Validation of the prognostic value of NF-κB p65 in prostate cancer: A retrospective study using a large multi-institutional cohort of the Canadian Prostate Cancer Biomarker Network

Abstract

Background The identification of patients with high-risk prostate cancer (PC) is a major challenge for clinicians, and the improvement of current prognostic parameters is an unmet clinical need. We and others have identified an association between the nuclear localization of NF-κB p65 and biochemical recurrence (BCR) in PC in small and/or single-centre cohorts of patients. Methods and findings In this study, we accessed 2 different multi-centre tissue microarrays (TMAs) representing cohorts of patients (Test-TMA and Validation-TMA series) of the Canadian Prostate Cancer Biomarker Network (CPCBN) to validate the association between p65 nuclear frequency and PC outcomes. Immunohistochemical staining of p65 was performed on the Test-TMA and Validation-TMA series, which include PC tissues from patients treated by first-line radical prostatectomy ( n = 250 and n = 1,262, respectively). Two independent observers evaluated the p65 nuclear frequency in digital images of cancer tissue and benign adjacent gland tissue. Kaplan–Meier curves coupled with a log-rank test and univariate and multivariate Cox regression models were used for statistical analyses of continuous values and dichotomized data (cutoff of 3%). Multivariate analysis of the Validation-TMA cohort showed that p65 nuclear frequency in cancer cells was an independent predictor of BCR using continuous (hazard ratio [HR] 1.02 [95% CI 1.00–1.03], p = 0.004) and dichotomized data (HR 1.33 [95% CI 1.09–1.62], p = 0.005). Using a cutoff of 3%, we found that this biomarker was also associated with the development of bone metastases (HR 1.82 [95% CI 1.05–3.16], p = 0.033) and PC-specific mortality (HR 2.63 [95% CI 1.30–5.31], p = 0.004), independent of clinical parameters. BCR-free survival, bone-metastasis-free survival, and PC-specific survival were shorter for patients with higher p65 nuclear frequency ( p < 0.005). As the small cores on TMAs are a limitation of the study, a backward validation of whole PC tissue section will be necessary for the implementation of p65 nuclear frequency as a PC biomarker in the clinical workflow. Conclusions We report the first study using the pan-Canadian multi-centre cohorts of CPCBN and validate the association between increased frequency of nuclear p65 frequency and a risk of disease progression.

Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifiesERGas the strongest independent predictor of recurrence

“…Recently, three studies evaluated the prognostic value of selected biomarkers for association with biochemical recurrence as an indicator for prostate cancer progression. Grosset and colleagues examined two tissue microarrays, representing test and validation cohorts, for the association of nuclear NF-kB p65 with BCR, development of bone metastasis and prostate cancer-specific death [85]. They showed, by multivariate analysis, that p65 nuclear localization was an independent predictor for BCR using continuous (Hazard ratio [HR] 1.03; 95% Confidence interval [CI] 1.02–1.04]; p < 0.001) and dichotomized (HR 1.60; 95% CI 1.32–1.94; p < 0.001) p65 expression data in the validation cohort.…”

“…Furthermore, while the racial or ethnic status of the patient cohort were not defined in these recently published studies, our study is based on a diverse patient cohort, consisting of approximately 70% CA and 30% AA patients. Moreover, in evaluating the predictive value of detecting ERG for BCR, our study we not only used the NanoString platform, but we compared it to IHC and qRT-PCR, whereas only IHC [85, 86] or IHC and FISH [87] were used in the other studies. Lastly, we evaluated a total of 121 genes or gene alteration events for association with progression to BCR while the other studies examined the association of either a single biomarker [85], or two interacting proteins [86], or protein expression and copy number amplification associated with a single gene [87].…”

Elevated Expression of Glycerol-3-phosphate Phosphatase as a Biomarker of Poor Prognosis and Aggressive Prostate Cancer

“…The TF123-TMA cohort is composed of 285 treatment naïve PC patients who signed an informed consent to participate in the Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) PC biobank, a liated to the Cancer Research Network (RRCancer) (13)(14)(15)(16). These patients underwent radical All patients signed an informed consent for the use of their prostate tissue samples in research.…”

“…We rst studied the expression of G3PP in the TF123 cohort and then examined the CPCBN-TMA series (13)(14)(15)(16). Clinicopathological characteristics of PC patients in each cohort are presented in Table 1.…”

Grading Evolution and Contemporary Prognostic Biomarkers of Clinically Significant Prostate Cancer

“…A multi-institutional study showed that elevated nuclear frequency of p65 (a NF-κB subunit), as measured by IHC, is an independently significant prognostic factor of development of bone metastasis and PCa-related death after RP [ 44 ]. Different subunits of NF-κB function with various mechanisms regulating tumor initiation and growth, one of which is immunological environment regulation.…”