Genomic characterization of response to chemoradiation in urothelial bladder cancer

Neil B. Desai, Sasinya N. Scott, Emily C. Zabor, Eugene K. Cha, Joseph Hreiki, John P. Sfakianos, Ricardo Ramirez, Aditya Bagrodia, Jonathan E. Rosenberg, Dean F. Bajorin, Michael F. Berger, Bernard H. Bochner, Michael J. Zelefsky, Marisa A. Kollmeier, Irina Ostrovnaya, Hikmat A. Al-Ahmadie, David B. Solit, Gopa Iyer

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3715-3723
Number of pages9
JournalCancer
Volume122
Issue number23
DOIs
StatePublished - Dec 1 2016

Fingerprint

Urinary Bladder Neoplasms
Urinary Bladder
DNA Damage
Neoplasms
Carcinoma
Mutation
Recurrence
DNA Repair
Genetic Recombination
Genes
Treatment Failure
Sample Size
Proteins
Biomarkers
Neoplasm Metastasis
Population

Keywords

  • bladder chemoradiation
  • bladder preservation
  • DNA damage response
  • excision repair cross-complementation group 2 (ERCC2)
  • radiation resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Desai, N. B., Scott, S. N., Zabor, E. C., Cha, E. K., Hreiki, J., Sfakianos, J. P., ... Iyer, G. (2016). Genomic characterization of response to chemoradiation in urothelial bladder cancer. Cancer, 122(23), 3715-3723. https://doi.org/10.1002/cncr.30219

Genomic characterization of response to chemoradiation in urothelial bladder cancer. / Desai, Neil B.; Scott, Sasinya N.; Zabor, Emily C.; Cha, Eugene K.; Hreiki, Joseph; Sfakianos, John P.; Ramirez, Ricardo; Bagrodia, Aditya; Rosenberg, Jonathan E.; Bajorin, Dean F.; Berger, Michael F.; Bochner, Bernard H.; Zelefsky, Michael J.; Kollmeier, Marisa A.; Ostrovnaya, Irina; Al-Ahmadie, Hikmat A.; Solit, David B.; Iyer, Gopa.

In: Cancer, Vol. 122, No. 23, 01.12.2016, p. 3715-3723.

Research output: Contribution to journalArticle

Desai, NB, Scott, SN, Zabor, EC, Cha, EK, Hreiki, J, Sfakianos, JP, Ramirez, R, Bagrodia, A, Rosenberg, JE, Bajorin, DF, Berger, MF, Bochner, BH, Zelefsky, MJ, Kollmeier, MA, Ostrovnaya, I, Al-Ahmadie, HA, Solit, DB & Iyer, G 2016, 'Genomic characterization of response to chemoradiation in urothelial bladder cancer', Cancer, vol. 122, no. 23, pp. 3715-3723. https://doi.org/10.1002/cncr.30219
Desai NB, Scott SN, Zabor EC, Cha EK, Hreiki J, Sfakianos JP et al. Genomic characterization of response to chemoradiation in urothelial bladder cancer. Cancer. 2016 Dec 1;122(23):3715-3723. https://doi.org/10.1002/cncr.30219
Desai, Neil B. ; Scott, Sasinya N. ; Zabor, Emily C. ; Cha, Eugene K. ; Hreiki, Joseph ; Sfakianos, John P. ; Ramirez, Ricardo ; Bagrodia, Aditya ; Rosenberg, Jonathan E. ; Bajorin, Dean F. ; Berger, Michael F. ; Bochner, Bernard H. ; Zelefsky, Michael J. ; Kollmeier, Marisa A. ; Ostrovnaya, Irina ; Al-Ahmadie, Hikmat A. ; Solit, David B. ; Iyer, Gopa. / Genomic characterization of response to chemoradiation in urothelial bladder cancer. In: Cancer. 2016 ; Vol. 122, No. 23. pp. 3715-3723.
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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.",
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T1 - Genomic characterization of response to chemoradiation in urothelial bladder cancer

AU - Desai, Neil B.

AU - Scott, Sasinya N.

AU - Zabor, Emily C.

AU - Cha, Eugene K.

AU - Hreiki, Joseph

AU - Sfakianos, John P.

AU - Ramirez, Ricardo

AU - Bagrodia, Aditya

AU - Rosenberg, Jonathan E.

AU - Bajorin, Dean F.

AU - Berger, Michael F.

AU - Bochner, Bernard H.

AU - Zelefsky, Michael J.

AU - Kollmeier, Marisa A.

AU - Ostrovnaya, Irina

AU - Al-Ahmadie, Hikmat A.

AU - Solit, David B.

AU - Iyer, Gopa

PY - 2016/12/1

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N2 - 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.

AB - 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.

KW - bladder chemoradiation

KW - bladder preservation

KW - DNA damage response

KW - excision repair cross-complementation group 2 (ERCC2)

KW - radiation resistance

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