CTC subtypes: A prognostic marker in GU cancer patients?

In a study of circulating tumor cells (CTCs) in metastatic genitourinary cancer patients, shorter survival was associated with high CTC counts at baseline and on therapy, specific CTC morphologic subtypes, PD-L1-positive CTCs, and low percent CD4 and percent CD8 T-cells. In addition, poor response was associated with low percent CD4 T-cells at baseline and on therapy, reported first author Heather Chalfin, MD, a urologic oncology fellow at the National Cancer Institute, Bethesda, MD. Dr. Chalfin, who presented the findings at the Society of Urologic Oncology annual meeting in Washington, discusses the data and explains how CTCs may offer an advantage over other forms of liquid biopsy.

What was the rationale for your study, and what needs might circulating tumor cells address in the management of genitourinary cancers?

Circulating tumor cells (CTCs) are a minimally invasive liquid biopsy with the potential to improve risk stratification and treatment selection for cancer patients. Unlike ctDNA or exosomes, CTCs offer the ability to image cell morphology, similar to how pathologists might examine the cellular features of a solid tumor. CTC heterogeneity is a term that refers to the degree of uniformity of the CTC morphologic subtypes for an individual patient. So, for example, a patient with low heterogeneity would have all small round CTCs, whereas a patient with some large, some small, and some elongated CTCs would be termed as having high heterogeneity.

That's important because in the literature we see in prostate cancer that patients with high CTC heterogeneity have worse survival and worse responses to targeted therapy. And separately, we've also seen in prostate cancer that patients with high heterogeneity are better responders to immunotherapy. So one idea that puts these two things together is the hypothesis that maybe CTC heterogeneity is a surrogate marker of tumor mutational burden.

What were the key findings of your study?

In our cohort of metastatic GU cancer patients on combination immunotherapy, we found that the presence of specific CTC morphologic subtypes was associated with 1 to 2 months of median survival versus 28 months in their counterparts in the remainder of the cohort. Also, the presence of PDL-1-positive CTCs was associated with worse overall survival.

We also used the CTC technology to detect and characterize the T cell populations in our patients. We found that having a low percent CD4 or CD8 count at baseline or on therapy was associated with worse overall survival, as well as in the case of CD4, a poor response category.

What are the next steps in your research?

We definitely feel that our results aren't ready for prime time yet. The statistical methods we used were exploratory and hypothesis generating. And ideally, this would be confirmed an independent cohort, particularly that's more homogenous than what we explored because our cohort included heterogeneous types of metastatic GU cancers. In addition, not all patients received ipilimumab in our study.

But we are very excited about the technology, and at our center we have upcoming a study of a PARP inhibitor in the metastatic setting. We'll be including this as a correlative, and additionally we have two trials in the localized setting for urothelial cancer patients on checkpoint inhibitor therapy.

Are CTCs available for commercial use in GU cancer?

It's important to remember that CTCs in urothelial cancer are definitely not ready for prime time at this time, but CTCs offer an edge over other liquid biopsies in that you can image cell morphology, and specifically look at biomarkers at the single cell level. In our project, we use PDL-1, but there's potential to include other biomarkers of interest moving forward. Hopefully this will improve treatment selection and risk stratification in our cancer patients.