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. Issue 10 (17th March 2022)

• Record Type: Journal Article
• Authors: Mendelaar, Pauline A. J.; Robbrecht, Debbie G. J.; Rijnders, Maud; de Wit, Ronald; de Weerd, Vanja; Deger, Teoman; Westgeest, Hans M.; Aarts, Maureen J. B.; Voortman, Jens; Martens, John W. M.; van der Veldt, Astrid A. M.; Nakauma‐González, José Alberto; Wilting, Saskia M.; Lolkema, Martijn
• Is Part Of: Molecular oncology. Volume 16:Issue 10(2022)
• Page Start: 2086
• Page End: 2097
• Publication Date: 2022-03-17
• Subjects: advanced urothelial carcinoma -- biomarker -- chromosomal instability -- ctDNA -- liquid biopsies -- pembrolizumab; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.13196
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : Second‐line immune checkpoint inhibition in patients with metastatic urothelial cancer (mUC) has a low success rate. ctDNA levels may guide patient stratification; however, a high‐throughput and affordable method is lacking. Here, we report that a high aneuploidy score detected by the mFast‐SeqS method is independently associated to a lack of clinical benefit from pembrolizumab treatment. Following independent validation, mFast‐SeqS could stratify patients with mUC for response to therapy.