TY - JOUR
T1 - Genome-wide aneuploidy detected by mFast-SeqS in circulating cell-free DNA is associated with poor response to pembrolizumab in patients with advanced urothelial cancer
AU - Mendelaar, Pauline A. J.
AU - Robbrecht, Debbie G. J.
AU - Rijnders, Maud
AU - de Wit, Ronald
AU - de Weerd, Vanja
AU - Deger, Teoman
AU - Westgeest, Hans M.
AU - Aarts, Maureen J. B.
AU - Voortman, Jens
AU - Martens, John W. M.
AU - van der Veldt, Astrid A. M.
AU - Nakauma-González, José Alberto
AU - Wilting, Saskia M.
AU - Lolkema, Martijn
N1 - Funding Information: The graphical abstract was created with BioRender.com. We thank the Hartwig Medical Foundation, and Stichting Stelvio for Life for financial support of clinical studies and WGS analyses. We thank the Center for Personalized Cancer Treatment for proving the clinical data. We would like to thank all local principal investigators, medical specialists, and nurses of all contributing centers for their help with patient accrual. We are particularly grateful to all participating patients and their families. Funding Information: The graphical abstract was created with BioRender.com. We thank the Hartwig Medical Foundation, and Stichting Stelvio for Life for financial support of clinical studies and WGS analyses. We thank the Center for Personalized Cancer Treatment for proving the clinical data. We would like to thank all local principal investigators, medical specialists, and nurses of all contributing centers for their help with patient accrual. We are particularly grateful to all participating patients and their families. Publisher Copyright: © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2022/5
Y1 - 2022/5
N2 - Second-line treatment with immune checkpoint inhibition in patients with metastatic urothelial cancer (mUC) has a low success rate (~ 20%). Circulating tumour-derived DNA (ctDNA) levels may guide patient stratification, provided that an affordable and robust assay is available. Here, we investigate whether the modified fast aneuploidy screening test-sequencing system (mFast-SeqS) may provide such an assay. To this end, mFast-SeqS was performed on cell-free DNA (cfDNA) from 74 patients with mUC prior to treatment with pembrolizumab. Results were associated with corresponding tissue-based profiles, plasma-based variant allele frequencies (VAFs) and clinical response. We found that plasma-derived mFast-SeqS-based aneuploidy scores significantly correlated with those observed in the corresponding tumour tissue as well as with the ctDNA level in the plasma. In multivariate logistic regression analysis, a high aneuploidy score was independently associated with lack of clinical benefit from treatment with pembrolizumab. In conclusion, mFast-SeqS provides a patient-friendly, high-throughput and affordable method to estimate ctDNA level. Following independent validation, this test could be used to stratify mUC patients for response prior to the initiation of treatment with pembrolizumab.
AB - Second-line treatment with immune checkpoint inhibition in patients with metastatic urothelial cancer (mUC) has a low success rate (~ 20%). Circulating tumour-derived DNA (ctDNA) levels may guide patient stratification, provided that an affordable and robust assay is available. Here, we investigate whether the modified fast aneuploidy screening test-sequencing system (mFast-SeqS) may provide such an assay. To this end, mFast-SeqS was performed on cell-free DNA (cfDNA) from 74 patients with mUC prior to treatment with pembrolizumab. Results were associated with corresponding tissue-based profiles, plasma-based variant allele frequencies (VAFs) and clinical response. We found that plasma-derived mFast-SeqS-based aneuploidy scores significantly correlated with those observed in the corresponding tumour tissue as well as with the ctDNA level in the plasma. In multivariate logistic regression analysis, a high aneuploidy score was independently associated with lack of clinical benefit from treatment with pembrolizumab. In conclusion, mFast-SeqS provides a patient-friendly, high-throughput and affordable method to estimate ctDNA level. Following independent validation, this test could be used to stratify mUC patients for response prior to the initiation of treatment with pembrolizumab.
KW - advanced urothelial carcinoma
KW - biomarker
KW - chromosomal instability
KW - ctDNA
KW - liquid biopsies
KW - pembrolizumab
UR - http://www.scopus.com/inward/record.url?scp=85126383380&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/1878-0261.13196
DO - https://doi.org/10.1002/1878-0261.13196
M3 - Article
C2 - 35181986
SN - 1574-7891
VL - 16
SP - 2086
EP - 2097
JO - Molecular Oncology
JF - Molecular Oncology
IS - 10
ER -