http://informahealthcare.com/bmk ISSN: 1354-750X (print), 1366-5804 (electronic) Biomarkers, 2015; 20(2): 162–167 ! 2015 Informa UK Ltd. DOI: 10.3109/1354750X.2015.1045033
RESEARCH ARTICLE
Cancer antigen-125 levels predict long-term mortality in chronic obstructive pulmonary disease Hakki Kaya1, Ali Zorlu1#, Hasan Yucel1, Omer Tamer Dogan2, Savas Sarikaya3, Gulay Aydin4, Tarik Kivrak5, and Mehmet Birhan Yilmaz1 Department of Cardiology and 2Department of Chest Disease, Cumhuriyet University Medical School, Sivas, Turkey, 3Department of Cardiology, Bozok University Medical School, Yozgat, Turkey, 4Department of Cardiology, Unye State Hospital, Ordu, Turkey, and 5Department of Cardiology, Sivas State Hospital, Sivas, Turkey
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Abstract
Keywords
Background: Cancer antigen-125 (CA-125) might be a useful biomarker to predict long-term mortality in patients with recent exacerbation of chronic obstructive pulmonary disease (COPD). Methods: A total of 87 consecutive patients with COPD were evaluated prospectively. Mean age of patients was 68 ± 10 years (55% males, 45% females) with a median follow-up period of 49 months. Optimal cut-off value of CA-125 to predict mortality was found as493.34 U/ml, with 91% specificity and 40% sensitivity. Results: After follow-up, 20 out of 87 (23%) experienced cardiovascular death. CA-125 levels were higher among those who died compared to those who survived [55 (12–264) versus 28 (5–245) U/ml, p ¼ 0.013]. In multivariate Cox proportional-hazards model with forward stepwise method, only CA-125493.34 U/ml on admission (HR ¼ 3.713, 95% CI: 1.035–13.323, p ¼ 0.044) remained associated with an increased risk of death. Conclusions: For the first time, we demonstrated that CA-125 helps the risk stratification of patients with COPD.
CA-125, cancer antigen-125, chronic obstructive pulmonary disease, long-term mortality, risk stratification
Introduction Chronic obstructive pulmonary disease (COPD) is the most frequently encountered lung disease in clinical practice with a clinical course of permanent airway obstruction due to chronic inflammation in the airways and systemic circulation (GOLD Guidelines, 2013; Agusti 2005). Prevalence and related mortality has been gradually increasing and COPD is estimated to become the third major cause of mortality worldwide until the year 2020 (Hurd, 2000; Mannino et al., 2006; Murray & Lopez, 1997). COPD, in addition to its high mortality, accompanies many cardiovascular diseases such as heart failure (HF), hypertension (HT), diabetes mellitus (DM), coronary artery disease (CAD) and atrial fibrillation (AF) (Jenkins et al., 2009; Olguin et al., 2005; Terzano et al., 2014). Advanced age, forced expiratory volume at the first second, pH, arterial blood oxygen pressure, arterial blood carbon dioxide pressure, frequency of hospitalization, development of AF, congestive HF, corpulmonale and presence of right ventricular (RV) hypertrophia in the ECG were #Ali Zorlu is responsible for statistical design and analysis. E-mail:
[email protected] Address for correspondence: Hakki Kaya, Assistant Professor, Department of Cardiology, Cumhuriyet University Medical School, Sivas, Turkey. Tel: +903462581807. Fax: +903462191268. E-mail:
[email protected] History Received 16 February 2015 Accepted 14 April 2015 Published online 19 May 2015
demonstrated to be predictors of mortality in patients with COPD (Connors et al., 1996; Groenewegen et al., 2003; Gunen et al., 2005; Matkovic et al., 2012; Soler-Cataluna et al., 2005). However, studies based on affordable and easily accessible biomarkers are still scarce. Cancer antigen-125 (CA-125) is a biomarker that has been long used for diagnostic and screening purposes primarily in ovarian cancer and many benign and malignant diseases. It is a high molecular weight soluble glycoprotein that is released from the normal cells of many different tissues originating from coelomic or Mullerian epithelium in response to inflammatory stimulus and increased interstitial fluid (Halila et al., 1986; Miralles et al., 2003; O’Brien et al., 2003; Topalak et al., 2002). However, CA125 serum levels have been demonstrated to increase in many cardiovascular and pulmonary diseases such as CAD, HF, AF and COPD and be related with mortality and morbidity in many of those diseases (D’Aloia et al., 2003; Kouris et al., 2005; Li et al., 2013; Yilmaz et al., 2011a,b). On the other hand, in a published study performed by our team, the CA-125 level was demonstrated to be increased and associated with development of right HF in patients with COPD (Yilmaz et al., 2011a). In this study, for the first time in the literature, we aimed to detect whether there is an association between the serum CA-125 levels and mortality during the 5-year follow-up of patients with COPD exacerbation.
CA-125 and mortality in COPD
DOI: 10.3109/1354750X.2015.1045033
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Materials and methods Eighty-seven consecutive patients with COPD, who had at least a 10-year history of COPD and who were hospitalized with exacerbation, were prospectively enrolled into the current study after obtaining informed consent. Patients with previous history or suspicion of malignancy, patients with active inflammatory disease including those during index exacerbation yielding hospitalization of the patient, patients with signs of inflammation and patients with significant accompanying left-heart pathology were excluded from the analysis. The study was performed in accordance with the Declaration of Helsinki for Human Research, and was approved by the institutional review board. Disease severity of the COPD patients was evaluated based on the criteria of the Global Initiative for Chronic Obstructive Lung Disease according to respiratory function tests (Minas et al., 2005). Respiratory-function testing was also performed with a spirometer (VmaxSeries 20C, SensorMedics, Yorba Linda, CA) at least 3 times in sitting posture after being trained for forced vital capacity maneuver during stable period. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) were measured, and best results were recorded as absolute (ml) and percentage (percentage of expected) values (Minas et al., 2005). Data collection, per protocol, included age, gender, history of HT and DM, admission CA-125 and other blood parameters, electrocardiogram, transthoracic echocardiography, respiratory function tests and detailed physical examination. All the patients underwent routine laboratory investigation at admission, and serum CA-125 levels were obtained after initial stabilization during hospital stay. Serum levels of CA125 were determined using a commercially available kit (AxSYM System, Abbott Laboratories, Abbott Park, IL). The AxSYM CA-125 assay is based on microparticle enzyme immunoassay; this technology uses a solution of suspended, submicron-sized latex particles to measure analytes. HT was defined as blood pressure 4140/90 mmHg on 42 occasions during office measurements or being on antihypertensive treatment. DM was defined as fasting blood glucose 126 mg/dl or being on antidiabetic treatment. Rhythm was evaluated. Echocardiographic examinations were performed via the Vivid 7 system (GE Healthcare, Wauwatosa, WI) with 2.5–5 MHz probes. Ejection fraction (EF) was calculated by modified Simpson method. Chamber sizes were defined according to recent guidelines (Lang et al., 2006). RV dimensions were evaluated according to the most recent guideline (Lang et al., 2006): RV dimension 43.4 cm at basal plane or 43.8 cm at midplane was used to designate moderate RV dilation as per guidelines. Those with moderate to severe dilation of RV according to guideline thresholds were considered to have significant RV dilatation (Lang et al., 2006). Right atrium (RA) size was measured on minor-axis dimension extending from the lateral border of the RA to the interatrial septum (Lang et al., 2006). The left atrium size was measured at end-ventricular systole by M-mode linear dimension, obtained from the parasternal long-axis view. Systolic pulmonary artery pressure (sPAP) was calculated as
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shown previously (Yock & Popp, 1984). Presence or absence of pericardial effusion was noted. Tricuspid annulus velocities, and tricuspid annular plane systolic excursion (TAPSE) were measured accordingly (Galderisi et al., 2002; Milan et al., 2010; Saxena et al., 2006). RV failure was defined by the combination of TAPSE and lateral wall tissue Doppler systolic (S) velocity according to previous thresholds (S velocity 510 cm/s and TAPSE 518 mm were used to define significant RV dysfunction) (Forfia et al., 2006; L’opez-Candales et al., 2008; Saxena et al., 2006; Tu¨ller et al., 2005), in addition to the presence of signs and symptoms of right HF (according to clinical notes at admission) – mostly pretibial edema, with some patients exhibiting jugular-vein distention and a few who had ascites during admission.
Statistical analysis Continuous variables were expressed as mean ± SD or median (min–max or 25–75% percentiles) in the presence of abnormal distribution, and categorical variables as percentages. Receiver operator characteristic curve analysis was performed to identify the optimal cut-off point of CA-125 (at which sensitivity and specificity would be maximal) for the prediction of mortality. Areas under the curve (AUC) were calculated as measures of the accuracy of the tests. We compared the AUC with use of the Z test. Comparisons between groups of patients were made by use of a 2 test for categorical variables, independent samples t test for normally distributed continuous variables, and Mann–Whitney U test when the distribution was skewed. Kaplan–Meier curves were used to display mortality in two patient subgroups, defined as having no increased (Group I) or increased (Group II) CA-125 based on a cut off value. We used univariate analysis to quantify the association of variables with mortality. Variables found to be statistically significant in univariate analysis and potential other confounders were used in a multivariate Cox proportional-hazards model with forward stepwise method in order to determine the independent prognostic factors of mortality. All the statistical procedures were performed using SPSS software version 14.0 (SPSS Inc., Chicago, IL). A p value of 0.05 was considered as statistically significant.
Results Median age of the patient was 68 (46–90) years (55% males, 45% females with a median follow up period of 49 months (25–75% percentiles; 47–57). Receiver operator characteristic curve analysis of CA-125 is shown in Figure 1. According to the ROC curve analysis, optimal cut-off value of CA-125 to predict mortality was found as 493.34 U/ml, with 40% sensitivity and 91% specificity (AUC 0.684, 95% CI 0.575–0.779). After follow-up, 20 out of 87 (23%) experienced cardiovascular death. Patients were classified into two groups as those who survived versus those who died (Table 1). CA-125 levels were higher among those who died compared to those who survived [55 (12–264) versus 28 (5–245) U/ml, p ¼ 0.013]. Hence, patients who died had above cut-off CA-125 levels at baseline (493.34 U/ml) more frequently than those survived [8 (40%) versus 6 (9%), p ¼ 0.003].
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Figure 1. ROC curve of CA-125 to predict long-term mortality.
Furthermore, there was no statistically significant difference between the two groups regarding many of the other parameters, though, median age was higher, and TAPSE level was lower among those who died compared to those who survived (Table 1). Most of the transthoracic echocardiograms and respiratory function tests were examined within the first 24 h of admission (upon admission for most of the patients). Echocardiographic examinations (n ¼ 4) and respiratory function tests (n ¼ 13) with extended deadlines were not considered in the study, because findings could have changed. Furthermore, CA-125 levels were negatively correlated with FEV 1, FEV 1/FVC and TAPSE, positively correlated with BUN level, COPD stage, sPAP, presence of HT, AF, RV dilatation and RV failure (Table 2). Results of the univariate and multivariate Cox proportional-hazards analyses for mortality are depicted in Table 3. Age, CA-125493.34 U/ml on admission and TAPSE level were found to have prognostic significance in univariate analyses. In multivariate Cox proportional-hazards model with forward stepwise method, only CA-125493.34 U/ml on admission (HR ¼ 3.713, 95% CI: 1.035–13.323, p ¼ 0.044) remained associated with an increased risk of death after adjustment for variables found to be statistically significant in univariate analysis and correlated with CA-125 level. Kaplan–Meier analysis yielded diverging survival curves for two previously defined subgroups of CA-125 with a threshold of 93.34 U/ml (p ¼ 0.001, Figure 2).
Discussion To the best of our knowledge, this is the first study to demonstrate that CA-125 aids in the risk stratification of patients with COPD. We have also shown that high CA-125 levels upon admission were associated with poor hemodynamic parameters such as poor pulmonary capacity, RV dysfunction and presence of AF and HT.
Biomarkers, 2015; 20(2): 162–167
It has long been known that a complex inflammatory process has a significant role in the development of COPD. Predictors of mortality have become more and more important in COPD in which the mortality rates have been progressively increasing due to systemic effects and accompanying comorbidities. Advanced age, male gender, increased frequency of hospitalization and accompanying HF have been demonstrated to increase mortality in many studies (Connors et al., 1996; Groenewegen et al., 2003; Gunen et al., 2005; Hurst & Wedzicha, 2009; McGhan et al., 2007; SolerCataluna et al., 2005). Although advanced age was found to be associated with mortality in univariate analysis in our study, it was not detected to be an independent predictor in the multivariate analysis. Gender, frequency of hospitalization and EF were not found to be associated with mortality in the present study, which is contrary to other studies. Furthermore, low FEV1, poor nutrition status and cigarette smoking in addition to advanced age and frequency of hospitalization, were clinical factors that were found to be independently associated with mortality in a meta-analysis performed by Steer et al. (2010). In our study, although the FEV1 values in patients died were observed to be lower compared to the patients who survived, no statistical significant difference was found between the groups. In addition, no association between cigarette smoking and mortality was found. In a meta-analysis performed by Sinhanayagam et al. (2013) low body weight, presence of DM and congestive HF were found to be independently related with mortality. Additionally, it has been demonstrated in previous studies that the development of right HF worsens the prognosis in patients with COPD (Barnes & Celli, 2009; Terzano et al., 2010). On the other hand, TAPSE, a marker of systolic right heart function was found to be associated with mortality by univariate analysis; however, it was not found to be an independent marker of mortality in multivariate analysis in this present study. In addition to the aforementioned studies, some studies have been conducted based on biomarkers reflecting the effect of inflammation in the development of COPD. The subgroup analysis of the ECLIPS cohort demonstrated that increased levels of two or more of white blood cell count, fibrinogen, CRP, IL-6 and IL-8 were associated with increased mortality (Agustı´ et al., 2012). In particular, elevated CRP was demonstrated in many studies to be associated with increased mortality in COPD (Dahl et al., 2007; Man et al., 2006). CA-125 levels increase in many diseases such as lung cancer, gastrointestinal cancers, endometriosis and pelvic inflammatory disease, though not as much as it increases in ovarian cancer (Halila et al., 1986; O’Brien et al. 2003). It has been previously demonstrated that CA-125 is released by mesothelial cells present in the pericardium, peritoneum and pleura and that the serum level of CA-125 increases in the presence of effusion in those locations (Me´ndez et al., 2014). Elevated CA-125 levels in HF due to mechanical stress and also increased inflammatory stimuli have been the subject of many studies (D’Aloia et al., 2003; Kouris et al., 2005; Yilmaz et al., 2011b). In the studies of HF, CA-125 levels were associated with mortality (D’Aloia et al., 2003), were found to be correlated with PAP, right atrial pressure and pulmonary artery wedge pressure (D’Aloia et al., 2003;
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Table 1. Baseline characteristics of study patients.
Baseline characteristics Median age (min–max) (years) Women Presence of hypertension Presence of diabetes mellitus Smoking Atrial fibrillation Frequency of rehospitalization Spirometer findings FEV 1 FEV1/FVC COPD stage (I/II/III/IV) (n:74) Echocardiography at admission (n:83) Presence of pericardial effusion Left ventricular parameters LV ejection fraction (%) Left atrial diameter (cm) LV diastolic dysfunction Right ventricular parameters RV failure sPAP (mmHg) RV dilatation TAPSE S velocity Laboratory findings CA-125 (U/ml) CA-125493.34 U/ml Hemoglobin (g/dl) Platelet counts BUN (mg/dl) Creatinine (mg/dl)
All patients (n:87)
Patients who survived (n ¼ 67)
Patients who died (n ¼ 20)
p Value
68 (46–90) 39 (45%) 55 (63%) 13 (15%) 41 (47%) 20 (23%) 1 (0–17)
67 (46–90) 28 (42%) 41 (61%) 10 (15%) 35 (52%) 16 (24%) 1 (0–17)
73 (50–84) 11 (55%) 14 (70%) 3 (15%) 6 (30%) 4 (20%) 1 (1–10)
0.022 0.432 0.651 1.000 0.135 1.000 0.785
44 ± 16 63 ± 11 1/25/34/19
46 ± 17 63 ± 10 1/22/26/15
39 ± 14 64 ± 16 0/3/8/4
0.153 0.619 0.674
8 (10%)
6 (10%)
2 (10%)
1.000
60 (30–68) 4.1 ± 0.7 69 (83%)
60 (30–68) 4.0 ± 0.7 55 (87%)
60 (45–62) 4.2 ± 0.6 14 (70%)
0.498 0.376 0.091
44 (53%) 41 ± 21 56 (68%) 1.9 (1.2–8) 10 (5–22)
33 (52%) 39 ± 19 43 (68%) 2.0 (1.2–8) 10 (5–22)
11 (55%) 44 ± 27 13 (65%) 1.9 (1.2–2.2) 10 (5–20)
0.838 0.408 0.787 0.028 0.611
33 (5–264) 14 (16%) 14.4 ± 2.2 237 ± 95 19.5 (6–74) 1.0 (0.3–3.3)
28 (5–245) 6 (9%) 14.4 ± 2.1 244 ± 93 20 (6–74) 1.0 (0.5–2.4)
55 (12–264) 8 (40%) 14.6 ± 2.5 210 ± 103 19 (14–38) 0.9 (0.3–1.3)
0.013 0.003 0.727 0.185 0.942 0.263
FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity; COPD, chronic obstructive pulmonary disease; LV, left ventricle, RV, right ventricle; sPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion.
Table 2. Spearman correlation coefficients for CA-125.
Presence of hypertension COPD stage FEV 1 FEV 1/FVC Presence of atrial fibrillation sPAP (mmHg) Presence of RV dilatation Presence of RV failure TAPSE BUN
CA-125
p Value
0.262 0.234 0.311 0.248 0.305 0.468 0.305 0.315 0.434 0.361
0.014 0.003 0.006 0.027 0.004 50.001 0.005 0.004 50.001 0.001
COPD, chronic obstructive pulmonary disease; FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity; RV, right ventricle; sPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion.
De Gennaro et al., 2012; Kouris et al., 2005). Uz et al. (2011) demonstrated in their study that CA-125 levels were independently associated with sPAP in patients with COPD. The results of this present study also demonstrated that CA-125 levels are strongly correlated with parameters of poor right heart function. Primarily two mechanisms have been proposed to be the causes of increased serum CA-125 levels in COPD. The first mechanism is that various inflammatory mediators are released from the increased monocytes and macrophages
during the inflammatory process in COPD (Corrigan & Kay, 1991) and those mediators cause tissue damage (Chung, 2001). Neutrophil-originated proteinases and monocyteoriginated matrix metallopeptidases are released as a result of the development of tissue damage in the lungs and those mediators cause a progressive increase in the inflammation that is already present in patients with COPD, and thus release of CA-125 from the mesothelial cells (Aldonyte et al., 2003; Maus et al., 2002). The second proposed mechanism is increased venous congestion due to the development of right HF in patients with COPD result in an increased mechanical stress and thus increase the release of CA-125 even more (Huang et al., 2012). Study limitations There are some limitations of the current study. Our study was limited by its monocentric nature, and hence, the findings should not be generalized to overall population of patients with COPD. The most important limitation was the relatively small sample size. Relatively small sample size might have influenced wide 95% CI for hazard ratios of CA-125. Also, in our study, inflammatory parameters, which are related to mortality and morbidity in COPD, were not evaluated. B-type natriuretic peptides are established biomarkers in HF; however, this was not examined in our study.
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Table 3. Univariate and multivariate Cox regression analyses for predicting mortality. Univariate Variable
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Statistically significant variables CA-125493.34 U/ml on admission Age (years) TAPSE Variables which correlated with CA-125 Presence of hypertension COPD stage FEV 1 FEV 1/FVC Presence of atrial fibrillation sPAB (mmHg) Presence of RVD Presence of RV failure BUN
Multivariate
p Value
HR
(95% CI)
p Value
HR
(95% CI)
0.002 0.017 0.045
4.323 1.058 0.201
1.730–10.804 1.010–1.108 0.042–0.968
0.044
3.713
1.035–13.323
0.531 0.473 0.216 0.495 0.790 0.193 0.815 0.613 0.453
1.358 1.280 0.978 1.018 0.861 1.017 0.896 1.258 0.986
0.521–3.538 0.652–2.515 0.944–1.013 0.967–1.071 0.287–2.582 0.991–1.044 0.357–2.246 0.518–3.054 0.950–1.023
All the variables from Table 1 were examined and only those significant at p50.05 level and correlated with CA-125 are shown in univariate analysis. Multivariate Cox proportional-hazards model including all the variables in univariate analysis with forward stepwise method. CI, confidence interval; HR, hazard ratio; COPD, chronic obstructive pulmonary disease; FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion.
References
Figure 2. Kaplan–Meier curve for long-term mortality.
Conclusion In the presence of the other clinical and laboratory parameters, CA-125 levels upon admission to the hospital were shown to be an independent predictor of long-term mortality in COPD. In addition, CA-125 levels were associated with the presence of systemic HT and AF and were found to be correlated with parameters of poor pulmonary function and right HF. In addition, since the CA-125 levels upon admission to the hospital have a high specificity of 91%, it is suggested that this level could be helpful in deciding the ‘‘rule in for long-term mortality’’.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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