Background: Acquired drug resistance is the major obstacle in controlling high-grade serous ovarian cancer (HGSC) and leads to poor overall survival. Comparatively little massively parallel sequencing data exist from HGSC patients with recurrent or end-stage disease who have been extensively treated with chemotherapy or newer targeted agents, such as antiangiogenics or PARP inhibitors (PARPi). We previously identified four mechanisms of acquired resistance from whole-genome sequencing (WGS) of 23 HGSC patients with recurrent disease; a resistance mechanism of any kind was only identified in half of the patients.
Aim: To characterize genomic features and identify mechanisms of acquired drug resistance in end-stage HGSC patients.
Methods: Since 2012, we have collected tumor samples from 19 HGSC patients through our rapid-autopsy program. On average, we collect 17 tumor sites per patient during the autopsy, which is performed a median 6 hours after death. SNP array, WGS, and RNA sequencing were performed to detect germline and somatic mutations, copy number alterations and gene expression patterns.
Results: A total of 89 end-stage tumor samples from 15 patients with germline or somatic mutations in components of the homologous recombination (HR) DNA repair pathway have been analyzed by SNP array, and a subset of those have undergone WGS (n=44) and RNAseq (n=47). As expected, all samples had a somatic pathogenic TP53 mutation and have highly aberrant somatic copy number profiles. Prominent mutational signatures (single- and double-base substitutions) are associated with defective HR and prior treatment with platinum drugs. The total single-base substitution mutation burden is similar across tumor samples within patients; however, many mutations are unique to individual tumor samples. Currently, reversion mutations, which are secondary mutations in HR genes, are the most common resistance mechanism identified in our cohort of end-stage patients.
Conclusion: Our data are allowing us to understand HGSC at end stage, by examining the catalogue of resistance mechanisms within an individual patient and reconstructing the natural history of HGSC.
Citation Format: Elizabeth L. Christie, Kathryn Alsop, George Au-Yeung, Ahwan Pandey, Australian Ovarian Cancer Study, David D.L. Bowtell. Drug resistance in end-stage high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA04.