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

San Francisco, CA (UroToday.com) The development of biomarkers has led to increasing interest of circulating tumor cell DNA as a prognostic biomarker. At today’s risk stratification and management of high-risk muscle invasive urothelial carcinoma session at ASCO GU 2020, Alexander Wyatt, B.Sc.D.Phil, from the University of British Columbia discussed the role of circulating tumor cell DNA in muscle invasive bladder cancer (MIBC). Dr. Wyatt notes that the collection of cell-free DNA is simple and inexpensive – cell-free DNA is shed by dying cells and circulating tumor cell DNA is a tumor-derived fraction. The advantage of urine/plasma cell-free DNA is that it is practical for collection and processing. However, the circulating tumor cell DNA fraction (ie. tumor content) is highly variable. Highly sensitive assays can detect somatic mutations in cell-free DNA, but we must take caution to exclude non-cancer somatic variants. Furthermore, detection versus genomic characterization requires a nuanced approach that provides an opportunity for developing predictive biomarkers and assessing disease biology. A schematic of the limits of detection is as follows:

ASCOGU_LimitsofDetection.png

Ultimately, the detection of circulating tumor cell DNA indicates residual disease. In a study assessing the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy, Christensen et al. found that in 68 patients the presence of circulating tumor DNA was highly prognostic at diagnosis before chemotherapy (HR 29.1, p = 0.001).1 After cystectomy, circulating tumor DNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). In addition, for high-risk patients (circulating tumor DNA positive before or during treatment), the dynamics of circulating tumor DNA during chemotherapy was associated with disease recurrence (p = 0.023), whereas pathologic downstaging was not.

Regarding genomic characterization of circulating tumor DNA in metastatic urothelial carcinoma, early studies suggest that the genetic landscape is similar to aggressive MIBC. Furthermore, matched tissue vs circulating tumor DNA has concordance of >80%. Deep whole exome sequencing suggests two mutational signatures: HRR deficiency and APOBEC.

But what is the significance of a biomarker negative result? According to Dr. Wyatt it depends on whether there is sufficient circulating tumor DNA fraction (tumor content) to identify an alteration. If there is not, there is absence of evidence and the tumor may still carry the alteration – Dr. Wyatt suggests we should test again or test the tissue. If there is sufficient circulating tumor DNA fraction, there is evidence of absence and the tumor is alteration negative.

Dr. Wyatt concluded with several take-home points:

  • Detection of circulating tumor DNA in MIBC context informs a poor prognosis
  • Circulating tumor DNA is a clinically practical and reliable biomarker source in metastatic urothelial carcinoma
  • Some patients have no/low circulating tumor DNA, so in these patients we should fallback on tissue for genomics
  • There should be an urgency for incorporating circulating tumor DNA into molecularly guided clinical trials

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: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

References:

  1. Christensen E, Birkenkamp-Demtroder K, Sethi H, 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. J Clin Oncol 2019 Jun 20;37(18):1547-1557.
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