American Association for Cancer Research
Browse

sorry, we can't preview this file

ccr-23-0797_supplementary_table_s4_suppts4.xlsx (9.6 kB)

Supplementary Table S4 from 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

Download (9.6 kB)
dataset
posted on 2023-08-08, 13:00 authored by Stephanie Lheureux, Stephenie D. Prokopec, Leslie E. Oldfield, Eduardo Gonzalez-Ochoa, Jeffrey P. Bruce, Derek Wong, Arnavaz Danesh, Dax Torti, Jonathan Torchia, Alexander Fortuna, Sharanjit Singh, Matthew Irving, Kayla Marsh, Bernard Lam, Vanessa Speers, Aleksandra Yosifova, Ana Oaknin, Ainhoa Madariaga, Neesha C. Dhani, Valerie Bowering, Amit M. Oza, Trevor J. Pugh

Supplementary Table S4: Targeted Lesions at Baseline. The baseline sum of targeted lesions (mm) for each patient, determined at baseline by CT for RECIST1.1 evaluation.

Funding

Princess Margaret Cancer Foundation (PMCF)

Ontario Institute for Cancer Research (OICR)

History

ARTICLE ABSTRACT

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). 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. 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). 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.

Usage metrics

    Clinical Cancer Research

    Categories

    Keywords

    cancer

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC