TY - JOUR
T1 - Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer
AU - Gil-Jimenez, Alberto
AU - van Dorp, Jeroen
AU - Contreras-Sanz, Alberto
AU - van der Vos, Kristan
AU - Vis, Daniel J.
AU - Braaf, Linde
AU - Broeks, Annegien
AU - Kerkhoven, Ron
AU - van Kessel, Kim E. M.
AU - Ribal, María José
AU - Alcaraz, Antonio
AU - Wessels, Lodewyk F. A.
AU - Seiler, Roland
AU - Wright, Jonathan L.
AU - Mengual, Lourdes
AU - Boormans, Joost
AU - van Rhijn, Bas W. G.
AU - Black, Peter C.
AU - van der Heijden, Michiel S.
N1 - Funding Information: Financial disclosures: Michiel S. van der Heijden certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Michiel S. van der Heijden has received institutional research funding from Bristol-Myers Squibb, 4SC, Roche, Astellas Pharma Netherlands and AstraZeneca, and institutional consultancy fees from Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, AstraZeneca, Pfizer, Janssen, and Seattle Genetics. Bas W.G. van Rhijn has participated in advisory boards for AstraZeneca, Ferring, and QED Therapeutics. Lodewyk F.A. Wessels has received institutional research funding from Genmab. Peter C. Black has been a consultant for AbbVie, Astellas Pharma, EMD-Serono, Pfizer, Janssen Oncology, Bayer, Merck, Sanofi Canada, Biosyent, Ferring, Roche Canada, MDxHealth, AstraZeneca, UroGen Pharma, Bristol-Myers Squibb, Fergene, Prokarium, Protara, QED, STIMIT, Theralase, and Verity; has received research funding from iProgen; and shares a patent with Decipher Biosciences. Joost Boormans has received institutional research funding from Decipher and Merck/Pfizer and institutional consultancy fees from Roche, Merck Sharp & Dohme, AstraZeneca, Pfizer, Janssen, AMBU, and Eight Medical. The remaining authors have nothing to disclose. Funding Information: Funding/Support and role of the sponsor: This project was partially funded by the NWO (Dutch Research Council) and financial contributions from DUOS (Duth Uro-oncology group) and Astellas Pharma Netherlands. The sponsor played no direct role in the study. Publisher Copyright: © 2022 European Association of Urology
PY - 2023/4
Y1 - 2023/4
N2 - Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated. Patient summary: It is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.
AB - Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated. Patient summary: It is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.
KW - Cisplatin-based chemotherapy
KW - DNA sequencing
KW - Muscle-invasive bladder cancer
KW - Neoadjuvant chemotherapy
KW - Response prediction
KW - Somatic mutations
UR - http://www.scopus.com/inward/record.url?scp=85136761422&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.eururo.2022.07.023
DO - https://doi.org/10.1016/j.eururo.2022.07.023
M3 - Article
C2 - 35965206
SN - 0302-2838
VL - 83
SP - 313
EP - 317
JO - European Urology
JF - European Urology
IS - 4
ER -