ASCO GU 2020: Risk Stratification and Management of High-Risk Muscle Invasive Urothelial Carcinoma

San Francisco, California (UroToday.com) There is a significant interest in analyzing cell-free DNA (cfDNA) for risk stratification and management of high-risk muscle-invasive urothelial carcinoma. cfDNA is shed by dying cells; circulating tumor DNA (ctDNA) represents the tumor-derived fraction of cfDNA. Advantages of plasma and/or urine-derived cfDNA include the ease of sampling and processing and feasibility of serial collection. An important consideration, however, is that ctDNA fraction is highly variable and different genomic alterations have different limits of detection. For example, copy number alterations require a higher ctDNA fraction than mutations and rearrangements. This has important clinical implications. If a genetic alteration is not detected, one must consider whether sufficient ctDNA fraction (tumor content) was present to identify the alteration. The absence of an alteration does not necessarily mean that the alteration was not present; it may not have been detectable due to insufficient ctDNA. In this case, repeat testing can be helpful. Another consideration is that at low ctDNA fraction, technical and biological artifacts, such as clonal hematopoiesis of indeterminate potential, can introduce false positives and complicate interpretation of results.

ctDNA levels post-cystectomy demonstrate clear prognostic value. Investigators collected cfDNA after cystectomy in 68 patients. Undetectable ctDNA post-cystectomy was associated with dramatically improved relapse-free survival and overall survival compared to those with detectable ctDNA. Further, no patients with undetectable ctDNA relapsed during the study period, whereas detectable ctDNA portended imminent relapse. As a result of these findings, the investigators have designed a Phase II study (NCT04138628) where patients with detectable ctDNA are treated with systemic therapy.

detectino of ctdna indicates residual disease

detectino of ctdna indicates residual disease

The ctDNA fraction is very high In metastatic urothelial cancer allowing for comprehensive genomic characterization using cfDNA. In an analysis of paired tumor and ctDNA profiling in 65 patients, there was high concordance (>80%) of genomic alterations as well as tumor mutational burden.

genomic characterization of ctdna in muc

genomic characterization of ctdna in muc

In conclusion, ctDNA clearly informs prognosis in MIBC post-cystectomy and is a clinically-practical and reliable biomarker source in metastatic urothelial carcinoma. However, some patients have no or low ctDNA in which case tissue can be used for genomic analysis. Moving forward, ctDNA will likely be increasingly incorporated into molecularly-guided trials, which will help inform its role in clinical practice.

Presented by: Alexander Wyatt, PhD, Senior Research Scientist, Vancouver Prostate Centre, Assistant Professor, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, Boston, Massachusetts, Twitter: @jberchuck at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

Reference:

1. Christensen, Emil, Karin Birkenkamp-Demtröder, Himanshu Sethi, Svetlana Shchegrova, Raheleh Salari, Iver Nordentoft, Hsin-Ta Wu et al. "Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma." Journal of Clinical Oncology 37, no. 18 (2019): 1547-1557.

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