Abstract
Background
Combination platinum chemotherapy is standard first-line therapy for metastatic urothelial
carcinoma (mUC). Defining the platinum response biomarkers for patients with mUC could
establish personalize medicine and provide insights into mUC biology. Although DNA
repair mechanisms have been hypothesized to mediate the platinum response, we sought
to analyze whether increased expression of DNA damage genes would correlate with worse
overall survival (OS) in patients with mUC.
Patients and Methods
We retrospectively identified a clinically annotated cohort of patients with mUC,
who had been treated with first-line platinum combination chemotherapy. A tissue microarray
was constructed from formalin-fixed paraffin-embedded tissue from the primary tumor
before treatment. Immunohistochemical analysis of the following DNA repair proteins
was performed: ERCC1, RAD51, BRCA1/2, PAR, and PARP-1. Nuclear and cytoplasmic expression
was analyzed using multispectral imaging. Nuclear staining was used for the survival
analysis. Cox regression analysis was used to evaluate the associations between the
percentage of positive nuclear staining and OS in multivariable analysis, controlling
for known prognostic variables.
Results
In a cohort of 104 patients with mUC, a greater percentage of nuclear staining of
ERCC1 (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-4.9; P = .0007), RAD51 (HR, 5.6; 95% CI, 1.7-18.3; P = .005), and PAR (HR, 2.2; 95% CI, 1.1-4.4; P = .026) was associated with worse OS. BRCA1, BRCA2, and PARP-1 expression was not
associated with OS (P = .76, P = .38, and P = .09, respectively). A greater percentage of combined ERCC1 and RAD51 nuclear staining
was strongly associated with worse OS (P = .005).
Conclusion
A high percentage of nuclear staining of ERCC1, RAD51, and PAR, assessed by immunohistochemistry,
correlated with worse OS for patients with mUC treated with first-line platinum combination
chemotherapy, supporting the evidence of the DNA repair pathways' role in the prognosis
of mUC. We also report new evidence that RAD51 and PAR might play a role in the platinum
response. Additional prospective studies are required to determine the prognostic
or predictive nature of these biomarkers in mUC.
Keywords
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Article info
Publication history
Published online: December 24, 2015
Accepted:
December 19,
2015
Received in revised form:
December 17,
2015
Received:
October 9,
2015
Identification
Copyright
© 2015 Elsevier Inc. All rights reserved.
