Predicting resistance to chemotherapy using chromosomal instability signatures
Joe Sneath Thompson, Laura Madrid, Bárbara Hernando, Carolin M. Sauer, Maria Vias, Maria Escobar-Rey, Wing‐Kit Leung, Diego Garcia-Lopez, Jamie Huckstep, Magdalena Sekowska, Karen Hosking, Mercedes Jimenez-Linan, Marika Reinius, Abhipsa Roy, Omar Abdulle, Justina Pangonyte, Harry Dobson, Amy E Cullen, Dilrini De Silva, David Gómez-Sánchez, Marina Torres Lázaro, Ángel Fernández-Sanromán, Deborah A. Sanders, Filipe Correia Martins, Ionut-Gabriel Funingana, Giovanni Codacci-Pisanelli, Miguel Quintela-Fandiño, Florian Markowetz, Jason Yip, James D. Brenton, Anna Piskorz, Geoff Macintyre
Abstract
Chemotherapies are often given without precision biomarkers, exposing patients to toxic side effects without guaranteed benefit. Here we present chromosomal instability signature biomarkers that identify resistance to platinum-, taxane- and anthracycline-based treatments using a single genomic test. In retrospectively emulated randomized-control biomarker clinical trials using real-world cohorts (n = 840), predicted resistant patients had elevated treatment failure risk for taxane (hazard ratio (HR) of 7.44) and anthracycline (HR of 1.88) in ovarian, taxane (HR of 3.98) and anthracycline (HR of 3.69) in metastatic breast and taxane (HR of 5.46) in metastatic prostate. Nonrandomized emulations showed predictive capacity for platinum resistance in ovarian (HR of 1.46) and anthracycline in sarcoma (HR of 3.59). We demonstrate feasibility using whole-genome sequencing, capture-panel sequencing and cell-free DNA. Our findings highlight the clinical value of chromosomal instability signatures in predicting resistance to chemotherapies across multiple cancer types, with the potential to transform the one-size-fits-all chemotherapy approach into precise, tailored treatment.