Genomic differences between “primary” and “secondary” muscle-invasive bladder cancer as a basis for disparate outcomes to cisplatin-based neoadjuvant chemotherapy Journal Article


Authors: 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.; Al-Ahmadie, H.; Bochner, B. H.; Solit, D. B.; Iyer, G.
Article Title: Genomic differences between “primary” and “secondary” muscle-invasive bladder cancer as a basis for disparate outcomes to cisplatin-based neoadjuvant chemotherapy
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. © 2018 European Association of Urology Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). It is unknown whether this treatment strategy is appropriate for patients who progress to MIBC after treatment for prior noninvasive disease (secondary MIBC). Objective: To determine whether clinical and genomic differences exist between primary and secondary MIBC treated with NAC and RC. Design, setting, and participants: Clinicopathologic outcomes were compared between 245 patients with clinical T2-4aN0M0-stage primary MIBC and 43 with secondary MIBC treated with NAC and RC at Memorial Sloan Kettering Cancer Center (MSKCC) from 2001 to 2015. Genomic differences were assessed in a retrospective cohort of 385 prechemotherapy specimens sequenced by whole-exome or targeted exon capture by the Cancer Genome Atlas or at MSKCC. Findings were confirmed in an independent validation cohort of 94 MIBC patients undergoing prospective targeted exon sequencing at MSKCC. Outcome measurements and statistical analysis: Pathologic response rates, recurrence-free survival (RFS), bladder cancer-specific survival (CSS), and overall survival (OS) were measured. Differences in somatic genomic alteration rates were compared using Fisher's exact test and the Benjamini-Hochberg false discovery rate method. Results and limitations: Patients with secondary MIBC had lower pathologic response rates following NAC than those with primary MIBC (univariable: 26% vs 45%, multivariable: odds ratio = 0.4 [95% confidence interval = 0.18 − 0.84] p = 0.02) and significantly worse RFS, CSS, and OS. Patients with secondary MIBC treated with NAC had worse CSS compared with cystectomy alone (p = 0.002). In a separate genomic analysis, we detected significantly more likely deleterious somatic ERCC2 missense mutations in primary MIBC tumors in both the discovery (10.9% [36/330] vs 1.8% [1/55], p = 0.04) and the validation (15.7% [12/70] vs 0% [0/24], p = 0.03) cohort. Conclusions: Patients with secondary MIBC treated with NAC had worse clinical outcomes than similarly treated patients with primary MIBC. ERCC2 mutations predicted to result in increased cisplatin sensitivity were enriched in primary versus secondary MIBC. Prospective validation is still needed, but given the lack of clinical benefit with cisplatin-based NAC in patients with secondary MIBC, upfront RC or enrollment in clinical trials should be considered. Patient summary: A retrospective cohort study of patients with “primary” and “secondary” muscle-invasive bladder cancer (MIBC) treated with chemotherapy before surgical removal of the bladder identified lower response rates and shorter survival in patients with secondary MIBC. Tumor genetic sequencing of separate discovery and validation cohorts revealed that chemotherapy-sensitizing DNA damage repair gene mutations occur predominantly in primary MIBC tumors and may underlie the greater sensitivity of primary MIBC to chemotherapy. Prospective validation is still needed, but patients with secondary MIBC may derive greater benefit from upfront surgery or enrollment in clinical trials rather than from standard chemotherapy. © 2018 European Association of Urology
Keywords: adult; cancer survival; aged; cancer surgery; primary tumor; major clinical study; overall survival; missense mutation; cisplatin; doxorubicin; sunitinib; gemcitabine; methotrexate; outcome assessment; metastasis; cohort analysis; retrospective study; bladder cancer; vinblastine; genome analysis; cancer specific survival; radical cystectomy; cystectomy; genomics; mutation rate; neoadjuvant chemotherapy; recurrence free survival; clinical outcome; muscle invasive bladder cancer; muscle-invasive bladder cancer; human; male; female; priority journal; article; ercc2; non–muscle-invasive bladder cancer
Journal Title: European Urology
Volume: 75
Issue: 2
ISSN: 0302-2838
Publisher: Elsevier Science, Inc.  
Date Published: 2019-02-01
Start Page: 231
End Page: 239
Language: English
DOI: 10.1016/j.eururo.2018.09.002
PUBMED: 30290956
PROVIDER: scopus
PMCID: PMC6339572
DOI/URL:
Notes: Export Date: 1 February 2019 -- Source: Scopus
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MSK Authors
  1. Dean Bajorin
    382 Bajorin
  2. Guido Dalbagni
    246 Dalbagni
  3. David Solit
    420 Solit
  4. Gopakumar Vasudeva Iyer
    121 Iyer
  5. Emily Craig Zabor
    119 Zabor
  6. Bernard Bochner
    315 Bochner
  7. Ahmet Zehir
    145 Zehir
  8. Wenhuo Hu
    28 Hu
  9. Michael Forman Berger
    373 Berger
  10. Maria Eugenia Arcila
    328 Arcila
  11. Harry W Herr
    396 Herr
  12. Nikolaus D Schultz
    193 Schultz
  13. Jonathan Eric Rosenberg
    210 Rosenberg
  14. David   Barron
    6 Barron
  15. Samuel Aaron Funt
    18 Funt
  16. Min Yuen   Teo
    27 Teo
  17. Qiang   Li
    6 Li
  18. Eugene J Pietzak
    17 Pietzak
  19. Joshua   Armenia
    21 Armenia