Profiling of genomic alterations in MAPK/ERK signaling in a large cohort of metastatic prostate cancer (mPC) patients.

Abstract

5032 Background: All mPC patients eventually progress on current treatments and prognosis remains poor. In vitro models and small patient cohorts have shown that mPC progression is associated with increased MAPK/ERK signaling. However, in clinical mPC, the genomic alterations that cause aberrant MAPK/ERK signaling and their frequency are poorly defined. We hypothesize that profiling of genomic alterations in MAPK/ERK in a large cohort of heavily pretreated progressive mPC patients will provide a robust measure of importance, and reveal recurrent patterns of alteration. Given the large number of drugs that target MAPK/ERK, these may be incorporated into novel combinatorial treatments for mPC. Methods: 2,679 plasma samples from 2,309 men with mPC were assessed by a validated ctDNA NGS panel that sequences 73 clinically relevant cancer genes (Guardant360, Redwood City, CA) and profiles indels, amplifications, and fusions with high sensitivity and specificity. Genes were assigned to gene sets corresponding to biological pathways and molecular functional classes using the REACTOME database, followed by calculation of summary statistics. Interdependencies between genetic alterations at inter- and intra-gene set levels were discovered by a Bayesian network approach. Results: 56% of mPC samples harbored alterations in MAPK/ERK signaling genes. These included receptor tyrosine kinases (RTKs), MAP kinase cascade, and cell cycle control genes. Gene amplifications were the most frequent alterations in RTK, RAF, and cell cycle control genes, a novel finding. Bayesian network analysis revealed positive interdependencies between all MAPK/ERK genes. In RTK genes, co-amplifications were especially frequent between MET & EGFR and PDGFRA & KIT. Conclusions: In a large cohort of mPC patients, we show that MAPK/ERK gene alterations are present in over half of mPC patients. RTKs, BRAF, and CDK4/6 amplifications are among the most frequent events, display recurrent patterns of co-alteration, and are targetable by existing drugs. Future work to assess the biological and clinical significance of these recurrent patterns of alteration will pave the way for novel combinatorial treatments.