2026-04-13T13:42:47Zhttps://recercat.cat/oai/requestoai:recercat.cat:11351/103462024-12-13T10:14:23Zcom_2072_378070com_2072_378040col_2072_378092
RECERCAT
author
Lheureux, Stephanie
author
Prokopec, Stephenie
author
Oldfield, Leslie E.
author
Gonzalez-Ochoa, Eduardo
author
Bruce, Jeff
author
Wong, Derek
author
OAKNIN, ANA
2023-11-08T10:21:32Z
2023-11-08T10:21:32Z
2023-09-22T11:52:42Z2023-09-22T11:52:42Z2023-09-15
http://hdl.handle.net/11351/10346
Circulating tumor; Cediranib; Ovarian cancerADN tumoral circulante; Cediranib; Cáncer de ovarioADN tumoral circulant; Cediranib; Càncer d'ovariPurpose:
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.
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess
Ovaris - Càncer - Tractament
Ovaris - Càncer - Aspectes genètics
Quimioteràpia combinada
DISEASES::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms
Other subheadings::Other subheadings::Other subheadings::/drug therapy
ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Drug Therapy::Drug Therapy, Combination
ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::farmacoterapia::farmacoterapia combinada
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
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion