Abstract 757P
Background
An increasing number of ovarian cancer patients are becoming resistant to PARP inhibitor (PARPi). Many potential resistant mechanisms are proposed, yet patient-specific molecular alterations which underlie the development of acquired resistance are unknown. Thus, we have analyzed serially obtained circulating tumor DNA (ctDNA) samples from patients receiving PARPi.
Methods
Patients receiving PARPi were prospectively enrolled since January 2018. Whole blood was collected every 3 months during treatment until progression on PARPi. Cell-free DNA was extracted from plasma and genomic DNA was extracted from peripheral blood mononuclear cells for germline variants filtering. 531 cancer-related genes were included in the NGS panel and paired-end 150bp reads were generated on NovaSeq 6000 System (Illumina, USA). The sequencing data was analyzed using our custom analysis pipeline. Variants were classified into ASCO/AMP four-tier system. All tier I, II, III and BRCA variants were visually confirmed using the Integrated Genomics Viewer.
Results
A total of 55 patients were enrolled, and recurrence was observed in 23 patients. Preliminary analysis was performed in 9 patients with paired ctDNA samples before and after PARPi. In one patient, reversion of BRCA mutation was observed. Analysis of pre-treatment samples showed ctDNA-specific mutations, which were not found in tumor sequencing data and were implicated in various signaling pathways. Furthermore, analysis of samples after progression on PARPi identified variants that were unobserved in the matched patient samples prior to therapy. Such mutations included druggable target genes including CHEK2, ATM, TET2, DICER1, CARD11, NF1, DNMT3A, and SMAD4.
Conclusions
ctDNA, a less-invasive alternative to serial tumor biopsy, helps capture both the spatial and temporal dynamism of response to PARPi. Analysis of paired samples may provide useful insights to overcome PARPi resistance. Updated analysis with additional patients will be shared at the conference.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Dxome Co., Ltd.
Disclosure
S. Lee, J.R. Choi: Financial Interests, Personal, Stocks/Shares: Dxome. All other authors have declared no conflicts of interest.