Dr. Faltas and his lab sought to characterize the genetic evolution of urothelial carcinoma as it mutates from a primary untreated lesion to an advanced chemotherapy-resistant metastatic lesion. Through this work, they hope to better understand the mechanisms that lead to chemoresistance, and to potentially identify targets for novel treatments. To do this, they obtained tumor samples from patients' primary lesions, and subsequent metastatic lesions, if they were to develop any. They performed whole-exome sequencing of these lesions and compared the genetic differences. They discovered that chemotherapy-resistant metastatic lesions often have significant intra-patient genetic heterogeneity when compared to the primary lesion, or even other metastatic lesions. There are frequent single nucleotide variations between lesions, as well as “driver” mutations, however copy-number variations often remain clonally static.
Dr. Faltas outlined the evolutionary pathway of a tumor from primary to metastatic lesion in a single patient and characterized the multiple genetic mutations that occur and drive the process of metastasis. Interestingly, distinct metastatic lesions in a single patient can often be genetically heterogeneous. This finding may explain why chemoresistance occurs commonly in these patients.
He then discussed how chemotherapy influences the genetic landscape of tumor cell populations in patients with advanced urothelial carcinoma. His group evaluated tumors from patients both before and then after they have undergone chemotherapy. They found that chemotherapy acts as a bottleneck to minimize the heterogeneity of tumor clonality, which they found is an early event in the development of advanced disease. He suggests that early systemic therapy may be of benefit in some patients to slow the genetic evolution of tumors and potentially decrease the risk of disease progression, however further work is necessary to identify which genetic alterations specifically contribute to the process of metastasis.
Presented by: Bishoy Faltas, MD, medical oncologist, Assistant Professor of Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, Weill Cornell Medical Center NY, NY
Written by: Brian Kadow, MD, Fox Chase Cancer Center, Philadelphia, PA at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC