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original article

Annals of Oncology 22: 2625–2630, 2011 doi:10.1093/annonc/mdr007 Published online 17 March 2011

An elevated progastrin-releasing peptide level in patients with well-differentiated neuroendocrine tumours indicates a primary tumour in the lung and predicts a shorter survival
C. M. Korse1*, B. G. Taal2, J. M. G. Bonfrer1, A. Vincent3, M. L. van Velthuysen4 & P. Baas2
Departments of 1Clinical Chemistry; 2Medical Oncology; 3Biometrics and 4Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

Received 16 November 2010; revised 28 December 2010; accepted 31 December 2010

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Background: Progastrin-releasing peptide (proGRP) is a recently identi?ed biomarker of small-cell lung cancer. In
well-differentiated neuroendocrine tumours (WDNETs), this study investigates the association between proGRP and tumour characteristics and the prognostic value of proGRP levels compared with chromogranin A (CgA) levels. Patients and methods: Serum samples were obtained in 282 patients with WDNET. The receiver operating characteristic (ROC) curve technique was used to assess speci?city and sensitivity in the identi?cation of a primary tumour location. Cox proportional hazards models and Kaplan–Meier curves were constructed to determine the association of patients’ characteristics and tumour markers with survival. Results: For proGRP, the ROC curve indicated a cut-off level of 90 ng/l (approximately twice the upper reference value), with a speci?city of 99% and a sensitivity of 43% in distinguishing primary pulmonary tumours from other sites. In the multivariate Cox model, both proGRP and CgA were strongly associated with survival (P < 0.0001 for both variables). Conclusions: A high-risk proGRP level (more than twice the upper reference value) in patients with WDNETs is a strong indication for a primary tumour in the lung. Besides CgA, proGRP is a complementary tumour marker for prognosis and treatment monitoring in patients with neuroendocrine tumour. Key words: chromogranin A, diagnosis, progastrin-releasing peptide, prognosis, neuroendocrine tumours, survival analysis

Introduction
Chromogranin A (CgA) is the most frequently used tumour marker in well-differentiated neuroendocrine tumours (WDNETs) [1–3]. Although CgA is a more sensitive marker than 5-hydroxyindoleacetic acid, which was used until the last decade, it has some limitations [4]. Elevated CgA may also occur in chronic atrophic gastritis, in?ammatory diseases, renal impairment and, often, during the widely used treatment of proton pump inhibitors (PPIs) [5, 6]. Progastrin-releasing peptide (proGRP) was recently reported as a promising tumour marker for small-cell lung cancer (SCLC) [7, 8]. ProGRP is a precursor form of gastrin-releasing peptide (GRP) (or mammalian bombesin), which is a neuropeptide hormone originally isolated from porcine gastric tissue [9]. GRP is widely distributed throughout the gastrointestinal and pulmonary tract. GRP is produced by
*Correspondence to: C. M. Korse, MSc, Department of Clinical Chemistry, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, PO Box 90203, 1006 BE Amsterdam, The Netherlands. Tel: +31-20-512-2794; Fax: +31-20-512-2799; E-mail: t.korse@nki.nl

SCLC cells and could be helpful in the monitoring of patients [10]. However, because GRP is extremely unstable (half-life time is 62 min), it is not suitable as a tumour marker. On the other hand, proGRP is very stable and has a long half-life of 19– 28 days. Therefore, several immunoassays have been developed to measure this peptide. ProGRP has been studied extensively in SCLC [7, 11–15]. However, few data are available on proGRP levels in the blood of patients with neuroendocrine tumour (NET). Only one group (in Spain) found signi?cantly high proGRP levels in two of four patients with NET [16]. The aims of this study were to investigate the association between proGRP and tumour characteristics (e.g. localisation, grade of differentiation); and to examine the prognostic value of proGRP compared with CgA in patients with WDNETs.

patients and methods
patients and healthy individuals
All patients diagnosed with WDNET who were referred to The Netherlands Cancer Institute from 1994 to 2009 were included in this study. They were

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original article

original article
diagnosed according to the recommendations of the World Health Organization [17, 18]. Grade of differentiation was based on the number of mitoses: grade 1 (G1), <2 per 2 mm2 and grade 2 (G2), 2–10 per 2 mm2 [19, 20]. Patient characteristics were extracted from patient records. Blood samples were collected before starting treatment in our institute and were stored at 230°C until the measurements. A total of 297 healthy volunteers (visitors of our institute from 2003 to 2009) were asked to donate blood to establish reference values. All participants of the study gave their informed consent.

Annals of Oncology

assays
ProGRP was measured on the ARCHITECT i System, an immunoassay analyser using the chemiluminescent technique (Abbott, Wiesbaden, Germany) [21]. The expected upper limit of normal (ULN) for proGRP is 63 ng/l. CgA was measured by means of the chromogranin A radioimmunoassay coated tube (CGA-RIACT) as described previously (CIS Bio-International, Gif-sur-Yvette, France) [4]. The manufacturer suggests a ULN of 98 lg/l for CgA.

statistics
Due to the asymmetric distribution of the biomarker values, log transformations were applied. The ULN for healthy persons was de?ned as the 95th percentile according to the guidelines of the Clinical and Laboratory Standards Institute (C28-A3) [22]. A two-group Gaussian mixture model was constructed to determine outliers [23], which were excluded before the calculation of the ULN. Associations between age and the log-transformed tumour markers were calculated with Pearson’s correlation coef?cients. Comparison of median values was done with nonparametric tests. The receiver operating characteristic curve (ROC) technique was used to assess speci?city and sensitivity in the identi?cation of tumour origin (lung versus other) and grade of differentiation (G1 versus G2) of different thresholds de?ning elevated proGRP. A multivariate logistic regression model was used to investigate the association between tumour characteristics and proGRP. Therefore, proGRP was dichotomised according to the threshold as found in the ROC curves. Martingale residual plots were used to assess the appropriate functional form of proGRP and CgA in relation to overall survival [24]. Unadjusted (univariate) and adjusted (multivariate) Cox proportional hazard models were constructed to determine the association of patient characteristics and tumour markers with overall survival. Schoenfeld residuals were tested for correlation with time to ensure the appropriateness of the proportional hazards assumption. The Kaplan–Meier technique was employed to depict the association between the tumour markers and survival.

Men and women were equally divided between the groups. Most G1 primary tumours were found in the small bowel (29%), while the lung was the predominant site in the G2 NET (50%). Of the 282 patients, 89 (31%) presented with metastatic disease of primary tumours of unknown origin. At the time of the analyses, 125 patients (44%) had died. The median followup time was 3 (range 0–12) years. High proGRP levels were only found in patients with WDNET in pulmonary tumours and tumours of unknown origin (Figure 1). Moreover, Mann–Whitney tests showed no association between proGRP values and the grade of differentiation for patients with primary sites outside of the lung and for patients with primary tumours of unknown origin (P = 0.337 and 0.251, respectively). However, for the group with a primary lung tumour, higher values were found in G2 than in G1 NET (P = 0.003). In Figure 2A, the ROC curve indicates that a proGRP with a cut-off value of 90 ng/l results in a speci?city of 99% and a sensitivity of 43% (Figure 2). This value had the highest speci?city while maintaining a reasonable sensitivity to distinguish primary lung tumours from the other primary tumours (negative and positive predictive values were 86% and 90%, respectively). At this same level of 90 ng/l, the speci?city was 97% and sensitivity 42% when an ROC curve was generated according to the grade of differentiation (G1 versus G2) (Figure 2B). Primary site as well as grade of differentiation were signi?cant predictive variables to detect a proGRP ?90 ng/l (Table 2). Using this threshold value, in 9 of 89 patients with a tumour of unknown origin, the proGRP level was >90 ng/l. All nine patients were treated according to the accepted guidelines for patients with NET containing somatostatin analogues and/or metaiodinebenzylguanidine (MIBG), depending on the results of the radionucleotide tests. In ?ve patients, interferon-alpha was used as an additional treatment. One female patient in poor condition received no treatment because the octreotide and MIBG scans were negative. There was no association between CgA levels and primary tumour location or grade of differentiation (data not shown).

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results
reference values Fifteen of the 297 healthy individuals (5%) showed abnormal CgA values. These individuals were excluded from subsequent analyses. No outliers were identi?ed in the proGRP levels. The ULN for CgA was then established as 88 lg/l and for proGRP as 53 ng/l. Log-transformed CgA was positively correlated with age (r = 0.41, P < 0.001). No difference in CgA levels was found between men and women. There was a weak association of proGRP with age (r = 0.13, P = 0.027) but no association was found with gender. patients The study population (n = 282) consisted of 244 patients with G1 differentiated and 38 with G2 differentiated NET (Table 1)

survival analyses The martingale residual plot indicated that proGRP should be split into two groups with a threshold of 90 ng/l, the same value as found in the ROC curve. CgA required a log-transform. In the univariate analysis, age, grade of differentiation, primary site, metastatic disease and both tumour markers were associated with overall survival (Table 3). Correlations between time and Schoenfeld residuals indicated that hazards were proportional. In the multivariate model, both proGRP and CgA were strongly associated with survival (P < 0.0001 for both variables). To illustrate the association between these markers and overall survival, Kaplan–Meier curves were constructed with proGRP dichotomised at the 90 ng/l threshold (as established in the martingale residuals plot) and CgA at the ULN (88 lg/l) (Figure 3). The overall 5-year survival with low values for both markers was 78% [95% con?dence interval (CI) 67% to 89%]; however, with both markers elevated this was only 15% (95% CI 0% to 38%). With one of the markers elevated, the 5-year survival rate was in between these two values.

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original article
Healthy (N = 297) Well-differentiated neuroendocrine tumours Grade 1 (N = 244) Grade 2 (N = 38) 117 127 60 (12) 121 (50) 123 (50) 71 8 34 17 23 10 81 (29) (3) (14) (7) (10) (4) (33) 20 18 54 (13) 22 (58) 16 (42) 0 (0) 0 (0) 5 (13) 3 (8) 19 (50) 3 (8) 8 (21) 6 (16) 32 (84) 15 (40) 23 (60) All (N = 282) 137 145 59 (12) 143 (50) 139 (50) 71 8 39 20 42 13 89 (25) (3) (14) (7) (15) (5) (31)

Table 1. Baseline characteristics of healthy individuals and of patients with well-differentiated neuroendocrine tumours

Sex Male Female Age (years) Mean (SD) Pretreatment, n (%) No Yes Site, n (%) Small bowel Appendix Colon/rectum Pancreas Lung Remainder of sites Unknown Metastatic disease, n (%) No Yes Deceased, n (%) No Yes

148 149 49 (13) n.a.

n.a.

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n.a.

55 (22) 189 (78) 142 (58) 102 (42)

61 (22) 221 (78) 157 (56) 125 (44)

n.a.

SD, standard deviation; n.a., not applicable.

Figure 1. proGRP levels according to primary site and grade of differentiation in patients with WDNET compared with proGRP in healthy controls. High proGRP levels were only found in patients with WDNET in pulmonary tumours and tumours of unknown origin. proGRP, progastrin-releasing peptide; WDNET, well-differentiated neuroendocrine tumours.

discussion
In the last decade, proGRP has proven to be a promising biomarker for monitoring treatment in patients with SCLC [15, 16, 25, 26]. Since there was a suggestion that proGRP might be a useful marker in patients with NET, we investigated its value in WDNET in comparison with CgA [16]. The present study

shows that elevated proGRP levels (?90 ng/l) are only found in NET originating from the lung or from unknown primary site. Furthermore, Cox regression models show that proGRP offers additional prognostic value compared with that provided by CgA. In the present study, the reference values for proGRP and CgA were lower than the manufacturer’s recommendations: for proGRP, we found a lower ULN of 53 ng/l as compared with the recommended 63 ng/l. Also, in this study, proGRP was measured in sera that had been stored at 230°C for an average of 3.5 years. It is suggested that thrombin (a serine protease), which is generated during the clotting process, inactivates the stability of proGRP by proteolysis, which could cause a decrease of proGRP in serum [14, 27]. Unfortunately, nothing is known about the effects of long storage. In our opinion, the difference of 10 ng/l (i.e. 53 ng/l instead of 63 ng/l) was acceptable and con?rms that, in the present study, measurement of proGRP in long-stored serum was feasible. We also found a lower ULN of 88 lg/l for CgA, as compared with the manufacturer’s recommended ULN of 98 lg/l. Our lower value could be due to the exclusion of the 5% of healthy individuals with unusually high values. Although an elevated CgA level is primarily associated with NET disease, it may also occur in conjunction with renal failure, in?ammatory diseases, gastrointestinal disorders and heart failure [28]. However, the main cause of false-positive CgA levels is the use of PPIs [6], which are widely administered in the general population [29]. PPIs suppress acid secretion and elevate CgA as a consequence of gastric enterochromaf?n-like neuroendocrine cell hyperplasia. Therefore, a considerable number of healthy

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original article

Annals of Oncology

Table 3. Univariate and multivariate Cox regression analyses of prognostic variables in patients with well-differentiated neuroendocrine tumours n Univariate Age (years) Sex Male Female Differentiation Grade 1 Grade 2 Primary site Non-lung Lung Unknown Pretreatment No Yes Metastasis No Yes proGRP (ng/l) <90 ?90 log_CgA (lg/l) Multivariate Age (years) Sex Male Female Differentiation Grade 1 Grade 2 Primary site Non-lung Lung Unknown Pretreatment No Yes Metastasis No Yes proGRP (ng/l) <90 ?90 log_CgA (lg/l) 282 137 145 244 38 151 42 89 143 139 61 221 253 29 282 Events 125 69 56 102 23 53 18 54 66 59 11 114 106 19 125 HR 1.04 1 0.69 1 2.37 1 1.42 1.94 1 0.88 1 4.20 1 2.87 2.13 1.04 1 0.72 1 2.24 1 0.77 1.06 1 1.08 1 2.16 1 3.43 1.71 P value <0.0001 0.04

0.0002

0.003 0.2 0.001 0.50

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<0.0001

<0.0001 <0.0001 <0.0001 0.08

Figure 2. Receiver operating characteristic curves for the performance of proGRP according to primary lung and non-lung (A) neuroendocrine tumours and according to grade of differentiation (B). The highest speci?city with a reasonable sensitivity was found at a level of 90 ng/l. proGRP, progastrin-releasing peptide.

0.01

Table 2. Multivariate logistic regression model to predict a progastrinreleasing peptide level ?90 ng/l in patients with well-differentiated neuroendocrine tumours based on grade of differentiation and primary tumour site P value Grade 1 versus grade 2 Non-lung versus lung <0.0001 <0.0001 OR 10.9 12.3 95% CI 3.9–30.2 3.7–41.0

0.66 0.44 0.80 0.69

0.03

<0.0001 <0.0001

OR, odds ratio; CI, con?dence interval.

individuals could present with falsely elevated CgA levels. Since this phenomenon might not have been taken into account, the former reference values may have been slightly too high. In future studies, we recommend to record all medications that are used by the study volunteers. The high speci?city of proGRP for diagnosing pulmonary NET may help clinicians to localise the primary tumour in patients with a metastatic NET of unknown origin. The present study also shows that survival is shorter among patients in whom both markers are elevated. Most likely this occurred only

HR, hazard ratio; proGRP, progastrin-releasing peptide; CgA, chromogranin A.

in patients with lung NETs since proGRP had a speci?city of 99%. If a patient has a high proGRP and a chest X-ray is inconclusive, a chest computed tomography scan or nuclear scans are more reliable to detect lung tumour lesions. Patients with WDNET are generally treated with weak antiproliferative agents (such as somatostatin analogues) when there are metastases. Our study indicates that in patients with a primary

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Annals of Oncology

original article
disclosure
The authors declare no con?ict of interest.

references
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Figure 3. Kaplan–Meier overall survival curves according to low and high CgA and proGRP levels. proGRP, progastrin-releasing peptide; CgA, chromogranin A.

tumour in the lung, a more aggressive therapy is needed because they have a less favourable prognosis [30]. For these patients with pulmonary NET, interferon-alpha or an SCLC regimen (cisplatin plus etoposide) may be advised [31–33]. In the present study, nine patients with a primary tumour of unknown origin had elevated proGRP levels, which were suggestive for pulmonary NET; in retrospect, this might have implied the need for a more intensive therapy. The Cox proportional hazard models showed that both CgA and proGRP have signi?cant prognostic value and that proGRP is a useful complementary tumour marker in addition to CgA in pulmonary NET for monitoring treatment. First, proGRP could be valuable due to the relatively low speci?city of CgA caused by elevated levels related to, for example, in?ammatory diseases, renal impairment and during treatment with PPIs; secondly, proGRP could be the marker of choice in patients with normal CgA levels. The sensitivity of CgA was 68%, which means that in the present study 91 patients (32%) had normal values. Of these 91 patients, 15 (19%) had elevated proGRP levels. With the recent availability of an automated proGRP assay, these latter patients could easily be monitored during their disease [21]. In summary, the threshold value of 90 ng/l, obtained from the ROC curve and also found in the survival analyses when examining the prognostic value of proGRP, is approximately twice the ULN. This means that patients with proGRP greater than twice the ULN have high-risk proGRP levels; a high-risk proGRP level in WDNET is a strong indication for a primary tumour in the lung. If a patient with pulmonary NET presents both an elevated CgA and a high-risk proGRP level, the clinician should consider this as a strong indication to apply earlier a more intensive treatment. ProGRP appears to be a complementary marker for prognosis in pulmonary NET.

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acknowledgements
The authors thank T.C. Linders and J.C.G.M. Buning-Kager for their conscientious technical assistance.

funding
Novartis Pharma B.V.; Abbott Diagnostics.

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original article
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Annals of Oncology

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