Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy [Figure presented]

Eugene J. Pietzak; Emily C. Zabor; Aditya Bagrodia; Joshua Armenia; Wenhuo Hu; Ahmet Zehir; Samuel Funt; Francois Audenet; David Barron; Noelia Maamouri; Qiang Li; Min Yuen Teo; Maria E. Arcila; Michael F. Berger; Nikolaus Schultz; Guido Dalbagni; Harry W. Herr; Dean F. Bajorin; Jonathan E. Rosenberg; Hikmat Al-Ahmadie; Bernard H. Bochner; David B. Solit; Gopa Iyer

doi:10.1016/j.eururo.2018.09.002

Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy [Figure presented]

Eugene J. Pietzak, Emily C. Zabor, Aditya Bagrodia, Joshua Armenia, Wenhuo Hu, Ahmet Zehir, Samuel Funt, Francois Audenet, David Barron, Noelia Maamouri, Qiang Li, Min Yuen Teo, Maria E. Arcila, Michael F. Berger, Nikolaus Schultz, Guido Dalbagni, Harry W. Herr, Dean F. Bajorin, Jonathan E. Rosenberg, Hikmat Al-AhmadieBernard H. Bochner, David B. Solit, Gopa Iyer

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

Patients with secondary muscle-invasive bladder cancer (MIBC) treated with neoadjuvant chemotherapy had worse clinical outcomes than patients treated similarly with primary MIBC. These contrasting clinical outcomes may have resulted from differing rates of cisplatin-sensitizing ERCC2 mutations that were enriched in primary MIBC.

Original language	English (US)
Pages (from-to)	231-239
Number of pages	9
Journal	European urology
Volume	75
Issue number	2
DOIs	https://doi.org/10.1016/j.eururo.2018.09.002
State	Published - Feb 2019

Keywords

Bladder cancer
ERCC2
Muscle-invasive bladder cancer
Neoadjuvant chemotherapy
Non–muscle-invasive bladder cancer
Radical cystectomy

ASJC Scopus subject areas

Urology

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10.1016/j.eururo.2018.09.002

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Pietzak, E. J., Zabor, E. C., Bagrodia, A., Armenia, J., Hu, W., Zehir, A., Funt, S., Audenet, F., Barron, D., Maamouri, N., Li, Q., Teo, M. Y., Arcila, M. E., Berger, M. F., Schultz, N., Dalbagni, G., Herr, H. W., Bajorin, D. F., Rosenberg, J. E., ... Iyer, G. (2019). Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy [Figure presented]. European urology, 75(2), 231-239. https://doi.org/10.1016/j.eururo.2018.09.002

Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy [Figure presented]. / Pietzak, Eugene J.; Zabor, Emily C.; Bagrodia, Aditya; Armenia, Joshua; Hu, Wenhuo; Zehir, Ahmet; Funt, Samuel; Audenet, Francois; Barron, David; Maamouri, Noelia; Li, Qiang; Teo, Min Yuen; Arcila, Maria E.; Berger, Michael F.; Schultz, Nikolaus; Dalbagni, Guido; Herr, Harry W.; Bajorin, Dean F.; Rosenberg, Jonathan E.; Al-Ahmadie, Hikmat; Bochner, Bernard H.; Solit, David B.; Iyer, Gopa.

In: European urology, Vol. 75, No. 2, 02.2019, p. 231-239.

Research output: Contribution to journal › Article › peer-review

Pietzak, EJ, Zabor, EC, Bagrodia, A, Armenia, J, Hu, W, Zehir, A, Funt, S, Audenet, F, Barron, D, Maamouri, N, Li, Q, Teo, MY, Arcila, ME, Berger, MF, Schultz, N, Dalbagni, G, Herr, HW, Bajorin, DF, Rosenberg, JE, Al-Ahmadie, H, Bochner, BH, Solit, DB & Iyer, G 2019, 'Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy [Figure presented]', European urology, vol. 75, no. 2, pp. 231-239. https://doi.org/10.1016/j.eururo.2018.09.002

Pietzak, Eugene J. ; Zabor, Emily C. ; Bagrodia, Aditya ; Armenia, Joshua ; Hu, Wenhuo ; Zehir, Ahmet ; Funt, Samuel ; Audenet, Francois ; Barron, David ; Maamouri, Noelia ; Li, Qiang ; Teo, Min Yuen ; Arcila, Maria E. ; Berger, Michael F. ; Schultz, Nikolaus ; Dalbagni, Guido ; Herr, Harry W. ; Bajorin, Dean F. ; Rosenberg, Jonathan E. ; Al-Ahmadie, Hikmat ; Bochner, Bernard H. ; Solit, David B. ; Iyer, Gopa. / Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy [Figure presented]. In: European urology. 2019 ; Vol. 75, No. 2. pp. 231-239.

@article{796af1313cda477fb304cce6ae09bc50,

title = "Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy [Figure presented]",

abstract = "Patients with secondary muscle-invasive bladder cancer (MIBC) treated with neoadjuvant chemotherapy had worse clinical outcomes than patients treated similarly with primary MIBC. These contrasting clinical outcomes may have resulted from differing rates of cisplatin-sensitizing ERCC2 mutations that were enriched in primary MIBC.",

keywords = "Bladder cancer, ERCC2, Muscle-invasive bladder cancer, Neoadjuvant chemotherapy, Non–muscle-invasive bladder cancer, Radical cystectomy",

author = "Pietzak, {Eugene J.} and Zabor, {Emily C.} and Aditya Bagrodia and Joshua Armenia and Wenhuo Hu and Ahmet Zehir and Samuel Funt and Francois Audenet and David Barron and Noelia Maamouri and Qiang Li and Teo, {Min Yuen} and Arcila, {Maria E.} and Berger, {Michael F.} and Nikolaus Schultz and Guido Dalbagni and Herr, {Harry W.} and Bajorin, {Dean F.} and Rosenberg, {Jonathan E.} and Hikmat Al-Ahmadie and Bochner, {Bernard H.} and Solit, {David B.} and Gopa Iyer",

note = "Funding Information: Our results suggest that primary and secondary MIBC have disparate clinical outcomes and differential responses to cisplatin-based NAC. Genomic analysis of chemotherapy-na{\"i}ve specimens reveals that primary MIBC, but not secondary MIBC, is more likely to harbor likely pathogenic ERCC2 mutations predicted to be sensitizing to cisplatin-based chemotherapy. Although cystectomy should ideally be performed before NMIBC progresses to secondary MIBC, the findings of our study suggest that patients with secondary MIBC derive little benefit from current standard cisplatin-based NAC. Further investigation is warranted into whether upfront cystectomy or enrollment into clinical trials of novel agents may be a preferred clinical approach for secondary MIBC. Author contributions : Eugene J. Pietzak had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design : Pietzak, Al-Ahmadie, Bochner, Solit, Iyer. Acquisition of data : Pietzak, Bagrodia, Audenet, Funt, Barron, Maamouri, Li. Analysis and interpretation of data : Pietzak, Zabor, Bagrodia, Armenia, Hu, Zehir, Berger, Schultz, Teo, Dalbagni, Herr, Bajorin, Rosenberg, Al-Ahmadie, Bochner, Solit, Iyer. Drafting of the manuscript : Pietzak, Solit, Iyer. Critical revision of the manuscript for important intellectual content : All authors. Statistical analysis : Zabor. Obtaining funding : Pietzak, Bochner, Solit. Administrative, technical, or material support : Arcila, Berger, Schultz. Supervision : Pietzak, Iyer. Other : None. Financial disclosures: Eugene J. Pietzak 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 (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Pietzak: Scientific Advisory Board: Merck. Berger: Consultant: Roche; Research Support: Illumina. Funt: Research Support: Genentech, AstraZeneca; Stock ownership: Kite Pharma, Urogen Pharma, Allogene Therapeutics, Kronos Bio. Bajorin: Honoraria from the speaker's bureau of Merck; Consultant/advisory board: Merck, Pfizer, Bristol-Myers Squibb, Urogen, Genentech, Eli Lilly. Rosenberg: Stock and Other Ownership Interests: Merck, Illumina; Honoraria: UpToDate, Bristol-Myers Squibb, AstraZeneca, Medscape, Vindico, Peerview, Chugai Pharma; Consulting or Advisory Role: Lilly, Merck, Agensys, Roche/Genentech, Sanofi, AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, Seattle Genetic, Bayer, Inovio Pharmaceuticals, BioClin Therapeutics, QED Therapeutic, Adicet Bio, Sensei Biotherapeutics; Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity; Research Funding: Genentech, Oncogenex, Agensys, Mirati Therapeutics, Novartis, Viralytics, Genentech/Roche, Incyte, Seattle Genetics, Bayer; Travel, Accommodations, Expenses: Genentech/Roche, Bristol-Myers Squibb. Bochner: Chair of data safety monitoring committee: Genentech; Course Instructor: Olympus. Al-Ahmadie: Consultant: Bristol-Myers-Squibb, AstraZeneca, EMD Serono. Solit: Consultant for Pfizer, Loxo Oncology and Illumina. Iyer: Consultant: Bayer. Funding/Support and role of the sponsor : 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-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR-002384, and the National Cancer Institute Cancer Center Core Grant Number P30-CA008748. Acknowledgments: The authors thank Jessica Moore and Carol Hoidra for their editorial assistance with this manuscript. Appendix A ",

year = "2019",

month = feb,

doi = "10.1016/j.eururo.2018.09.002",

language = "English (US)",

volume = "75",

pages = "231--239",

journal = "European Urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "2",

}

TY - JOUR

T1 - Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy [Figure presented]

AU - Pietzak, Eugene J.

AU - Zabor, Emily C.

AU - Bagrodia, Aditya

AU - Armenia, Joshua

AU - Hu, Wenhuo

AU - Zehir, Ahmet

AU - Funt, Samuel

AU - Audenet, Francois

AU - Barron, David

AU - Maamouri, Noelia

AU - Li, Qiang

AU - Teo, Min Yuen

AU - Arcila, Maria E.

AU - Berger, Michael F.

AU - Schultz, Nikolaus

AU - Dalbagni, Guido

AU - Herr, Harry W.

AU - Bajorin, Dean F.

AU - Rosenberg, Jonathan E.

AU - Al-Ahmadie, Hikmat

AU - Bochner, Bernard H.

AU - Solit, David B.

AU - Iyer, Gopa

N1 - Funding Information: Our results suggest that primary and secondary MIBC have disparate clinical outcomes and differential responses to cisplatin-based NAC. Genomic analysis of chemotherapy-naïve specimens reveals that primary MIBC, but not secondary MIBC, is more likely to harbor likely pathogenic ERCC2 mutations predicted to be sensitizing to cisplatin-based chemotherapy. Although cystectomy should ideally be performed before NMIBC progresses to secondary MIBC, the findings of our study suggest that patients with secondary MIBC derive little benefit from current standard cisplatin-based NAC. Further investigation is warranted into whether upfront cystectomy or enrollment into clinical trials of novel agents may be a preferred clinical approach for secondary MIBC. Author contributions : Eugene J. Pietzak had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design : Pietzak, Al-Ahmadie, Bochner, Solit, Iyer. Acquisition of data : Pietzak, Bagrodia, Audenet, Funt, Barron, Maamouri, Li. Analysis and interpretation of data : Pietzak, Zabor, Bagrodia, Armenia, Hu, Zehir, Berger, Schultz, Teo, Dalbagni, Herr, Bajorin, Rosenberg, Al-Ahmadie, Bochner, Solit, Iyer. Drafting of the manuscript : Pietzak, Solit, Iyer. Critical revision of the manuscript for important intellectual content : All authors. Statistical analysis : Zabor. Obtaining funding : Pietzak, Bochner, Solit. Administrative, technical, or material support : Arcila, Berger, Schultz. Supervision : Pietzak, Iyer. Other : None. Financial disclosures: Eugene J. Pietzak 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 (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Pietzak: Scientific Advisory Board: Merck. Berger: Consultant: Roche; Research Support: Illumina. Funt: Research Support: Genentech, AstraZeneca; Stock ownership: Kite Pharma, Urogen Pharma, Allogene Therapeutics, Kronos Bio. Bajorin: Honoraria from the speaker's bureau of Merck; Consultant/advisory board: Merck, Pfizer, Bristol-Myers Squibb, Urogen, Genentech, Eli Lilly. Rosenberg: Stock and Other Ownership Interests: Merck, Illumina; Honoraria: UpToDate, Bristol-Myers Squibb, AstraZeneca, Medscape, Vindico, Peerview, Chugai Pharma; Consulting or Advisory Role: Lilly, Merck, Agensys, Roche/Genentech, Sanofi, AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, Seattle Genetic, Bayer, Inovio Pharmaceuticals, BioClin Therapeutics, QED Therapeutic, Adicet Bio, Sensei Biotherapeutics; Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity; Research Funding: Genentech, Oncogenex, Agensys, Mirati Therapeutics, Novartis, Viralytics, Genentech/Roche, Incyte, Seattle Genetics, Bayer; Travel, Accommodations, Expenses: Genentech/Roche, Bristol-Myers Squibb. Bochner: Chair of data safety monitoring committee: Genentech; Course Instructor: Olympus. Al-Ahmadie: Consultant: Bristol-Myers-Squibb, AstraZeneca, EMD Serono. Solit: Consultant for Pfizer, Loxo Oncology and Illumina. Iyer: Consultant: Bayer. Funding/Support and role of the sponsor : 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-Josée and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR-002384, and the National Cancer Institute Cancer Center Core Grant Number P30-CA008748. Acknowledgments: The authors thank Jessica Moore and Carol Hoidra for their editorial assistance with this manuscript. Appendix A

PY - 2019/2

Y1 - 2019/2

N2 - Patients with secondary muscle-invasive bladder cancer (MIBC) treated with neoadjuvant chemotherapy had worse clinical outcomes than patients treated similarly with primary MIBC. These contrasting clinical outcomes may have resulted from differing rates of cisplatin-sensitizing ERCC2 mutations that were enriched in primary MIBC.

AB - Patients with secondary muscle-invasive bladder cancer (MIBC) treated with neoadjuvant chemotherapy had worse clinical outcomes than patients treated similarly with primary MIBC. These contrasting clinical outcomes may have resulted from differing rates of cisplatin-sensitizing ERCC2 mutations that were enriched in primary MIBC.

KW - Bladder cancer

KW - ERCC2

KW - Muscle-invasive bladder cancer

KW - Neoadjuvant chemotherapy

KW - Non–muscle-invasive bladder cancer

KW - Radical cystectomy

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