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

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

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 languageEnglish
Pages (from-to)2086-2097
Number of pages12
JournalMolecular Oncology
Volume16
Issue number10
Early online date2022
DOIs
Publication statusPublished - May 2022

Keywords

  • advanced urothelial carcinoma
  • biomarker
  • chromosomal instability
  • ctDNA
  • liquid biopsies
  • pembrolizumab

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