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

Pauline A.J. Mendelaar; Debbie G.J. Robbrecht; Maud Rijnders; Ronald de Wit; Vanja de Weerd; Teoman Deger; Hans M. Westgeest; Maureen J.B. Aarts; Jens Voortman; John W.M. Martens; Astrid A.M. van der Veldt; José Alberto Nakauma-González; Saskia M. Wilting; Martijn Lolkema

doi:10.1002/1878-0261.13196

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

Pauline A.J. Mendelaar^*, Debbie G.J. Robbrecht, Maud Rijnders, Ronald de Wit, Vanja de Weerd, Teoman Deger, Hans M. Westgeest, Maureen J.B. Aarts, Jens Voortman, John W.M. Martens, Astrid A.M. van der Veldt, José Alberto Nakauma-González, Saskia M. Wilting, Martijn Lolkema

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	2086-2097
Number of pages	12
Journal	Molecular Oncology
Volume	16
Issue number	10
DOIs	https://doi.org/10.1002/1878-0261.13196
Publication status	Published - May 2022

Bibliographical note

Acknowledgements:
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.

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Molecular Oncology - 2022 - Mendelaar - Genome‐wide aneuploidy detected by mFast‐SeqS in circulating cell‐free DNA isFinal published version, 1.18 MBLicence: CC BY

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Mendelaar, P. A. J., Robbrecht, D. G. J., Rijnders, M., de Wit, R., de Weerd, V., Deger, T., Westgeest, H. M., Aarts, M. J. B., Voortman, J., Martens, J. W. M., van der Veldt, A. A. M., Nakauma-González, J. A., Wilting, S. M., & Lolkema, M. (2022). 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. Molecular Oncology, 16(10), 2086-2097. https://doi.org/10.1002/1878-0261.13196

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title = "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",

abstract = "Second-line treatment with immune checkpoint inhibition in patients with metastatic urothelial cancer (mUC) has a low success rate (\textasciitilde{} 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.",

author = "Mendelaar, \{Pauline A.J.\} and Robbrecht, \{Debbie G.J.\} and Maud Rijnders and \{de Wit\}, Ronald and \{de Weerd\}, Vanja and Teoman Deger and Westgeest, \{Hans M.\} and Aarts, \{Maureen J.B.\} and Jens Voortman and Martens, \{John W.M.\} and \{van der Veldt\}, \{Astrid A.M.\} and Nakauma-Gonz{\'a}lez, \{Jos{\'e} Alberto\} and Wilting, \{Saskia M.\} and Martijn Lolkema",

note = "Acknowledgements: 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: {\textcopyright} 2022 The Authors. Molecular Oncology published by John Wiley \& Sons Ltd on behalf of Federation of European Biochemical Societies.",

year = "2022",

month = may,

doi = "10.1002/1878-0261.13196",

language = "English",

volume = "16",

pages = "2086--2097",

journal = "Molecular Oncology",

issn = "1574-7891",

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Mendelaar, PAJ, Robbrecht, DGJ , Rijnders, M , de Wit, R , de Weerd, V, Deger, T, Westgeest, HM, Aarts, MJB, Voortman, J, Martens, JWM , van der Veldt, AAM , Nakauma-González, JA , Wilting, SM & Lolkema, M 2022, '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', Molecular Oncology, vol. 16, no. 10, pp. 2086-2097. https://doi.org/10.1002/1878-0261.13196

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. / Mendelaar, Pauline A.J.; Robbrecht, Debbie G.J.; Rijnders, Maud et al.
In: Molecular Oncology, Vol. 16, No. 10, 05.2022, p. 2086-2097.

Research output: Contribution to journal › Article › Academic › peer-review

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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 - Acknowledgements: 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.

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U2 - 10.1002/1878-0261.13196

DO - 10.1002/1878-0261.13196

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AN - SCOPUS:85126383380

SN - 1574-7891

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SP - 2086

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JF - Molecular Oncology

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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

Abstract

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