Loss of p53 tumor suppressor function is critical for many cancers and is achieved by mutation in ~50% of tumors, but may occur through additional mechanisms. MDM2 is an E3 ubiquitin ligase whose primary function is to inhibit p53 activity by impeding p53 transcriptional activity, promoting nuclear export, and inducing p53 degradation. The use of investigational MDM2 inhibitors such as milademetan (RAIN-32) may provide a therapeutic strategy for select tumors with wildtype (WT) TP53. Gene amplification (amp) represents a mechanism for cancer cells to upregulate expression of critical cancer related genes and can serve as a predictive biomarker for targeted therapies. Previous work established a gene copy number (CN) threshold of ≥ 12 for the MANTRA-2 basket study of milademetan in advanced solid tumors (Tirunagaru et al., AACR-NCI-EORTC 2021). We used publicly available AACR-GENIE data and The Cancer Genome Atlas (TCGA) to explore MDM2 amp in relation to TP53 status and other genetic biomarkers across solid tumors.

MDM2 amp occurs in most cancer types, with the most frequent rates of MDM2 amp occurring in sarcomas, bladder, hepatobiliary, non-small cell lung cancer, gastric/esophageal, breast, and melanoma cancers. MDM2 was mutually exclusive of TP53 mutations at CN ≥ 12 with OR = 0.21 (p = 5.3 x 10-8). Tumors with WT TP53 and MDM2 CN ≥ 12 comprised 1.19% of all solid tumors in the TCGA (n=9,090) and 1.22% in the AACR-Genie dataset (n=42,125). The MDM2 and CDK4 genes are located on chromosome 12q13-15 and these genes are frequently co-amplified in LPS and other sarcomas; however, MDM2 and CDK4 co-amp is variable in other tumors with less frequent co-amp occurring in NSCLC and melanoma and rare co-amp occurring in bladder, breast cancer and gastro-esophageal tumors, particularly at MDM2 CN ≥ 12. We also evaluated co-mutations in known oncogenes (filtered for oncogenic variants using cancerhotspots.org) in tumors with MDM2 CN ≥ 4. Co-alteration of MDM2 amp in this group of tumors was <15% for all MDM2 amp tumors and did not vary significantly with increasing MDM2 CN. OS survival analysis revealed that prognosis for patients with all levels of MDM2 amp was worse compared to non-amp tumors and OS at MDM2 CN ≥ 12 [41.7 months(m)] was similar to tumors harboring TP53 mutations (55.0m) as compared to patients with tumors harboring WT TP53 and MDM2 CN <12 (118.8m).

In conclusion, MDM2 amp was mutually exclusive of TP53 mutations at CN ≥ 12 and occurred in 1.2% of all cancers and occurred across multiple tumor types, supportive of a tumor agnostic therapeutic strategy for milademetan. CDK4 was not co-amplified with MDM2 in many tumor types and oncogenic alterations occurred infrequently with MDM2 amp. MDM2 amp was associated with a poor prognosis consistent with an unmet need in these cancer patients. The MANTRA-2 trial evaluating milademetan in patients with solid tumors harboring MDM2 CN ≥ 12 and WT TP53 is currently enrolling patients (NCT05012397).

Citation Format: Vijaya G. Tirunagaru, Feng Xu, Robert C. Doebele. Exploration of MDM2 gene amplification, co-mutation status, and prognosis in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1174.