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Int J Radiat Oncol Biol Phys. Author manuscript; available in PMC 2014 August 01.
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Int J Radiat Oncol Biol Phys. 2013 August 1; 86(5): 848–853. doi:10.1016/j.ijrobp.2013.04.043.
Prognostic utility of CCP score in men with prostate cancer after

primary external beam radiation therapy
Stephen Freedland, MD1, Leah Gerber, MS1, Julia Reid, MStat2, William Welbourn, PhD2,
Eliso Tikishvili, MD2, Jimmy Park, BS2, Adib Younus, BS2, Alexander Gutin, PhD2, Zaina
Sangale, MD2, Jerry S. Lanchbury, PhD2, Joseph K. Salama, MD3, and Steven Stone, PhD2
1Department of Surgery, Durham VA Medical Center, and Departments of Surgery (Urology) and
Pathology, Duke University School of Medicine, Durham, NC

2Myriad Genetics, Inc., 320 Wakara Way, Salt Lake City UT
3Department of Radiation Oncology, Durham VA Medical Center and Department of Radiation
Oncology, Duke University, Durham, NC
Abstract
Purpose—The cell cycle progression (CCP) score, a prognostic RNA signature based on the
average expression level of 31 CCP genes, has been shown to predict biochemical recurrence
(BCR) after prostatectomy and prostate cancer specific mortality in men undergoing observation.
However, the value of the CCP score in men who received primary external beam radiation
therapy (EBRT) is untested.
Methods and Materials—The CCP score was derived retrospectively from diagnostic biopsy
specimens of men diagnosed with prostate cancer from 1991 to 2006 (n=141). All patients were
treated with definitive EBRT; approximately half of the cohort was African-American. Outcome
was time from EBRT to BCR using the Phoenix definition. Median follow-up for patients without
BCR was 4.8 years. Association with outcome was evaluated by CoxPH survival analysis and
likelihood ratio tests.
Results—Of 141 patients, 19 (13%) had BCR. The median CCP score for patient samples was
0.12. In univariable analysis, CCP score significantly predicted BCR (p-value = 0.0017). The
hazard ratio (HR) for BCR was 2.55 for a one-unit increase in CCP score (equivalent to a doubling
of gene expression). In a multivariable analysis with Gleason score, PSA, percent positive cores,
and androgen deprivation therapy, the HR for CCP remained significant (p-value = 0.034),
indicating that CCP provides prognostic information that is not provided by standard clinical
parameters. With 10-year censoring, the CCP score was associated with prostate cancer specific
mortality (p-value = 0.013). There was no evidence for interaction between CCP and any clinical
variable, including ethnicity.
Correspondence: Stephen J. Freedland, MD, Division of Urology, DUMC, Box 2626, Duke University School of Medicine, Durham,
NC 27710; Phone: (919) 668-5946; Fax: (919) 668-7093; steve.freedland@duke.edu.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
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Conflicts of Interest Notification
A potential conflict of interest does exist since employees of Myriad Genetics, Inc. have received salary and stock from Myriad
Genetics, Inc. The other authors, not employed by Myriad Genetics, Inc., do not have a conflict of interest since they have not
received payment from Myriad Genetics, Inc.
Freedland et al. Page 2
Conclusions—Among men treated with EBRT, the CCP score significantly predicated outcome
and provided greater prognostic information than was available with clinical parameters. If
validated in a larger cohort, CCP score could identify high-risk men undergoing EBRT who may
need more aggressive therapy.
Keywords
CCP; radiation; biomarkers
Introduction
For men with newly diagnosed prostate cancer, accurate risk stratification enables
appropriate clinical management. Currently, clinical parameters such as Gleason score,
serum PSA, and clinical T stage provide some prognostic information. For men identified
with low-risk disease, active surveillance or other deferred intervention regimens may be the
best choice (1). Alternatively, for men with intermediate and high-risk disease, curative
therapy is warranted. However, within all of these risk groups, there is heterogeneity of
clinical outcomes. Therefore, improved discrimination would be useful to determine optimal
therapy for all patients.
For men treated with external beam radiation therapy (EBRT), existing prognostic models
are hindered by the fact that the tumor is not removed, precluding accurate ascertainment of
stage, grade and tumor volume (2). Moreover, no prognostic biomarkers with the exception
of PSA have proven sufficiently informative to impact clinical care. About 30% of the
patients treated with definitive ERBT progress biochemically. If these patients could be
identified at diagnosis, they might benefit from more aggressive therapies (e.g. EBRT with
brachytherapy boost) (3) and/or concurrent administration of systemic therapies like
androgen deprivation. However, as more intensive therapies also result in unwanted
morbidities they should be avoided in men who are likely to be controlled following EBRT
alone. As such, accurate assessment of the risk of biochemical progression is crucial to
provide optimal clinical care.
Recently, we developed a prognostic RNA signature that helps characterize prostate cancer
aggressiveness (4,5). The signature is based on determining the expression levels of cell
cycle progression (CCP) genes, and likely measures the fraction of tumor cells that are
actively dividing. Since the signature is based on fundamental cancer biology, it potentially
provides prognostic information in many different clinical settings. In fact, the signature has
been associated with adverse outcome in conservatively managed cohorts from the UK and
in surgically treated cohorts from the U.S. (4,5). However, its ability to predict outcome
after EBRT is untested. Here, we evaluated the prognostic utility of the CCP score for
predicting biochemical recurrence (BCR) in men treated with EBRT as their primary
curative therapy. We hypothesized that high CCP score would be correlated with poor
outcome (i.e. BCR) and that this association would hold even after controlling for standard
clinical characteristics.
Methods and Materials

Cohort
Patients were included if they underwent diagnostic biopsy for prostate cancer between 1991
and 2006, and were treated with definitive EBRT (either alone or in combination with
ADT). Patients without available formalin-fixed and paraffin embedded (FFPE) blocks
containing their original diagnostic biopsy were excluded. Additional predefined exclusion
criteria were pre-treatment PSA greater than 100 ng/ml and patients who began treatment >
2 years after diagnostic biopsy. Finally, patients with follow up data for less than 3 years
who had not developed BCR within this time frame were excluded.
Sample preparation and real-time PCR

FFPE biopsy tumor blocks underwent pathological evaluation. The original diagnostic
hematoxylin and eosin stained tissue sections from each block were evaluated for tumor
content. The tumor area was identified, measured (length in mm), and circled. Based on the
tumor length, additional unstained 10μm sections of tissue were cut so that at least 20 mm
of total tumor (mm on H&E × # slides) were used for subsequent RNA isolation.
Selected tumor regions were removed from the unstained slides by macro-dissection
according to pathologist’s instructions. The tumor region was dissected directly into a
centrifuge tube and the paraffin removed using xylene and washed with ethanol. Samples
were treated overnight with proteinase K digestion at 55°C. Total RNA was extracted using
miRNeasy (Qiagen) as described by the manufacturer (with the exception of the extended
proteinase K digestion). Isolated total RNA was treated with DNase I (Sigma) prior to
cDNA synthesis. High-capacity cDNA Archive Kit (Applied Biosystems) was used to
convert total RNA into single strand cDNA as described by manufacturer. Prior to
measuring expression levels, the cDNA was pre-amplified with a pooled reaction containing
31 CCP and 15 housekeeping (HK) gene TaqMan assays. Pre-amplification reaction
conditions were: 95°C for 10 min, 95°C for 15sec and 60°C for 14 cycles and dilute 1:20
using the 1XTE buffer prior to loading on Taqman Low Density Arrays (TLDA, Applied
Biosystems) to measure gene expression. All samples were run in triplicate.
CCP score calculation

The CCP score was calculated from the expression data of 31 CCP genes normalized by the
expression of 15 HK genes as previously described (4). CCP scores were rejected if more
than 9 CCP genes were missing (n=5), or if the standard deviation of the CCP scores within
the triplicate was greater than 0.5 (n=2; these two CCP scores were also part of the group of
CCP scores rejected due to missing genes).
Statistical Analysis
Survival analysis was carried out using Cox proportional hazards (PH) models, to assess the
association between the CCP score as a continuous variable and risk of BCR. The primary
endpoint was time to BCR event. BCR was defined as reaching a post-RT PSA of nadir +
2ng/ml (Phoenix criteria, 23 patients), or due to secondary treatment for a rising PSA prior
to meeting the Phoenix definition (5 patients). Prostate cancer specific mortality was defined
as death in any patient with metastases showing progression following ADT. Time zero was
defined as the start of radiation, and observations were censored on the date of last follow-
up or death. The majority of the analysis is based upon 5-year censoring to address the
observed time dependence of hazard ratio (HR) for CCP and the fact that BCR after 5-years
post-RT may be less clinically relevant. The exception was analysis of disease-specific
mortality, which was based on 10-year censoring due to the longer time frame required to
observe disease-related mortality. The clinical and demographic variables recorded were age
at diagnosis, ethnicity (African-American, White, Asian, Hispanic, Other), baseline PSA,
clinical stage, Gleason score, concurrent hormone use, percent positive cores, year of
biopsy, and radiation dose. We also used a modified D’Amico risk classification (6) to
stratify patient risk. Low-risk was defined as PSA <10 and Gleason <7, intermediate risk as
PSA 10–20 or Gleason 7, and high-risk as PSA >20 or Gleason 8–10 disease. All CCP
scores were assigned prior to unmasking the clinical and outcome data.
PSA concentration was modeled as the natural logarithm of 1 + PSA (ng/ml) to account for
the right-skewed distribution of PSA values. In addition, 1 was added to PSA prior to
transformation to prevent men with low PSA levels from having negative numbers. Gleason
scores were grouped into three categories: less than 7, equal to 7, and greater than 7. Models
were fitted with Gleason score considered as a three-level nominal categorical variable. All
test statistics were calculated as the change in the partial likelihood deviance metric between
the full model and the appropriate reduced model. HR was used to measure the risk of BCR
for a one-unit increase in CCP score.
A multivariable Cox PH model was fit to assess the added prognostic information of the
CCP score on BCR risk, after adjustment for other clinical characteristics including PSA,
Gleason score, and percent positive cores (considered continuous over the interval (0,1)). A
secondary analysis with fewer patients also included clinical stage, radiation dose, and
concurrent hormone use as these data were not available for all men. The CCP score was
evaluated as a linear and a quadratic term, and tested for interactions with all considered
clinical and demographic variables. The correlation between scaled Schoenfeld residuals
versus untransformed time was used to evaluate the proportional hazards assumption for
Cox regression, and specifically the time-dependence of the hazard associated with CCP.
The two-sample t-test was used to test for a difference in means for CCP scores. The
Wilcoxon rank-sum test was used to test for a difference in central location for PSA and
percent positive cores. Statistical inference was conducted within the R (version 2.15.1, June
2012, R Development Core Team) and SAS (version 9.2) software environments. Statistical
significance was set at the 5% level, prior to conducting inference. All p-values and
confidence intervals were two-sided.
Results
Initially, 179 men were identified for inclusion in this study. However, 27 patients (15%)
where eliminated from the study due to little or no tumor remaining in their diagnostic
biopsy, 5 patients (3%) with sufficient tumor failed to generate gene expression data, and 6
patients (3%) were eliminated because EBRT therapy was initiated more than two years
after diagnostic biopsy (Supplementary Figure 1). Therefore, the final study cohort
contained 141 patients. The clinical characteristics of the 141 patients are shown in Table 1,
and were similar to the 38 excluded patients, with the exception of Gleason score. As
expected, patients who were primarily excluded for no remaining tumor tended to have
lower Gleason scores. The CCP score distribution is shown in Figure 1. The African-
American patients had slightly higher scores than other ethnicities (mostly Caucasian), but
the difference was not statistically significant (p-value = 0.079). The African-American
patients also had higher PSA values (p-value = 0.0073), and tended to have a higher
percentage of positive biopsy cores (p-value = 0.074).
In evaluating the univariable association between CCP and BCR after EBRT with 10-year
censoring, we saw strong evidence for time-dependency in the CCP score hazard ratio (HR),
indicating that the CCP score was more predictive of BCR events in the first 5-years
compared to predicting BCR from 5 to 10 years (p-value = 0.0063). However, the median
follow-up time for patients who did not recur was only 4.75 years, and only 9 BCR events
happened after 5 years. Therefore, the results presented here are based on 5-year censoring.
Within this time frame, there was no evidence for time-dependency in CCP HR (p-value =
0.63). By 5 years, 13.4% (19/141) of the cohort had BCR. CCP score was associated with
BCR after EBRT (Table 2) (HR per CCP unit = 2.55; 95% CI (1.43, 4.55), p-value =
0.0017). The HR for a change from the 25th to 75th percentile of the score distribution was
2.75 (95% CI (1.47, 5.15)). The effect of a one-unit increase in CCP score (corresponding to
a doubling of RNA expression) on the 5-year risk of BCR is shown in Figure 2. Finally, 6
patients died from prostate cancer by 10 years. The CCP score was associated with disease
specific mortality (HR per CCP unit = 3.77; 95% CI (1.37, 10.4), p-value = 0.013).
Our multivariable analysis included adjustments for pretreatment PSA, Gleason, percent
positive cores, and concurrent ADT. The CCP score remained significantly predictive of
BCR (Table 3) (HR per CCP unit = 2.11 (95% CI (1.05, 4.25), p-value = 0.034). Further
adjustment for clinical stage or radiation dose did not materially alter the HR for CCP
(1.93), but the number of included patients was reduced to 105 so these variables were not
included in the final multivariable model. There was no evidence for an interaction between
CCP and any tested clinical variable including ethnicity (p-value ≥ 0.17). As in previous
studies (4,5), CCP score was only weakly correlated with other clinical variables (strongest
correlation with any single clinical variable was with clinical stage, ρ = 0.33), demonstrating
that the CCP score provides mostly independent information about prognosis.
To illustrate how the addition of CCP score to a prediction model changes patient prognosis,
we compared the prediction obtained using clinical parameters only to the prediction
obtained using clinical parameters combined with CCP score (Figure 3). It can be seen from
the figure that for any given risk connoted by clinical parameters, these patients could be
further risk stratified by adding CCP score. This was true across the entire spectrum of
clinical risk. The c-index for the model presented in Figure 3 including the CCP score was
0.80, which was an improvement over a model with clinical variables only (c-index = 0.78),
but is also indicative of the limited sensitivity of c-index to detect improved discrimination
in survival analysis (7).
Discussion
For patients opting for treatment of localized prostate cancer, prognostic biomarkers are
needed to inform appropriate intensity and duration of intervention. As demonstrated here,
the CCP score derived from the diagnostic biopsy is prognostic of biochemical failure and,
although there were few events, also predictive of disease specific morality after primary
EBRT. To our knowledge this is the first example of a prognostic molecular biomarker for
primary radiation therapy besides PSA. This result is also consistent with previous data
showing Ki67 expression (also a CCP gene) predicts failure after salvage radiation therapy
(8). Finally, this is the first demonstration of the prognostic utility of CCP score in African-
American patients.
Patients with high CCP scores were more likely to progress (Figure 2). Importantly, the
prognostic information provided by the CCP score was mostly independent of other clinical
variables (as demonstrated by the only modest reduction in HR in multivariable compared to
univariable analysis), and because the score is only modestly correlated with other variables,
it provides improved risk discrimination across the spectrum of clinical risk. Similar
characteristics regarding the prognostic utility of the CCP score and its relationship to other
clinical variables have been observed in previous studies (4,5).
In this study, we see evidence that the CCP score was a strong predictor of early treatment
failures, but that the prognostic utility declined over time (p-value of 0.0063 for time
dependency in CCP HR). Consistent with this observation, we have seen evidence of time
dependence in the CCP HR in some of our previous studies (5). Perhaps later failures (after
5 years) are less indicative of aggressive disease, and instead include more local recurrences
that are less clinically relevant. Alternatively, late recurrences may be due technical issues in
radiation delivery. If true, then these events (recurrence due to less aggressive disease or
technical issues) would not be predicted by disease biology, which CCP measures. In fact,
short time to EBRT failure has been shown to be a poor prognostic indicator in other studies
(9). This can be contrasted to the lack of time dependency in the observed association in this
study between CCP score and disease-specific mortality, supporting the view that disease-
specific death is indicative of aggressive disease regardless of elapsed time from diagnosis.
Perhaps the CCP score predicts micrometastatic disease present at the time of initial
diagnosis and treatment. If true, then a high CCP score, and thus, a high risk for
micrometastases, would indicate the need for treatment with both a local and systemic
therapy (i.e. HRT + ADT). However, given the limitations of this study including the small
size of the cohort, small number of treatment failures, and the relatively short follow-up
time, definitive conclusions regarding time dependency will require additional studies.
The data presented here, confirm and extend our previous work demonstrating the
prognostic utility of the CCP score. Earlier studies have shown the score to be prognostic in
biopsies from conservatively treated men from the UK and from surgically resected tumors
in post-prostatectomy cohorts from the U.S. (4,5). In this study, patients were treated with
EBRT as their primary curative therapy. Previously, the univarable HR (per unit score) for
CCP score has ranged from 1.89 to 2.92, which is consistent with the HR reported here
(2.55). The CCP score probably measures the fraction of dividing cells within the sampled
tumor tissue, and as such, gives a quantitative measure of tumor growth. The consistent
behavior of the CCP score indicates that the relationship between this measure and prostate
cancer outcome is robust to both patient composition and specific clinical treatment.
However, as noted, given the small sample size and modest follow-up, these results require
validation in larger cohorts with longer clinical follow-up.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Funding: Funding for this study was provided by Myriad Genetics, Inc.
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Summary
This study evaluated whether a mRNA based diagnostic assay (CCP score) can be used
as a prognostic indicator in EBRT-treated prostate cancer patients. The CCP score was
significantly predictive of biochemical recurrence even after adjustment for standard
clinical parameters. This is also the first study that evaluated the prognostic utility of
CCP score in African-American patients.
Figure 1.
Distribution of CCP scores. A) Distribution in entire cohort. Red tick marks indicate the
25th (Q1, −0.43), the median (Q2, 0.12), and 75th (Q3, 0.66) percentile of score values. B)
CCP score distribution stratified by ethnicity.
Figure 2.
Kaplan-Meier for 5-year recurrence free survival illustrating the effect of a one-unit increase
in CCP score (also equivalent to a doubling in gene expression levels).
Figure 3.
Scatter plot of the 5-year predicted risk of BCR for a model including CCP score (x-axis)
versus clinical parameters only (y-axis). Patient’s Gleason score is indicated by dot color.
For any given patient, the added contribution of the CCP score to the predicted risk, based
on Gleason, PSA, percent positive cores, and concurrent ADT, can be determined by the
horizontal distance between the dot and the diagonal dashed line.
Table 1
Summary measures for the considered clinical and demographic characteristics.
Characteristic N Summary Measure
CCP score, median (IQR) 141 0.12 (−0.43, 0.66)
Age, years at diagnosis, median (IQR) 141 66 (60, 71)
Ethnicity† (%)
African-American 81 57.4
Other 60 42.6
Baseline PSA‡ (ng/ml), median (IQR) 140 8.04 (5.45, 13.47)
Clinical stage (%)

T1 72 60.0
T2 44 36.7
T3 4 3.3
Gleason score (%)

<7 54 38.3
7 70 49.6
>7 17 12.1
Concurrent hormone use (%)

No 74 52.5
Yes 67 47.5
Percent positive cores, median (IQR) 134 45 (24, 67)
Year of biopsy, median (IQR) 141 2004 (2001, 2005)
Modified D’Amico risk (%)

Low 38 27.3
Intermediate 72 51.8
High 29 20.9
Radiation Dose (Gy), median (IQR) 116 74 (71, 74)
Abbreviations: CCP = cell cycle progression; IQR = interquartile range; PSA = prostate-specific antigen; Gy = gray.
†
Data were collected upon 81 African-Americans, 58 Whites, and 2 patients of “Other” ethnicity. We dichotomized ethnicity, to avoid statistical
modeling issues resulting from data sparseness.
‡
Maximum baseline PSA was 87.7 ng/ml.
Table 2
Summary of the fitted univariable Cox models.
Covariate Number Hazard ratio χ2 (df) P-value

of events (95% CI)
CCP score 19 2.55 (1.43, 4.55) 9.81 (1) 0.0017
Age, years at diagnosis 19 1.06 (0.99, 1.13) 2.74 (1) 0.098
Ethnicity
African-American 11 1.00 (ref)
Other 8 0.99 (0.40, 2.47) 4.0×10−4 (1) 0.984
log(1 + PSA) 19 2.72 (1.57, 4.71) 11.9 (1) 0.00057
Clinical stage
T1 4 1.00 (ref)
10.1 (2) 0.0066
T2 9 3.53 (1.09, 11.5)
T3 2 19.08 (3.43, 106.2)
Gleason score
<7 3 1.00 (ref)
5.95 (2) 0.051
7 13 3.87 (1.10, 13.6)
>7 3 3.67 (0.74, 18.2)
Concurrent hormone use

No 8 1.00 (ref)
Yes 11 1.65 (0.66, 4.11) 1.17 (1) 0.280
Percent positive cores 17 6.24 (1.05, 36.9) 4.02 (1) 0.045
Year of biopsy 19 0.90 (0.79, 1.03) 2.15 (1) 0.142
Modified D’Amico risk

Low 1 1.00 (ref)
8.49 (2) 0.014
Intermediate 10 6.20 (0.79, 48.6)
High 7 11.12 (1.37, 90.5)
Radiation dose 15 0.98 (0.94, 1.02) 0.84 (1) 0.358
Abbreviations: CCP = cell cycle progression; CI = confidence interval; χ2 = chi-square; df = degrees of freedom; PSA = prostate-specific antigen;
Gy = gray; ref = reference category.
Table 3
Summary of the fitted multivariable Cox model.(a)

Covariate Hazard ratio χ2 (df) P-value

(95% CI)
CCP score 2.11 (1.05, 4.25) 4.48 (1) 0.034
log(1 + PSA) 1.77 (0.90, 3.48) 2.93 (1) 0.087
Gleason score
<7 1.00 (ref)
3.25 (2) 0.197
7 3.73 (0.76, 18.2)
>7 2.71 (0.42, 17.5)
Percent positive cores 1.11 (0.13, 9.19) 0.01 (1) 0.920
Concurrent hormone use

No 1.00 (ref)
Yes 1.14 (0.35, 3.78) 0.05 (1) 0.826
Abbreviations: CCP = cell cycle progression; CI = confidence interval; χ2 = chi-square; df = degrees of freedom; PSA = prostate-specific antigen;
ref = reference category;
(a)
N = 134, with 17 events

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Prognostic utility of CCP score in men with prostate cancer after

Pathology, Duke University School of Medicine, Durham, NC

need more aggressive therapy.

Methods and Materials

Sample preparation and real-time PCR

CCP score calculation

percentage of positive biopsy cores (p-value = 0.074).

validation in larger cohorts with longer clinical follow-up.

Characteristic N Summary Measure

CCP score, median (IQR) 141 0.12 (−0.43, 0.66)

Age, years at diagnosis, median (IQR) 141 66 (60, 71)

Baseline PSA‡ (ng/ml), median (IQR) 140 8.04 (5.45, 13.47)

Clinical stage (%)

Gleason score (%)

Concurrent hormone use (%)

Percent positive cores, median (IQR) 134 45 (24, 67)

Year of biopsy, median (IQR) 141 2004 (2001, 2005)

Modified D’Amico risk (%)

Radiation Dose (Gy), median (IQR) 116 74 (71, 74)

Covariate Number Hazard ratio χ2 (df) P-value

CCP score 19 2.55 (1.43, 4.55) 9.81 (1) 0.0017

Age, years at diagnosis 19 1.06 (0.99, 1.13) 2.74 (1) 0.098

log(1 + PSA) 19 2.72 (1.57, 4.71) 11.9 (1) 0.00057

Concurrent hormone use

Percent positive cores 17 6.24 (1.05, 36.9) 4.02 (1) 0.045

Year of biopsy 19 0.90 (0.79, 1.03) 2.15 (1) 0.142

Modified D’Amico risk

Radiation dose 15 0.98 (0.94, 1.02) 0.84 (1) 0.358

Summary of the fitted multivariable Cox model.(a)

Covariate Hazard ratio χ2 (df) P-value

CCP score 2.11 (1.05, 4.25) 4.48 (1) 0.034

log(1 + PSA) 1.77 (0.90, 3.48) 2.93 (1) 0.087

Percent positive cores 1.11 (0.13, 9.19) 0.01 (1) 0.920

Concurrent hormone use

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