Acquired drug resistance is a major challenge in controlling recurrent high-grade serous ovarian cancer (HGSC) and leads to poor overall survival. There has been comparatively little characterisation of the tumour samples from HGSC patients with recurrent disease who have been extensively treated with chemotherapy or targeted agents, such as PARP inhibitors (PARPi).
Making use of our unique end-stage tumour samples collected through the CASCADE rapid autopsy program, we sought to understand resistance and heterogeneity in HGSC patients with mutations in components of the homologous recombination (HR) DNA repair pathway. Through multi-omic analysis, including whole genome sequencing and RNA sequencing, we observed substantial intra- and inter-patient heterogeneity at the level of mutation burden, mutational signatures, and pathogenic mutations. We have identified multiple events contributing to treatment resistance, and examples of convergent evolution of resistance within patients.