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Serial ctDNA analysis predicts clinical progression in patients with advanced urothelial carcinoma

Abstract

Background

Targeted sequencing of circulating tumour DNA (ctDNA) is a promising tool to monitor dynamic changes in the variant allele frequencies (VAF) of genomic alterations and predict clinical outcomes in patients with advanced urothelial carcinoma (UC).

Methods

We performed targeted sequencing of 182 serial ctDNA samples from 53 patients with advanced UC.

Results

Serial ctDNA-derived metrics predicted the clinical outcomes in patients with advanced UC. Combining serial ctDNA aggregate VAF (aVAF) values with clinical factors, including age, sex, and liver metastasis, improved the performance of prognostic models. An increase of the ctDNA aVAF by ≥1 in serial ctDNA samples predicted disease progression within 6 months in 90% of patients. The majority of patients with aVAFs ≤0.7 in three consecutive ctDNA samples achieved durable clinical responses (≥6 months).

Conclusions

Serial ctDNA analysis predicts disease progression and enables dynamic monitoring to guide precision medicine in patients with advanced UC.

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Fig. 1: Swimmer plot showing the disease course in each patient, treatment, ctDNA status, and radiographic response.
Fig. 2: Serial ctDNA captures actionable genomic alterations.
Fig. 3: ctDNA measurements are prognostic.
Fig. 4: ctDNA dynamics reflect radiographic disease burden.
Fig. 5: Serial ctDNA predicts clinical outcomes.

Data availability

Data access and responsibility: NJV and BMF had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Data sharing policy: Data are available for bona fide researchers upon request from the authors.

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Acknowledgements

BMF was supported by the Department of Defense CDMRP grant (CA160212), a STARR Cancer Consortium grant (I14-0047), and the Gellert Family-John P. Leonard, MD Research Scholarship in Hematology and Medical Oncology. This work was also supported by a Conquer Cancer Foundation Long Term International Fellowship Award (KSS) and the Englander Institute for Precision Medicine at WCM (OE, BMF). Guardant performed sequencing and initial mutational testing of ctDNA samples. We thank Duy Nguyen for his assistance with editing the text.

Funding

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Authors and Affiliations

Authors

Contributions

Initiation and design of the study: KSS, KSP, RN, PG, NJV and BMF. Subject enrollment, sample, and clinical data collection: KSS, DV, YC, JT, STT, AMM, CNS, DMN, JMM, OE, GPS, PV, NJV and BMF. Sample sequencing: KSP and RN. Statistical, and bioinformatic analyses: KSS and OE. Supervision of research: NV and BMF. Writing of the first draft of the manuscript: KSS, OE, GPV, PG, NV and BMF. All authors contributed to the writing and editing of the revised manuscript and approved the manuscript.

Corresponding authors

Correspondence to Nicholas J. Vogelzang or Bishoy Morris Faltas.

Ethics declarations

Competing interests

KSS, DMV, YC and JT: No competing interests. AMM: Honoraria—ASCO, Consulting or advisory role—EISAi; Exelixis; Janssen. KSP and RN: Employment—Guardant Health Inc. CNS: Consulting or advisory role—Astellas Pharma; AstraZeneca; Bayer; Genzyme; Immunomedics; Incyte; Medscape; Merck; MSD; Pfizer; Roche; UroToday. STT: Consulting or advisory role—Abbvie; Amgen; Astellas Pharma; Bayer; Clovis Oncology; Dendreon; Endocyte; Genentech; Immunomedics; Janssen; Karyopharm Therapeutics; Medivation; Pfizer; QED Therapeutics; Sanofi; Tolmar, Research funding—Abbvie (Inst); Amgen (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); AVEO (Inst); Bayer (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Clovis Oncology (Inst); Dendreon (Inst); Endocyte (Inst); Exelixis (Inst); Genentech (Inst); Immunomedics (Inst); Inovio Pharmaceuticals (Inst); Janssen (Inst); Karyopharm Therapeutics (Inst); Lilly (Inst); Medivation (Inst); Merck (Inst); Millennium (Inst); Newlink Genetics (Inst); Novartis (Inst); Progenics (Inst); Rexahn Pharmaceuticals (Inst); Sanofi (Inst); Stem CentRx (Inst), Travel, Accommodations, expenses—Amgen; Immunomedics; Sanofi. DMN: Consulting or advisory role—Roche/Genentech, Research funding—Boehringer Ingelheim (Inst); Novartis (Inst); Zenith Epigenetics (Inst). JMM: Research funding—Personal genome diagnostics, Travel, accommodations, expenses—Personal genome diagnostics. OE: Stock and other ownership interests—OneThree Biotech; Owkin; Volastra Therapeutics. GPS: Honoraria—UpToDate, Consulting or advisory role—Astellas Pharma; AstraZeneca; Bicycle Therapeutics; Bristol-Myers Squibb; Eisai; EMD Serono; Exelixis; Genentech; Janssen; Merck; Pfizer; Seattle Genetics, Speakers’ Bureau - Medscape; Onclive; Physicans’ Education Resource; Research to practice, research funding—AstraZeneca (Inst); Janssen (Inst); Sanofi (Inst), Travel, Accommodations, expenses—Bristol-Myers Squibb, Other relationship—Astellas Pharma; AstraZeneca; Bavarian Nordic; Bristol-Myers Squibb; Debiopharm Group; Elsevier; QED Therapeutics. PG: Consulting or advisory role—AstraZeneca; Bayer; Bristol-Myers Squibb; Clovis Oncology; Driver, Inc; EMD Serono; Exelixis; Foundation Medicine; Genzyme; GlaxoSmithKline; HERON; Janssen; Merck; Mirati Therapeutics; Pfizer; QED Therapeutics; Roche; Seattle Genetics, Research funding—Bavarian Nordic (Inst); Bristol-Myers Squibb (Inst); Clovis Oncology (Inst); Debiopharm Group (Inst); Immunomedics (Inst); Pfizer (Inst). NJV: Employment—US Oncology, Stock and Other Ownership interests—Caris Life Sciences, Honoraria—Novartis; Pfizer; UpToDate, Consulting or Advisory role—Astellas Pharma, AstraZeneca; Bayer; Boehringer Ingelheim; Caris Life Sciences; Clovis Oncology; Corvus Pharmaceuticals; Eisai; Genentech/Roche; Janssen Oncology; Merck; Modra Pharmaceuticals; Pfizer; Tolero Pharmaceuticals, Speakers’ Bureau—Bayer; Bristol-Myers Squibb; Clovis Oncology; Genentech/Roche; Sanofi; Seattle Genetics/Astellas, Research funding—Endocyte (Inst); Merck (Inst); Suzhou Kintor Pharmaceuticals (Inst); US Oncology (Inst), Expert testimony—Novartis, Travel, accommodations, expenses—AstraZeneca/MedImmune; Bayer/Onyx; Exelixis; Genentech/Roche; Pfizer; Sanofi/Aventis; US Oncology. BMF: Honoraria—Digital Science Press, Consulting or advisory role—QED therapeutics, Immunomedics, Merck, Seattle Genetics. Patent royalties Immunomedics/Gilead Research funding—Eli Lilly.

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The study was approved by the Western Institutional Review Board (Protocol No. 20152817).

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Shohdy, K.S., Villamar, D.M., Cao, Y. et al. Serial ctDNA analysis predicts clinical progression in patients with advanced urothelial carcinoma. Br J Cancer 126, 430–439 (2022). https://doi.org/10.1038/s41416-021-01648-8

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