Pd47-02 “actionable” Genomic Alterations in Chemotherapy Resistant Muscle-invasive Bladder Cancer
Year: 2020
Type: article
Abstract: You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV (PD47)1 Apr 2020PD47-02 “ACTIONABLE” GENOMIC ALTERATIONS IN CHEMOTHERAPY RESISTANT MUSCLE-INVASIVE BLADDER CANCER Leon Telis*, Timothy Clinton, Nima Almassi, Min Yuen Teo, Samuel Funt, Timothy Donahue, Nikolaus Schultz, Michael Berger, Hikmat Al-Ahmadie, David Solit, Dean Bajorin, Jonathan Rosenberg, Guido Dalbagni, Bernard Bochner, Gopa Iyer, and Eugene Pietzak Leon Telis*Leon Telis* More articles by this author , Timothy ClintonTimothy Clinton More articles by this author , Nima AlmassiNima Almassi More articles by this author , Min Yuen TeoMin Yuen Teo More articles by this author , Samuel FuntSamuel Funt More articles by this author , Timothy DonahueTimothy Donahue More articles by this author , Nikolaus SchultzNikolaus Schultz More articles by this author , Michael BergerMichael Berger More articles by this author , Hikmat Al-AhmadieHikmat Al-Ahmadie More articles by this author , David SolitDavid Solit More articles by this author , Dean BajorinDean Bajorin More articles by this author , Jonathan RosenbergJonathan Rosenberg More articles by this author , Guido DalbagniGuido Dalbagni More articles by this author , Bernard BochnerBernard Bochner More articles by this author , Gopa IyerGopa Iyer More articles by this author , and Eugene PietzakEugene Pietzak More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000934.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The standard of care for muscle invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy. Patients with residual MIBC after NAC have a poor prognosis. There are currently several large adjuvant clinical trials ongoing for immune checkpoint inhibitors, however <25% of patients have a durable response to immunotherapy. Recently, Erdafitinib, an oral small molecular inhibitor of FGFR1-4, was the first targeted therapy approved for patients with locally advanced or metastatic urothelial carcinoma . Here, we analyze the genomic landscape of actionable alterations in chemotherapy resistant tumors that may aid in patient selection for adjuvant treatments and guide the rationale for development of targeted therapy. METHODS: We identified patients who completed all four cycles of planned Gemcitabine and Cisplatin NAC followed by RC at our institution and were also enrolled on a prospective IRB-approved protocol for which targeted exon capture sequencing (MSK-IMPACT) was performed on post-chemotherapy tumor DNA. Of those patients, we identified those with >/=T2 disease or any lymph node positive disease. Actionable genomic alterations including somatic mutations and structural alterations that predict response to targeted drug therapy were identified and stratified by level of evidence using OncoKB. RESULTS: We identified 201 patients with muscle invasive UCC who underwent 4 cycles of neaoadjuvant gemcitabine/cisplatin chemotherapy and then found to have chemorefractory disease. 25 of these patients underwent sequencing of a post-chemotherapy specimen. IMPACT sequencing revealed one or more actionable alterations in 15 specimens (60%). In total 31 actionable alterations were identified, with 4 (16%) having an FGFR3 alteration, consistent with level 1 evidence for targeted drug therapy. There were also 3 separate specimens (12%) harboring alterations in CDK4, ERBB2 and TSC2 with level 2 evidence, which reflects alterations predictive of response to an FDA-approved drug in another indication. No patients had a level 3 alteration. There were 24 alterations (77%) were level 4 supported by compelling biologic evidence for response to targeted therapy. CONCLUSIONS: With the recent approval of FGFR3 inhibitors, there now exists OncoKB level 1 evidence for those with FGFR2/3 alterations, which are highly prevalent in urothelial carcinoma. There are multiple other potentially actionable alterations in chemotherapy-resistant MIBC that may provide rationale for future studies utilizing novel targeted therapies. Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Michael and Zena Wiener for Therapeutics Program in Bladder Cancer, Pin Down Bladder Cancer, Cycle for Survival, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR002384, the National Cancer Institute Cancer Center Core Grant Number P30-CA008748, MSKCC SPORE in Bladder Cancer P50-CA221745, NIH/NCI K12 Paul Calabresi Career Development Award for Clinical Oncology (K12 CA184746) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e925-e926 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Leon Telis* More articles by this author Timothy Clinton More articles by this author Nima Almassi More articles by this author Min Yuen Teo More articles by this author Samuel Funt More articles by this author Timothy Donahue More articles by this author Nikolaus Schultz More articles by this author Michael Berger More articles by this author Hikmat Al-Ahmadie More articles by this author David Solit More articles by this author Dean Bajorin More articles by this author Jonathan Rosenberg More articles by this author Guido Dalbagni More articles by this author Bernard Bochner More articles by this author Gopa Iyer More articles by this author Eugene Pietzak More articles by this author Expand All Advertisement PDF downloadLoading ...
Source: The Journal of Urology
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3021867744