Identifying Mechanisms of Resistance by Circulating Tumor DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at Time of PARP Inhibitor Progression

Author:

Lheureux Stephanie12ORCID,Prokopec Stephenie D.1ORCID,Oldfield Leslie E.1ORCID,Gonzalez-Ochoa Eduardo1ORCID,Bruce Jeffrey P.1ORCID,Wong Derek1ORCID,Danesh Arnavaz1ORCID,Torti Dax3ORCID,Torchia Jonathan3ORCID,Fortuna Alexander3ORCID,Singh Sharanjit3ORCID,Irving Matthew3ORCID,Marsh Kayla3ORCID,Lam Bernard3ORCID,Speers Vanessa1ORCID,Yosifova Aleksandra1ORCID,Oaknin Ana4ORCID,Madariaga Ainhoa1ORCID,Dhani Neesha C.12ORCID,Bowering Valerie1ORCID,Oza Amit M.12ORCID,Pugh Trevor J.135ORCID

Affiliation:

1. 1Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

2. 2Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

3. 3Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

4. 4Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

5. 5Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Abstract

Abstract Purpose: To evaluate the use of blood cell–free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC). Experimental Design: We used targeted sequencing (TS) to analyze 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared with whole-exome sequencing (WES) of baseline tumor tissues. Results: At baseline (time of initial PARPi progression), cfDNA tumor fractions were 0.2% to 67% (median, 3.25%), and patients with high ctDNA levels (>15%) had a higher tumor burden (sum of target lesions; P = 0.043). Across all timepoints, cfDNA detected 74.4% of mutations known from prior tumor WES, including three of five expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including seven TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed five of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (P = 0.001). Conclusions: Longitudinal testing of cfDNA by TS provides a noninvasive tool for detection of tumor-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation.

Funder

Princess Margaret Cancer Foundation

Ontario Institute for Cancer Research

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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