Integrative Pan-Cancer Genomic and Transcriptomic Analyses of Refractory Metastatic Cancer

Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profi led via whole-exome and transcriptome sequencing. META-PRISM tumors, particularly prostate, bladder, and pancreatic types, displayed the most transformed genomes com-pared with primary untreated tumors. Standard-of-care resistance biomarkers were identifi ed only in lung and colon cancers-9.6% of META-PRISM tumors, indicating that too few resistance mechanisms have received clinical validation. In contrast, we verifi ed the enrichment of multiple investigational and hypothetical resistance mechanisms in treated compared with nontreated patients, thereby confi rm-ing their putative role in treatment resistance. Additionally, we demonstrated that molecular markers improve 6-month survival prediction, particularly in patients with advanced breast cancer. Our analysis establishes the utility of the META-PRISM cohort for investigating resistance mechanisms and per-forming predictive analyses in cancer.