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
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-05-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13196 |
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| author | Pauline A. J. Mendelaar Debbie G. J. Robbrecht Maud Rijnders Ronald deWit Vanja deWeerd Teoman Deger Hans M. Westgeest Maureen J. B. Aarts Jens Voortman John W. M. Martens Astrid A. M. van derVeldt José Alberto Nakauma‐González Saskia M. Wilting Martijn Lolkema |
| author_facet | Pauline A. J. Mendelaar Debbie G. J. Robbrecht Maud Rijnders Ronald deWit Vanja deWeerd Teoman Deger Hans M. Westgeest Maureen J. B. Aarts Jens Voortman John W. M. Martens Astrid A. M. van derVeldt José Alberto Nakauma‐González Saskia M. Wilting Martijn Lolkema |
| author_sort | Pauline A. J. Mendelaar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T17:27:50Z |
| format | Article |
| id | doaj.art-697816219cc74830a6f744569b38649b |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-13T17:27:50Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-697816219cc74830a6f744569b38649b2022-12-22T02:37:41ZengWileyMolecular Oncology1574-78911878-02612022-05-0116102086209710.1002/1878-0261.13196Genome‐wide aneuploidy detected by mFast‐SeqS in circulating cell‐free DNA is associated with poor response to pembrolizumab in patients with advanced urothelial cancerPauline A. J. Mendelaar0Debbie G. J. Robbrecht1Maud Rijnders2Ronald deWit3Vanja deWeerd4Teoman Deger5Hans M. Westgeest6Maureen J. B. Aarts7Jens Voortman8John W. M. Martens9Astrid A. M. van derVeldt10José Alberto Nakauma‐González11Saskia M. Wilting12Martijn Lolkema13Department of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Amphia Hospital Breda The NetherlandsDepartment of Medical Oncology GROW School for Oncology and Developmental Biology Maastricht University Medical Center+ The NetherlandsDepartment of Medical Oncology Cancer Center Amsterdam Amsterdam UMC, Vrije Universiteit Amsterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Medical Oncology Erasmus MC Cancer Institute Rotterdam The NetherlandsSecond‐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.https://doi.org/10.1002/1878-0261.13196advanced urothelial carcinomabiomarkerchromosomal instabilityctDNAliquid biopsiespembrolizumab |
| spellingShingle | Pauline A. J. Mendelaar Debbie G. J. Robbrecht Maud Rijnders Ronald deWit Vanja deWeerd Teoman Deger Hans M. Westgeest Maureen J. B. Aarts Jens Voortman John W. M. Martens Astrid A. M. van derVeldt José Alberto Nakauma‐González Saskia M. Wilting Martijn Lolkema 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 advanced urothelial carcinoma biomarker chromosomal instability ctDNA liquid biopsies pembrolizumab |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | advanced urothelial carcinoma biomarker chromosomal instability ctDNA liquid biopsies pembrolizumab |
| url | https://doi.org/10.1002/1878-0261.13196 |
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