ASCO 2017: Intra-patient heterogeneity in urothelial cancer circulating tumor cells and PDL1 expression to identify biomarkers of response and new therapeutic targets

Chicago, IL ( Immune checkpoint blockade (ICB) has become an important new therapy for metastatic or advanced urothelial carcinoma (UC), demonstrating objective response rates (ORRs) and survival benefit in a subset of patients despite prior chemotherapy treatment failure. However, patient selection has become the critical question, as not all patients appear to benefit from treatment.

Intra-patient tumoral heterogeneity and epithelial-to-mesenchymal transition (EMT) has been hypothesized as a driver of treatment resistance to both chemotherapy and ICB in UC. Evaluation of the tumoral heterogeneity will allow for better understanding of the progression of disease, but also shed light on biomarkers of treatment response and potentionally new actionable targets.

Trop2 (Tumor-associated calcium signal transducer 2, also known as epithelial glycoprotein-1 antigen [EGP-1]) is a protein encoded by the TACSTD2 gene. It is hypothesized to play a role in UC progression and is the target of a new antibody-drug conjugate, IMMU-132 (Sacituzumab govitecan) that is being tested in UC trials. It is a conjugate of the anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan (too toxic to administer as monotherapy).

In this study, the authors report the phenotypic comparison of PD-L1 and Trop-2 expression among circulating tumor cell (CTC) subpopulations in UC pts. After immunomagnetic capture and CTC enumeration using both EpCAM and Trop2 from matched blood samples was performed, protein expression for PDL1 in these CTC populations was quantified. Longitudinal analysis of UC pts treated with chemotherapy or ICB is ongoing. This is a proof of concept study.

A total of 10 patients were included in the study. CTCs were captured using EpCAM and Trop2 in all 10 pts in the initial cohort. The frequency of Trop2 CTC was higher than EpCAM CTC with a mean of 248 Trop2 CTC (range 2-1885) compared to 76 EpCAM CTC (range 1-632).

PDL1 expression was present in 40% of patients at baseline. It was more frequent in Trop2 CTC than EpCAM CTC. In two pts progressing on Atezolizumab, Trop2 CTC had a higher frequency of PDL1 expression compared to EpCAM CTC (85% vs 2% in pt 1 and 2% vs 0% in pt 2).

In pts followed longitudinally, Trop2 CTC dropped from 1885 to 1 in a pt with response to Atezolizumab and PDL1+ CTC declined from 4 to 0. After 1 cycle of Carbo/Gem in another pt, EpCAM CTC declined from 46 to 3 while Trop2 CTC from 116 to 47.

This is the first report of CTC heterogeneity in patients with UC. Obviously, this is a very small cohort. However, the few samples obtained suggest that these may serve as important biomarkers of response. Additionally, they highlight the heterogeneity of CTC expression.

Ongoing longitudinal studies will provide more temporal information regarding treatment response and utility as a biomarker.

Presented By: Waddah Arafat

Co-Authors: Charlotte Stahlfeld, Jamie M Sperger, Erika Heninger, Dharmesh Gopalakrishnan, Pedro C. Barata, Marcelo Lamenza, Sarah Devonshire, Nita Hoxha, Pam Profusek, Brian I. Rini, Moshe Chaim Ornstein, Jorge A. Garcia, Christos Kyriakopoulos, Joshua Michael Lang, Petros Grivas

Institution(s): University of Wisconsin, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI; Cleveland Clinic, Cleveland, OH; Cleveland Clinic Taussig Cancer Insitute, Cleveland, OH

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA