Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Abstract

Purpose MDM2 amplification can promote tumorigenesis directly or indirectly through p53 inhibition. MDM2 has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and MDM2 amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti–PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain MDM2 amplification status across a large number of diverse cancers. Methods We interrogated the molecular profiles of 102,878 patients with diverse malignancies for MDM2 amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). Results MDM2 amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with MDM2 amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied MDM2 amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), PI3K signaling (25.4% [926 of 3,650]), TP53 (24.9% [910 of 3,650]), and MAPK signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and PD-L1 amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration–approved or investigational agent. MDM2 amplifications were less frequently associated with high tumor mutation burden compared with the MDM2 wild-type population (2.9% v 6.5%; P < .001). An illustrative patient who harbored MDM2 amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. Conclusion MDM2 amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have MDM2 amplification as well as pharmacologically tractable co-alterations.

MDM2, MDM4 and EGFR Amplifications and Hyperprogression in Metastatic Acral and Mucosal Melanoma

“…In a large study of 102,878 patients with different malignancies, NGS of tumor tissue revealed MDM2 amplification in 3.5% of cases [41]. Tumors exhibiting MDM2 amplification were less often associated with a high TMB than MDM2 wild-type tumors [41].…”

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

“…There are inconsistencies between studies in that some have not shown age or sex to be predictors. Furthermore, although it has been described by several groups including ours , the putative genomic correlates (e.g., MDM2/MDM4 and EGFR alterations) require larger sample size validation and an understanding of potential mechanisms by which these alterations could mediate or facilitate accelerated tumor growth after checkpoint blockade.…”

“…Matos et al [13] TTF <2 months and minimum increase in measurable lesions of 10 mm plus (A) increase of ≥40% in target tumor burden compared with baseline or (B) increase ≥20% in target tumor burden plus multiple new lesions HPD was not associated with age, tumor type, checkpoint inhibitor regimens, previous checkpoint inhibitor, or metastatic site ours [10,12,19,34], the putative genomic correlates (e.g., MDM2/MDM4 and EGFR alterations) require larger sample size validation and an understanding of potential mechanisms by which these alterations could mediate or facilitate accelerated tumor growth after checkpoint blockade.…”

How Can Immune Checkpoint Inhibitors Cause Hyperprogression in Solid Tumors?

“…In a molecular profiling study of 102,878 patients, this same group identified the amplification of MDM2 in 3.5%, with large variations among tumor types (63.6% in liposarcoma and <1% in thyroid carcinoma and adenocarcinoma of colon and rectum). Interestingly most patients with MDM2 amplification had a low Tumor Mutational Burden (54).…”