Genomic characterization of response to chemoradiation in urothelial bladder cancer Journal Article

Authors: Desai, N. B.; Scott, S. N.; Zabor, E. C.; Cha, E. K.; Hreiki, J.; Sfakianos, J. P.; Ramirez, R.; Bagrodia, A.; Rosenberg, J. E.; Bajorin, D. F.; Berger, M. F.; Bochner, B. H.; Zelefsky, M. J.; Kollmeier, M. A.; Ostrovnaya, I.; Al-Ahmadie, H. A.; Solit, D. B.; Iyer, G.
Article Title: Genomic characterization of response to chemoradiation in urothelial bladder cancer
Abstract: BACKGROUND: The authors characterized the genetic landscape of chemoradiation-treated urothelial carcinoma of the bladder (UCB) with the objective of identifying potential correlates of response. METHODS: Primary tumors with (n = 8) or without (n = 40) matched recurrent tumors from 48 patients who had non-metastatic, high-grade UCB and received treatment primarily with chemoradiation were analyzed using a next-generation sequencing assay enriched for cancer-related and canonical DNA damage response (DDR) genes. Protein expression of meiotic recombination 11 homolog (MRE11), a previously suggested biomarker, was assessed in 44 patients. Recurrent tumors were compared with primary tumors, and the clinical impact of likely deleterious DDR gene alterations was evaluated. RESULTS: The profile of alterations approximated that of prior UCB cohorts. Within 5 pairs of matched primary-recurrent tumors, a median of 92% of somatic mutations were shared. A median 33% of mutations were shared between 3 matched bladder-metastasis pairs. Of 26 patients (54%) who had DDR gene alterations, 12 (25%) harbored likely deleterious alterations. In multivariable analysis, these patients displayed a trend toward reduced bladder recurrence (hazard ratio, 0.32; P =.070) or any recurrence (hazard ratio, 0.37; P =.070). The most common of these alterations, ERCC2 (excision repair cross-complementation group 2) mutations, were associated with significantly lower 2-year metastatic recurrence (0% vs 43%; log-rank P =.044). No impact of MRE11 protein expression on outcome was detected. CONCLUSIONS: A similar mutation profile between primary and recurrent tumors suggests that pre-existing, resistant clonal populations represent the primary mechanism of chemoradiation treatment failure. Deleterious DDR genetic alterations, particularly recurrent alterations in ERCC2, may be associated with improved chemoradiation outcomes in patients with UCB. A small sample size necessitates independent validation of these observations. Cancer 2016;122:3715-23. © 2016 American Cancer Society. © 2016 American Cancer Society
Keywords: dna damage response; bladder preservation; radiation resistance; bladder chemoradiation; excision repair cross-complementation group 2 (ercc2)
Journal Title: Cancer
Volume: 122
Issue: 23
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2016-12-01
Start Page: 3715
End Page: 3723
Language: English
DOI: 10.1002/cncr.30219
PROVIDER: scopus
PMCID: PMC5115929
PUBMED: 27479538
Notes: Article -- Export Date: 6 December 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Dean Bajorin
    516 Bajorin
  2. Michael J Zelefsky
    672 Zelefsky
  3. David Solit
    553 Solit
  4. Marisa A Kollmeier
    161 Kollmeier
  5. Gopakumar Vasudeva Iyer
    173 Iyer
  6. Emily Craig Zabor
    162 Zabor
  7. Bernard Bochner
    367 Bochner
  8. Michael Forman Berger
    501 Berger
  9. Jonathan Eric Rosenberg
    310 Rosenberg
  10. Sasinya Neka Scott
    69 Scott
  11. Ricardo   Ramirez
    19 Ramirez
  12. Eugene K. Cha
    68 Cha
  13. Joseph   Hreiki
    5 Hreiki