Jaegil Kim1, David Kwiatkowski2, David J McConkey3, Joshua J Meeks4, Samuel S Freeman1, Joaquim Bellmunt5, Gad Getz1, Seth P Lerner6. 1. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. 2. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 3. Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA. 4. Department of Urology and Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA. 5. PSMAR-IMIM Laboratory, Bladder Cancer Center, Department of Medicine, Dana-Farber Cancer Institute and Harvard University, Boston, MA, USA. 6. Scott Department of Urology and the Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. Electronic address: slerner@bcm.edu.
Abstract
Analysis of the IMvigor 210 trials involving patients with platinum-refractory or cisplatin-ineligible urothelial carcinoma who were treated with the PD-L1 inhibitor atezolizumab identified a resistance signature as an immune biomarker. Transcriptome profiling of 368 tumor samples from this trial revealed that the "genomically unstable" Lund subtype classification was associated with the best response. We developed and applied a novel single-patient subtype classifier based on The Cancer Genome Atlas 2017 expression-based molecular subtypes. We identified 11 patients with a neuronal subtype, with a 100% response rate in eight confirmed cases (2 complete response, 6 partial response), and 72% overall, including 3/11 patients with an unconfirmed response. The survival probability was extraordinarily high for the neuronal subtype, which represents a high-risk cohort with advanced disease, and may be secondary to low levels of TGFβ expression and high mutation/neoantigen burden. PATIENT SUMMARY: We describe a methodology for genomic classification of an individual patient's bladder cancer tumor and have identified a subtype that is associated with a high response rate to immunotherapy. This is an important step forward in identifying the right treatment for the right patient, which is the goal of personalized precision medicine.
Analysis of the IMvigor 210 trials involving patients with platinum-refractory or cisplatin-ineligible urothelial carcinoma who were treated with the PD-L1 inhibitor atezolizumab identified a resistance signature as an immune biomarker. Transcriptome profiling of 368 tumor samples from this trial revealed that the "genomically unstable" Lund subtype classification was associated with the best response. We developed and applied a novel single-patient subtype classifier based on The Cancer Genome Atlas 2017 expression-based molecular subtypes. We identified 11 patients with a neuronal subtype, with a 100% response rate in eight confirmed cases (2 complete response, 6 partial response), and 72% overall, including 3/11 patients with an unconfirmed response. The survival probability was extraordinarily high for the neuronal subtype, which represents a high-risk cohort with advanced disease, and may be secondary to low levels of TGFβ expression and high mutation/neoantigen burden. PATIENT SUMMARY: We describe a methodology for genomic classification of an individual patient's bladder cancer tumor and have identified a subtype that is associated with a high response rate to immunotherapy. This is an important step forward in identifying the right treatment for the right patient, which is the goal of personalized precision medicine.
Authors: Natalie J Miller; Ali Raza Khaki; Leonidas N Diamantopoulos; Mehmet A Bilen; Victor Santos; Neeraj Agarwal; Rafael Morales-Barrera; Michael Devitt; Ariel Nelson; Christopher J Hoimes; Evan Shreck; Hussein Assi; Benjamin A Gartrell; Alex Sankin; Alejo Rodriguez-Vida; Mark Lythgoe; David J Pinato; Alexandra Drakaki; Monika Joshi; Pedro Isaacsson Velho; Noah Hahn; Sandy Liu; Lucia Alonso Buznego; Ignacio Duran; Marcus Moses; Jayanshu Jain; Jure Murgic; Pedro Barata; Abhishek Tripathi; Yousef Zakharia; Matthew D Galsky; Guru Sonpavde; Evan Y Yu; Gary H Lyman; Petros Grivas Journal: J Urol Date: 2020-01-23 Impact factor: 7.450