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

• Published in: Molecular oncology Vol. 16; no. 10; pp. 2086 - 2097
• Main Authors: Mendelaar, Pauline A. J., Robbrecht, Debbie G. J., Rijnders, Maud, Wit, Ronald, Weerd, Vanja, Deger, Teoman, Westgeest, Hans M., Aarts, Maureen J. B., Voortman, Jens, Martens, John W. M., Veldt, Astrid A. M., Nakauma‐González, José Alberto, Wilting, Saskia M., Lolkema, Martijn
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2022; John Wiley and Sons Inc; Wiley
• Subjects: advanced urothelial carcinoma; Analysis; Aneuploidy; biomarker; Biomarkers; Cancer; Cancer therapies; Care and treatment; Chemotherapy; chromosomal instability; Chromosomes; ctDNA; Deoxyribonucleic acid; DNA; Ethics; Gene frequency; Genetic aspects; Genetic research; Genomes; Genomics; Immune checkpoint inhibitors; Immunotherapy; liquid biopsies; Metastases; Metastasis; Patients; Pembrolizumab; Plasma; Tumors; Urothelial cancer; United States > US; Netherlands; pembrolizumab; advanced urothelial carcinoma; biomarker; liquid biopsies; chromosomal instability; ctDNA
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13196

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. 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.