Fibrinogen

[pjoshea13]

"To celebrate the Prostate Cancer and Prostatic Diseases satellite meeting in Shangai on 7 December 2018, Dr Stephen Freedland and Dr Dingwei Ye selected some of our top papers from China."

nature.com/documents/PCAN_B...

I was particularly interested in [4]:

"Pretreatment plasma fibrinogen as an independent prognostic indicator of prostate cancer

patients treated with androgen deprivation therapy"

{I had discussed fibrinogen in:

healthunlocked.com/advanced....

"Inflammation. [3] SedRate, Fibrinogen, IL-6, TNFalpha."

Elevated fibrinogen is a sign of inflammation & can be brought into the normal range, IMO.}

Here is the study paper:

"Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer death in men in the United States.1 Androgen deprivation therapy (ADT) is the mainstay of therapy for locally advanced or metastatic PCa or early-stage disease with advanced age or poor medical status ineligible for local regional treatments.2

Growing evidence suggest that coagulation factors might have a major role in the development of human cancer, metastatic spread and prognostic assessment.3–5 Plasma D-dimer and platelet count could represent independent prognosticators of various human cancers.3–5 Similarly, plasma fibrinogen is overexpressed in many human tumors. Numerous studies have revealed that pretreatment plasma hyperfibrinogen independently predicts adverse clinical characteristics and poor prognosis in patients with tumors including esophageal squamous cell carcinoma,6 renal cell carcinoma,7 gallbladder cancer,8 upper tract urothelial carcinoma,9 colon cancer,10 non-small cell lung cancer11 and malignant pleural mesothelioma.12 Thurner et al.13 showed a significant association between an elevated plasma fibrinogen level and poor prognosis of PCa patients who underwent radiation therapy. Ziaran et al.14 demonstrated a significant increase of fibrinogen levels in PCa patients after 12 months of ADT, indicating that fibrinogen may be associated with tolerance of ADT and may be a factor for poor prognosis of PCa, but whether fibrinogen has important roles in the prognosis of PCa treated with ADT has not been reported.

Fibrinogen is one of the most prominent protein involved in the coagulation pathway, and its measurement is routinely performed in most clinical laboratories worldwide; we hypothesized that pretreatment plasma fibrinogen was an independent prognostic indicator of PCa patients treated with ADT. The objective of this study was to verify our hypotheses and evaluate whether it could improve the predictive accuracy for prognosis of PCa.

MATERIALS AND METHODS

Study population

After obtaining the approval from the Committee for Ethics of Renji Hospital, Shanghai Jiao Tong University School of Medicine, and informed consents of patients, a total of 325 patients who underwent ADT as first- line therapy for PCa between January 2010 and December 2014 were retrospectively reviewed. We finally included 290 patients with available data on fibrinogen within 2 weeks before the prostate biopsy. We excluded patients with coagulation-related diseases, inflammatory diseases, auto- immune diseases, cardiovascular and cerebrovascular diseases, and other tumors or those lost to follow-up.

Clinical and pathological evaluation

Data on clinical characteristics including age, PSA and fibrinogen at diagnosis, clinical tumor stage, biopsy Gleason score and follow-up information were collected. The pathologic slides were re-reviewed by the urologic pathologists, and their Gleason scores were retrieved from pathology records. For clinical tumor stage, patients underwent computed tomography or magnetic resonance imaging of the pelvis. Radionuclide bone scan was performed to evaluate whether bones metastasize or not. PCa patients were stratified into low-, intermediate- and high-risk groups according to the EAU guidelines;15 low-risk included PSA o 10 μg l − 1 and Gleason Scoreo7 and cT1c-2a, intermediate-risk referred to PSA 10–20 μg l − 1 or Gleason Score 7 or cT2b-2c, and high-risk referred to PSA420 μg l − 1 or Gleason Score 8–10 or 4cT2c.

Eligible patients were treated with continuous ADT as first-line therapy, including castration and anti-androgen therapy. Castration was achieved either by orchiectomy or luteinizing hormone-releasing hormone-a, such as goserelin 3.6 mg subcutaneously monthly. Anti-androgen therapy was achieved either by bicalutamide tablets 50 mg per day orally or flutamide 3 times a day, each time 250 mg orally.

Follow-up

Patients were followed up every 3 months. Duration of the follow-up was assessed from the date of treatment until the last follow-up (June 2015) or death, which was valued as cancer-related or not related to the tumor. Progression was defined as castration-resistant or death, and the castration-resistant was judged according to the EAU guidelines.16 The median follow-up duration was 37.0 months (interquartile range (IQR), 24.0–50.3).

Laboratory assays

Venous blood samples were collected before the prostate biopsy. Pretreatment plasma fibrinogen levels were measured as part of routine clinical procedures to exclude coagulation disorders or presence of acute infection, and by the Clauss standard method with bovine thrombin (100 NIH U ml − 1).

Statistical analysis

As to the clinical characteristics according to the fibrinogen levels, for continuous variables, Wilcoxon signed rank test was used for the variables reported as median with IQRs; for categorical variables, the chi-square tests were used. The cutoff value for the continuous variable plasma fibrinogen level was determined by applying a receiver operating characteristics curve analysis to test all possible cutoffs that would separate between patients’ survival and cancer-related death. The survival distributions, including progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) were estimated by the Kaplan–Meier method and compared by a log-rank test, and subgroup analyses were taken according to Gleason score and metastasis. PFS was calculated from the date of prostate biopsy to the date of disease progression or the time of the last follow-up. The effect of all variables (age, PSA, Gleason score, metastasis, risk stratification and fibrinogen) on PFS, CSS and OS were examined using Cox proportional hazard regression models. Five variables (age, PSA, Gleason score, metastasis and fibrinogen) with a P-value less than 0.05 for PFS and four variables (PSA, Gleason score, metastasis and fibrinogen) with a P-value less than 0.05 for CSS and OS on univariable analyses were entered into multivariable stepwise Cox regression analyses. As the variable risk stratification is made up of PSA, cT stage and Gleason score, and it was with a P-value higher than 0.05 for CSS and OS, risk stratification was not entered into multivariable stepwise Cox regression analyses. Hazard ratio (HR) and 95% confidence interval (CI) were computed. To examine whether fibrinogen data can provide additional prognostic power when used with basic clinical variables (Gleason score and metastasis), we built predictive models and calculated the c-index by integrating clinical variables with fibrinogen using the the R package 'survival'. For each core set, we randomly extracted 20% samples as the test set, and to generate a c-indexthe above procedure was repeated 100 times to generate 100 c-indexes. Then, we used the Wilcoxon signed rank test to calculate the P-value. All tests were two-sided. Differences were considered to be statistically significant if P o 0.05. Statistical analysis was carried out using SPSS, version 19.0.

RESULTS

Clinical characteristics

The basic characteristics of the patients are detailed in Table 1. The median age was 75 years (IQR, 67–79).

Association between fibrinogen and clinical and pathological characteristics

On the basis of receiver operating characteristic curve for survival analysis (CSS), the best cutoff value of fibrinogen was 3.225 g l − 1 (Figure 1), and all patients were divided into either lower fibrinogen group (n=170, 58.62%) or hyperfibrinogen group (n=120, 41.38%). Compared with patients with lower fibrinogen ( o 3.225 g l − 1), patients with hyperfibrinogen were more likely to have higher PSA (P o 0.001), Gleason score (P o 0.001), risk stratification (P = 0.024) and incidence of metastasis (P o 0.001). There was no significant difference between the groups according to age (Table 2).

Association between fibrinogen and prognosis of PCa

The median follow-up duration was 37.0 months, disease progression occurred in 126 (43.45%) patients, 70 (24.14%) patients died, including 60 (20.69%) who died because of PCa at the end of the last follow-up.

The patients with pretreatment hyperfibrinogen had a sig- nificantly worse survival than those with lower fibrinogen with regard to PFS, CSS and OS (Log-rank test, each P o 0.001, Figure 2).

As shown in Figures 3 and 4, in the Gleason score 47 or bone metastasis subgroup, hyperfibrinogen exhibited worse PFS, CSS and OS (Log-rank test, each P o 0.01), but in the Gleason score ⩽ 7 or non-metastasis subgroup, the prognostic difference was not significant between hyperfibrinogen group and lower fibrinogen group (Log-rank test, each P40.05). Univariable and multivariable Cox regression analyses (stepwise analysis) of the factors influencing PFS, CSS and OS were presented in Tables 3 and 4. Univariable analyses demonstrated that PSA, Gleason score, metastasis and fibrinogen were significant predictors for PFS, CSS and OS (each Po0.05), but age and risk stratification were significant predictors for PFS, not for CSS and OS. In the multivariate analyses, we identified that age, Gleason score, metastasis and fibrinogen were independent prognostic factors for PFS, and Gleason score, metastasis and fibrinogen were independent prognostic factors for CSS and OS. The HRs of fibrinogen were 2.000 (95% CI 1.388–2.882) for PFS, 2.209 (95% CI 1.253–3.894) for CSS and 1.965 (95% CI 1.181–3.270) for OS.

The predictive accuracy was calculated with and without the inclusion of fibrinogen. In the base models, including the traditional predictor variables of Gleason score and metastasis, predictive accuracy for PFS, CSS and OS was 73.0% (IQR, 71.1– 77.1%), 77.8% (IQR, 73.1–81.9%) and 74.6% (IQR, 71.8–77.7%), respectively; in the integrated models with the addition of fibrinogen 3.225gl−1, predictive accuracy for PFS, CSS and OS was 75.0% (IQR, 75.2–85.1%), 79.9% (IQR, 73.1–81.9%) and 76.7% (IQR, 73.8–80.6%), respectively. Notably, the integrated models resulted in statistically significantly improved predictive power compared with the base models (each Po0.001).

When fibrinogen was a continuous variable, in the univariable analyses, fibrinogen was a significant predictor for PFS, CSS and OS (each Po0.001), and in the multivariate analyses, fibrinogen was an independent prognostic factor for PFS, CSS and OS (each Po0.001). The HRs of fibrinogen were 1.397 (95% CI 1.209–1.613) for PFS, 1.569 (95% CI 1.260–1.956) for CSS and 1.456 (95% CI 1.190–1.782) for OS.

DISCUSSION

"Despite recent progress in the identification of genetic and molecular alterations in PCa, the routine prognostic risk assessment of PCa patients currently relies on traditional clinicopathological prognostic factors, including Gleason score, clinical tumor stage and PSA level at the time of diagnosis, which are used for the patients’ evaluation into low-, intermediate- or high-risk groups.15 The accuracy of traditional prognostic models need to be further improved by the incorporation of other prognostic biomarkers.

The plasma fibrinogen level is a routinely measured blood- based parameter, and hyperfibrinogen has been found as an independent factor of worse prognosis in many tumors.6–13 This study examined the data from a large Chinese cohort of patients treated with ADT as first-line therapy for PCa and found that patients with pretreatment hyperfibrinogen had significantly worse PFS, CSS and OS than patients with lower fibrinogen, even after adjusting for other known predictors of PCa prognosis, and we got similar results when fibrinogen was a continuous variable. In addition, we found that similar results existed in different subgroups (Gleason score 47 and bone metastasis), but not in the Gleason score ⩽ 7 or non-metastasis subgroup, for the reason that the percentages having reached the endpoints (progression, cancer-related death and overall death) in these subgroups were too low. In addition, we built prognostic predictive models, in the base models, which included the traditional predictor variables of Gleason score and metastasis, predictive accuracy was 73.0%, 77.8% and 74.6% for PFS, CSS and OS, respectively, which could be further improved by the addition of fibrinogen (75.0%, 79.9% and 76.7%, respectively).

To the best of our knowledge to date, this is the first study of fibrinogen focusing on the prognosis of PCa treated with ADT. Previously, only two studies analyzed the clinical significance of plasma fibrinogen in PCa patients who underwent other treatments. Thurner et al.13 showed a significant association between an elevated plasma fibrinogen level and poor prognosis of PCa patients who underwent radiation therapy, but their data have to be interpreted cautiously for the limited accuracy obtained using receiver operating characteristic curve analysis and potential confounding factors like cardiovascular disease and inflammatory diseases that have not been accounted for. Seal et al.17 showed a significant correlation of elevated pretreatment fibrinogen levels with overall mortality and a trend for an association between elevated fibrinogen levels and mortality of stage III and IV PCa treated with estrogens, but the median follow-up duration was 1 year. In addition, the authors reported a significant decrease of fibrinogen levels after treatment with estrogens in PCa patients.

In the present study, patients who had hyperfibrinogen were more likely to have higher PSA, Gleason score, risk stratification and incidence of metastasis. In our univariate Cox analysis, PSA and risk stratification were identified to be associated with an increased risk of progression, although there were no significance in multivariate analysis. Gleason score and metastasis were independent predictors. Taken together, these differences of tumor characteristics may partly explain why the patients with hyperfibrinogen in our cohort had more aggressive disease.

An exact explanation for this observation remains unclear. However, several previous experimental and clinical studies supported the observation of our study. McDonald et al.18 found that plasma fibrinogen was associated with elevated PSA in men without known prostatic disease, and because an elevated PSA is indicative of increased PCa risk, it is possible that men with elevated plasma fibrinogen and elevated PSA were a distinct subgroup at increased risk of future PCa. Shu et al.8 demonstrated that preoperative plasma fibrinogen predicts tumor progression

and outcome, and fibrinogen enhances cell migration and

invasion in vitro in gallbladder cancer. Yano et al.19 showed that

fibrinogen interacted with multiple integrin and non-integrin

receptors of cancer cells to regulate tumor cell proliferation,

migration and signaling. Sahni et al.20 noted that fibrinogen may

bind to vascular endothelial cell growth factors and stimulate

endothelial cell proliferation and angiogenesis. In another study,Sahni et al reported that fibrinogen promotes the growth of lung and PCa cells through interaction with fibroblast growth factor-2. Zheng et al.22 found that fibrinogen helps platelets to adhere to tumor cells, and platelets in turn promote more fibrinogen to aggregate around tumor cells by forming thrombin, and thus protect tumor cells from natural killer cell cytotoxicity, which is mediated by β3-integrins. Recently, Steinbrecher et al.23 identified a unique link between fibrin(ogen) and the develop- ment of inflammation-driven malignancy, and the growth of established adenomas suggest that therapies targeting fibrin (ogen)-α(M)β(2) interactions may be useful in preventing and/or treating this important subset of malignancies. Taken together, these data suggest that fibrinogen is involved in tumor cell invasion and metastasis, further supporting its potential as a prognostic factor for cancer patients.

reported that fibrinogen promotes the growth of

This study has some limitations. First, this study was a retrospective investigation. Despite the strict enrollment criteria used, we were unable to completely exclude conditions that might cause hematologic changes in the PCa. Second, the data were obtained from a single institution. Our results should be validated by prospective research and data from multiple centers.

In summary, the pretreatment plasma fibrinogen level was associated with tumor progression and might be a significant marker of prognosis for PCa patients treated with ADT, namely it increased the risk of progression and mortality. Thus, we recommend adding fibrinogen to the traditional prognostic model, which may improve its predictive accuracy.

See link for tables, etc.

-Patrick