MP58-02 GENOMIC DIFFERENCES BETWEEN “PRIMARY” AND “SECONDARY” MUSCLE INVASIVE BLADDER CANCER: IMPLICATIONS FOR NEOADJUVANT CHEMOTHERAPY

Abstract

You have accessJournal of UrologyBladder Cancer: Invasive V1 Apr 2017MP58-02 GENOMIC DIFFERENCES BETWEEN “PRIMARY” AND “SECONDARY” MUSCLE INVASIVE BLADDER CANCER: IMPLICATIONS FOR NEOADJUVANT CHEMOTHERAPY Eugene Pietzak, Aditya Bagrodia, Hikmat Al-Ahmadie, Harry Herr, Emily Zabor, David Barron, Qiang Li, Francois Audenet, Samuel Funt, Ahmet Zehir, Maria Arcila, Priscilla Baez, Michael Berger, Nikolaus Schultz, David Solit, Dean Bajorin, Jonathan Rosenberg, Eugene Cha, Bernard Bochner, and Gopa Iyer Eugene PietzakEugene Pietzak More articles by this author , Aditya BagrodiaAditya Bagrodia More articles by this author , Hikmat Al-AhmadieHikmat Al-Ahmadie More articles by this author , Harry HerrHarry Herr More articles by this author , Emily ZaborEmily Zabor More articles by this author , David BarronDavid Barron More articles by this author , Qiang LiQiang Li More articles by this author , Francois AudenetFrancois Audenet More articles by this author , Samuel FuntSamuel Funt More articles by this author , Ahmet ZehirAhmet Zehir More articles by this author , Maria ArcilaMaria Arcila More articles by this author , Priscilla BaezPriscilla Baez More articles by this author , Michael BergerMichael Berger More articles by this author , Nikolaus SchultzNikolaus Schultz 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 , Eugene ChaEugene Cha More articles by this author , Bernard BochnerBernard Bochner More articles by this author , and Gopa IyerGopa Iyer More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1797AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We recently reported that patients with secondary muscle-invasive bladder cancer (MIBC) have substantially worse outcomes with neoadjuvant chemotherapy compared to primary MIBC (Pietzak, et al. AUA 2016). We subsequently used next-generation sequencing to investigate genetic differences between primary and secondary MIBC specimens. METHODS We examined MIBC specimens from the Cancer Genome Atlas (TCGA) (n=131), our institutional genomic research database (n=569), and a prospective clinical sequencing protocol (n=214) to identify 342 chemotherapy-naive urothelial MIBC specimens (270 primary and 72 secondary) that underwent whole-exome or targeted exon-capture sequencing. Primary and secondary MIBC specimens were compared for genomic alterations in 341 known cancer genes. Primary MIBC was defined as clinical stage ≥T2 on either initial or re-staging TUR on first bladder tumor diagnosis. Patients with a history of NMIBC (Tis, Ta, or T1 with uninvolved detrusor muscle in specimen) confirmed by a second cystoscopy prior to the eventual diagnosis of clinical stage ≥T2 were considered to have secondary MIBC. RESULTS We compared 270 primary and 72 secondary MIBC specimens for differences in genomic alterations in 341 cancer-associated genes. We identified significantly different rates of ERCC2, APC, and FGFR3 alterations. FGFR3-activating mutations (S249C, Y373C) occurred more frequently in secondary MIBC specimens (18% [13/72] vs. 9% [24/270], p=0.03). APC mutations were only seen in primary MIBC specimens (5% [14/270] vs. 0% [0/72], p=0.047). Surprisingly, ERCC2 missense mutations, which are associated with extreme sensitivity to cisplatin chemotherapy, only occurred in primary MIBC specimens (12% [32/270] vs. 0% [0/72], p<0.001). After adjusting for multiple comparisons using the Benjamini-Hochberg false discovery rate method, only ERCC2 mutations remained significant (adjusted p =0.016). CONCLUSIONS ERCC2 is involved in repair of cisplatin-induced DNA damage, and mutations in ERCC2 are associated with clinical responses to cisplatin. ERCC2 mutations occurred exclusively in primary MIBC patients and may account for their improved outcomes with neoadjuvant chemotherapy compared to secondary MIBC patients. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e772-e773 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Eugene Pietzak More articles by this author Aditya Bagrodia More articles by this author Hikmat Al-Ahmadie More articles by this author Harry Herr More articles by this author Emily Zabor More articles by this author David Barron More articles by this author Qiang Li More articles by this author Francois Audenet More articles by this author Samuel Funt More articles by this author Ahmet Zehir More articles by this author Maria Arcila More articles by this author Priscilla Baez More articles by this author Michael Berger More articles by this author Nikolaus Schultz 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 Eugene Cha More articles by this author Bernard Bochner More articles by this author Gopa Iyer More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...