Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

Elizabeth R. Plimack, Roland L. Dunbrack, Timothy A. Brennan, Mark D. Andrake, Yan Zhou, Ilya G. Serebriiskii, Michael Slifker, Katherine Alpaugh, Essel Dulaimi, Norma Palma, Jean Hoffman-Censits, Marijo Bilusic, Yu Ning Wong, Alexander Kutikov, Rosalia Viterbo, Richard E. Greenberg, David Y.T. Chen, Costas D. Lallas, Edouard J. Trabulsi, Roman YelenskyDavid McConkey, Vincent A. Miller, Erica A. Golemis, Eric A. Ross

Research output: Contribution to journalArticle

Abstract

Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p = 0.024) and validation (p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p < 0.001; 87% sensitivity, 100% specificity) and better overall survival (p = 0.007). This test remained predictive for pathologic response in the validation set (p = 0.033), with a trend towards better overall survival (p = 0.055). These results require further validation in additional sample sets. Conclusions Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

Original languageEnglish (US)
Pages (from-to)959-967
Number of pages9
JournalEuropean Urology
Volume68
Issue number6
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Urinary Bladder Neoplasms
DNA Repair
Cisplatin
Drug Therapy
Muscles
Genes
Cystectomy
Biomarkers
Neoplasms
Survival
Neoplasm Genes
Residual Neoplasm
Standard of Care
Exons
Urinary Bladder
Clinical Trials
Sensitivity and Specificity
Mutation
DNA

Keywords

  • ATM
  • Biomarkers
  • Bladder cancer
  • Cisplatin resistance
  • Cisplatin sensitivity
  • DNA repair
  • FANCC
  • Neoadjuvant chemotherapy
  • RB1
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Urology

Cite this

Plimack, E. R., Dunbrack, R. L., Brennan, T. A., Andrake, M. D., Zhou, Y., Serebriiskii, I. G., ... Ross, E. A. (2015). Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. European Urology, 68(6), 959-967. https://doi.org/10.1016/j.eururo.2015.07.009

Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. / Plimack, Elizabeth R.; Dunbrack, Roland L.; Brennan, Timothy A.; Andrake, Mark D.; Zhou, Yan; Serebriiskii, Ilya G.; Slifker, Michael; Alpaugh, Katherine; Dulaimi, Essel; Palma, Norma; Hoffman-Censits, Jean; Bilusic, Marijo; Wong, Yu Ning; Kutikov, Alexander; Viterbo, Rosalia; Greenberg, Richard E.; Chen, David Y.T.; Lallas, Costas D.; Trabulsi, Edouard J.; Yelensky, Roman; McConkey, David; Miller, Vincent A.; Golemis, Erica A.; Ross, Eric A.

In: European Urology, Vol. 68, No. 6, 2015, p. 959-967.

Research output: Contribution to journalArticle

Plimack, ER, Dunbrack, RL, Brennan, TA, Andrake, MD, Zhou, Y, Serebriiskii, IG, Slifker, M, Alpaugh, K, Dulaimi, E, Palma, N, Hoffman-Censits, J, Bilusic, M, Wong, YN, Kutikov, A, Viterbo, R, Greenberg, RE, Chen, DYT, Lallas, CD, Trabulsi, EJ, Yelensky, R, McConkey, D, Miller, VA, Golemis, EA & Ross, EA 2015, 'Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer', European Urology, vol. 68, no. 6, pp. 959-967. https://doi.org/10.1016/j.eururo.2015.07.009
Plimack, Elizabeth R. ; Dunbrack, Roland L. ; Brennan, Timothy A. ; Andrake, Mark D. ; Zhou, Yan ; Serebriiskii, Ilya G. ; Slifker, Michael ; Alpaugh, Katherine ; Dulaimi, Essel ; Palma, Norma ; Hoffman-Censits, Jean ; Bilusic, Marijo ; Wong, Yu Ning ; Kutikov, Alexander ; Viterbo, Rosalia ; Greenberg, Richard E. ; Chen, David Y.T. ; Lallas, Costas D. ; Trabulsi, Edouard J. ; Yelensky, Roman ; McConkey, David ; Miller, Vincent A. ; Golemis, Erica A. ; Ross, Eric A. / Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. In: European Urology. 2015 ; Vol. 68, No. 6. pp. 959-967.
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title = "Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer",
abstract = "Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50{\%} of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p = 0.024) and validation (p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p < 0.001; 87{\%} sensitivity, 100{\%} specificity) and better overall survival (p = 0.007). This test remained predictive for pathologic response in the validation set (p = 0.033), with a trend towards better overall survival (p = 0.055). These results require further validation in additional sample sets. Conclusions Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.",
keywords = "ATM, Biomarkers, Bladder cancer, Cisplatin resistance, Cisplatin sensitivity, DNA repair, FANCC, Neoadjuvant chemotherapy, RB1, Urothelial carcinoma",
author = "Plimack, {Elizabeth R.} and Dunbrack, {Roland L.} and Brennan, {Timothy A.} and Andrake, {Mark D.} and Yan Zhou and Serebriiskii, {Ilya G.} and Michael Slifker and Katherine Alpaugh and Essel Dulaimi and Norma Palma and Jean Hoffman-Censits and Marijo Bilusic and Wong, {Yu Ning} and Alexander Kutikov and Rosalia Viterbo and Greenberg, {Richard E.} and Chen, {David Y.T.} and Lallas, {Costas D.} and Trabulsi, {Edouard J.} and Roman Yelensky and David McConkey and Miller, {Vincent A.} and Golemis, {Erica A.} and Ross, {Eric A.}",
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pages = "959--967",
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TY - JOUR

T1 - Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

AU - Plimack, Elizabeth R.

AU - Dunbrack, Roland L.

AU - Brennan, Timothy A.

AU - Andrake, Mark D.

AU - Zhou, Yan

AU - Serebriiskii, Ilya G.

AU - Slifker, Michael

AU - Alpaugh, Katherine

AU - Dulaimi, Essel

AU - Palma, Norma

AU - Hoffman-Censits, Jean

AU - Bilusic, Marijo

AU - Wong, Yu Ning

AU - Kutikov, Alexander

AU - Viterbo, Rosalia

AU - Greenberg, Richard E.

AU - Chen, David Y.T.

AU - Lallas, Costas D.

AU - Trabulsi, Edouard J.

AU - Yelensky, Roman

AU - McConkey, David

AU - Miller, Vincent A.

AU - Golemis, Erica A.

AU - Ross, Eric A.

PY - 2015

Y1 - 2015

N2 - Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p = 0.024) and validation (p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p < 0.001; 87% sensitivity, 100% specificity) and better overall survival (p = 0.007). This test remained predictive for pathologic response in the validation set (p = 0.033), with a trend towards better overall survival (p = 0.055). These results require further validation in additional sample sets. Conclusions Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

AB - Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p = 0.024) and validation (p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p < 0.001; 87% sensitivity, 100% specificity) and better overall survival (p = 0.007). This test remained predictive for pathologic response in the validation set (p = 0.033), with a trend towards better overall survival (p = 0.055). These results require further validation in additional sample sets. Conclusions Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

KW - ATM

KW - Biomarkers

KW - Bladder cancer

KW - Cisplatin resistance

KW - Cisplatin sensitivity

KW - DNA repair

KW - FANCC

KW - Neoadjuvant chemotherapy

KW - RB1

KW - Urothelial carcinoma

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U2 - 10.1016/j.eururo.2015.07.009

DO - 10.1016/j.eururo.2015.07.009

M3 - Article

C2 - 26238431

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SP - 959

EP - 967

JO - European Urology

JF - European Urology

SN - 0302-2838

IS - 6

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