concomitant activation PI3K signaling pathway with FGF signaling (FGFR2 and FGFR3), or with NRF2 mediated oxidative response have also been identified in several tumor types [16].…”

Personalized cancer therapy prioritization based on driver alteration co-occurrence patterns

“…A total of 276 PDXs were treated in at least one of the 53 treatment groups considered, each treatment being tested in 29 to 246 animals, with a median of 43 (IQR 38-93). We could obtain the molecular profile for 187 of them, which had been treated with a median of 18 (IQR [14][15][16][17][18][19][20] drugs. The final dataset consisted on 3127 experiments performed on 187 PDXs and 53 treatment responses, across 5 tumor types: BRCA (breast cancer, n = 38), CM (cutaneous melanoma, n = 32), COREAD (colorectal carcinoma, n = 51), NSCLC (non-small cell lung carcinoma, n = 27), PAAD (pancreatic adenocarcinoma, n = 38), and 1 PDX without tumor type annotation.…”