Although immune checkpoint inhibitors (ICIs) are increasingly used as second-line treatments for urothelial cancer (UC), only a small proportion of patients respond. Therefore, understanding the mechanisms of response to ICIs is critical to improve clinical outcomes for UC patients. The tumor microenvironment (TME) is recognized as a key player in tumor progression and the response to certain anti-cancer treatments. This study aims to investigate the mechanism of response using integrated genomic and transcriptomic profiling of a UC patient who was part of the KEYNOTE-045 trial and showed an exceptional response to pembrolizumab. Diagnosed in 2014 and receiving first-line chemotherapy without success, the patient took part in the KEYNOTE-045 trial for 2 years. She showed dramatic improvement and has now been free of disease for over 6 years. Recently described by Bagaev et al., the Molecular Functional (MF) Portrait was utilized to dissect genomic and transcriptomic features of the patient's tumor and TME. The patient's tumor was characterized as Immune Desert, which is suggestive of a non-inflamed microenvironment. Integrated whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analysis identified an ATM mutation and high TMB level (33.9 mut/mb), which are both positive biomarkers for ICI response. Analysis further revealed the presence of the APOBEC complex, indicating the potential for use of APOBEC signatures as predictive biomarkers for immunotherapy response. Overall, comprehensive characterization of the patient's tumor and TME with the MF Portrait revealed important insights that could potentially be hypothesis generating to identify clinically useful biomarkers and improve treatment for UC patients.
Frontiers in oncology. 2022 Oct 31*** epublish ***
Cora N Sternberg, Nara Shin, Konstantin Chernyshov, Fabio Calabro, Linda Cerbone, Giuseppe Procopio, Natalia Miheecheva, Georgy Sagaradze, Alisa Zaichikova, Naira Samarina, Alexandra Boyko, Jessica H Brown, Leysan Yunusova, Daniela Guevara, Jyothi Manohar, Michael Sigouros, Majd Al Assaad, Olivier Elemento, Juan Miguel Mosquera
Englander Institute for Precision Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Hematology and Oncology, New York-Presbyterian, New York, NY, United States., BostonGene, Corp, Waltham, MA, United States., Special Operative Unite (UOS) Oncologia Tumori Genito-urinari, Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy., Istituto Tumori, Department of Medical Oncology, Milan, Italy., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, United States., Department of Pathology and Laboratory Medicine, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, United States., Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, United States.