Skip to main content
Erschienen in: Tumor Biology 4/2015

01.04.2015 | Research Article

Assessing novel prognostic serum biomarkers in advanced pancreatic cancer: the role of CYFRA 21-1, serum amyloid A, haptoglobin, and 25-OH vitamin D3

verfasst von: Michael Haas, Christoph Kern, Stephan Kruger, Marlies Michl, Dominik P. Modest, Clemens Giessen, Christoph Schulz, Jobst C. von Einem, Steffen Ormanns, Rüdiger P. Laubender, Stefan Holdenrieder, Volker Heinemann, Stefan Boeck

Erschienen in: Tumor Biology | Ausgabe 4/2015

Einloggen, um Zugang zu erhalten

Abstract

The present prospective single-center study investigated the prognostic role of novel serum biomarkers in advanced pancreatic cancer (PC). Patients (pts) with locally advanced or metastatic PC treated with first-line palliative chemotherapy were included. Among others, the serum markers CYFRA 21-1, haptoglobin, serum-amyloid A (SAA), and 25-OH vitamin D3 were determined at baseline and categorized by pre-defined cut-offs [median values (MV), upper limits of normal (ULN), lower limits of normal (LLN), or the natural logarithm (ln)] and correlated with overall survival (OS). Among the 59 pts included, pre-treatment CYFRA 21-1 levels showed a strong correlation with OS independent of the applied cut-off (MV 4.9 ng/ml—14.2 vs. 4.2 months, HR 0.18, p = 0.001; ULN 3.3 ng/ml—14.2 vs. 4.4 months, HR 0.28, p = 0.003; [ln] CYFRA 21-1—HR 0.77, p = 0.013). Lower values of haptoglobin were additionally associated with an improvement in OS (categorized by LLN of 2.05 g/l—10.4 vs. 5.5 months, HR 0.46, p = 0.023; [ln] haptoglobin—HR 0.51, p = 0.036). Pts with baseline SAA values below the MV of 22 mg/l also had a prolonged OS (10.4 vs. 5.0 months, HR 0.47, p = 0.036). For 25-OH vitamin D3 levels, no significant correlation with OS was found. In multivariate analyses, pre-treatment CYFRA 21-1 levels (categorized by MV—HR 0.15, p = 0.032) as well as [ln] haptoglobin (HR 0.30, p = 0.006) retained their independent prognostic significance for OS. CYFRA 21-1, haptoglobin, and SAA might provide useful prognostic information in advanced PC. An external multicenter validation of these results is necessary.
Literatur
2.
Zurück zum Zitat Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.CrossRefPubMed Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.CrossRefPubMed
3.
Zurück zum Zitat Heinemann V, Vehling-Kaiser U, Waldschmidt D, Kettner E, Märten A, Winkelmann C, et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut. 2013;62:751–9.CrossRefPubMed Heinemann V, Vehling-Kaiser U, Waldschmidt D, Kettner E, Märten A, Winkelmann C, et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut. 2013;62:751–9.CrossRefPubMed
4.
Zurück zum Zitat Aranda E, Manzano JL, Rivera F, Galán M, Valladares-Ayerbes M, Pericay C, et al. Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study). Ann Oncol. 2012;23:1919–25.CrossRefPubMed Aranda E, Manzano JL, Rivera F, Galán M, Valladares-Ayerbes M, Pericay C, et al. Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study). Ann Oncol. 2012;23:1919–25.CrossRefPubMed
5.
Zurück zum Zitat Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.CrossRefPubMed Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.CrossRefPubMed
6.
Zurück zum Zitat Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.CrossRef Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.CrossRef
7.
Zurück zum Zitat Seufferlein T, Porzner M, Becker T, Budach V, Ceyhan G, Esposito I, et al. [S3-guideline exocrine pancreatic cancer]. Z Gastroenterol. 2013;51:1395–440.CrossRefPubMed Seufferlein T, Porzner M, Becker T, Budach V, Ceyhan G, Esposito I, et al. [S3-guideline exocrine pancreatic cancer]. Z Gastroenterol. 2013;51:1395–440.CrossRefPubMed
8.
Zurück zum Zitat Heinemann V, Haas M, Boeck S. Systemic treatment of advanced pancreatic cancer. Cancer Treat Rev. 2012;38:843–53.CrossRefPubMed Heinemann V, Haas M, Boeck S. Systemic treatment of advanced pancreatic cancer. Cancer Treat Rev. 2012;38:843–53.CrossRefPubMed
9.
Zurück zum Zitat Haas M, Heinemann V, Kullmann F, Laubender RP, Klose C, Bruns CJ, et al. Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy. J Cancer Res Clin Oncol. 2013;139:681–9.CrossRefPubMed Haas M, Heinemann V, Kullmann F, Laubender RP, Klose C, Bruns CJ, et al. Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy. J Cancer Res Clin Oncol. 2013;139:681–9.CrossRefPubMed
10.
Zurück zum Zitat Duffy MJ, Sturgeon C, Lamerz R, Haglund C, Holubec VL, Klapdor R, et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol. 2010;21:441–7.CrossRefPubMed Duffy MJ, Sturgeon C, Lamerz R, Haglund C, Holubec VL, Klapdor R, et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol. 2010;21:441–7.CrossRefPubMed
11.
Zurück zum Zitat Hess V, Glimelius B, Grawe P, Dietrich D, Bodoky G, Ruhstaller T, et al. CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial. Lancet Oncol. 2008;9:132–238.CrossRefPubMed Hess V, Glimelius B, Grawe P, Dietrich D, Bodoky G, Ruhstaller T, et al. CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial. Lancet Oncol. 2008;9:132–238.CrossRefPubMed
12.
Zurück zum Zitat Edelman MJ, Hodgson L, Rosenblatt PY, Christenson RH, Vokes EE, Wang X, et al. CYFRA 21-1 as a prognostic and predictive marker in advanced non-small-cell lung cancer in a prospective trial: CALGB 150304. J Thorac Oncol. 2012;7:649–54.CrossRefPubMed Edelman MJ, Hodgson L, Rosenblatt PY, Christenson RH, Vokes EE, Wang X, et al. CYFRA 21-1 as a prognostic and predictive marker in advanced non-small-cell lung cancer in a prospective trial: CALGB 150304. J Thorac Oncol. 2012;7:649–54.CrossRefPubMed
13.
Zurück zum Zitat Holdenrieder S, von Pawel J, Dankelmann E, Duell T, Faderl B, Markus A, et al. Nucleosomes and CYFRA 21-1 indicate tumor response after one cycle of chemotherapy in recurrent non-small cell lung cancer. Lung Cancer. 2009;63:128–35.CrossRefPubMed Holdenrieder S, von Pawel J, Dankelmann E, Duell T, Faderl B, Markus A, et al. Nucleosomes and CYFRA 21-1 indicate tumor response after one cycle of chemotherapy in recurrent non-small cell lung cancer. Lung Cancer. 2009;63:128–35.CrossRefPubMed
14.
Zurück zum Zitat Nakata B, Takashima T, Ogawa Y, Ishikawa T, Hirakawa K. Serum CYFRA 21-1 (cytokeratin-19 fragments) is a useful tumour marker for detecting disease relapse and assessing treatment efficacy in breast cancer. Br J Cancer. 2004;91:873–8.PubMedPubMedCentral Nakata B, Takashima T, Ogawa Y, Ishikawa T, Hirakawa K. Serum CYFRA 21-1 (cytokeratin-19 fragments) is a useful tumour marker for detecting disease relapse and assessing treatment efficacy in breast cancer. Br J Cancer. 2004;91:873–8.PubMedPubMedCentral
15.
Zurück zum Zitat Sun ZL, Zhu Y, Wang FQ, Chen R, Peng T, Fan ZN, et al. Serum proteomic-based analysis of pancreatic carcinoma for the identification of potential cancer biomarkers. Biochim Biophys Acta. 2007;1774:764–71.CrossRefPubMed Sun ZL, Zhu Y, Wang FQ, Chen R, Peng T, Fan ZN, et al. Serum proteomic-based analysis of pancreatic carcinoma for the identification of potential cancer biomarkers. Biochim Biophys Acta. 2007;1774:764–71.CrossRefPubMed
16.
Zurück zum Zitat Yokoi K, Shih LC, Kobayashi R, Koomen J, Hawke D, Li D, et al. Serum amyloid A as a tumor marker in sera of nude mice with orthotopic human pancreatic cancer and in plasma of patients with pancreatic cancer. Int J Oncol. 2005;27:1361–9.PubMed Yokoi K, Shih LC, Kobayashi R, Koomen J, Hawke D, Li D, et al. Serum amyloid A as a tumor marker in sera of nude mice with orthotopic human pancreatic cancer and in plasma of patients with pancreatic cancer. Int J Oncol. 2005;27:1361–9.PubMed
17.
Zurück zum Zitat Koomen JM, Shih LN, Coombes KR, Li D, Xiao LC, Fidler IJ, et al. Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins. Clin Cancer Res. 2005;11:1110–8.PubMed Koomen JM, Shih LN, Coombes KR, Li D, Xiao LC, Fidler IJ, et al. Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins. Clin Cancer Res. 2005;11:1110–8.PubMed
18.
Zurück zum Zitat Bulathsinghala P, Syrigos KN, Saif MW. Role of vitamin d in the prevention of pancreatic cancer. J Nutr Metab. 2010;2010:721365.CrossRefPubMed Bulathsinghala P, Syrigos KN, Saif MW. Role of vitamin d in the prevention of pancreatic cancer. J Nutr Metab. 2010;2010:721365.CrossRefPubMed
19.
Zurück zum Zitat Van Loon K, Owzar K, Jiang C, Kindler HL, Mulcahy MF, Niedzwiecki D, O’Reilly EM, Fuchs C, Innocenti F, Venook AP. Alliance for Clinical Trials in Oncology. 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). J Natl Cancer Inst. 2014;106. Van Loon K, Owzar K, Jiang C, Kindler HL, Mulcahy MF, Niedzwiecki D, O’Reilly EM, Fuchs C, Innocenti F, Venook AP. Alliance for Clinical Trials in Oncology. 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). J Natl Cancer Inst. 2014;106.
20.
Zurück zum Zitat Molina R, Holdenrieder S, Auge JM, Schalhorn A, Hatz R, Stieber P. Diagnostic relevance of circulating biomarkers in patients with lung cancer. Cancer Biomark. 2010;6:163–78.CrossRefPubMed Molina R, Holdenrieder S, Auge JM, Schalhorn A, Hatz R, Stieber P. Diagnostic relevance of circulating biomarkers in patients with lung cancer. Cancer Biomark. 2010;6:163–78.CrossRefPubMed
21.
Zurück zum Zitat Stieber P, Heinemann V. Sensible use of biomarkers. J Lab Med. 2008;32:339–60. Stieber P, Heinemann V. Sensible use of biomarkers. J Lab Med. 2008;32:339–60.
22.
Zurück zum Zitat Boeck S, Wittwer C, Heinemann V, Haas M, Kern C, Stieber P, et al. Cytokeratin 19-fragments (CYFRA 21-1) as a novel serum biomarker for response and survival in patients with advanced pancreatic cancer. Br J Cancer. 2013;108:1684–94.CrossRefPubMedPubMedCentral Boeck S, Wittwer C, Heinemann V, Haas M, Kern C, Stieber P, et al. Cytokeratin 19-fragments (CYFRA 21-1) as a novel serum biomarker for response and survival in patients with advanced pancreatic cancer. Br J Cancer. 2013;108:1684–94.CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Tempero MA, Uchida E, Takasaki H, Burnett DA, Steplewski Z, Pour PM. Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res. 1987;47:5501–3.PubMed Tempero MA, Uchida E, Takasaki H, Burnett DA, Steplewski Z, Pour PM. Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res. 1987;47:5501–3.PubMed
24.
Zurück zum Zitat Firpo MA, Gay DZ, Granger SR, Scaife CL, DiSario JA, Boucher KM, et al. Improved diagnosis of pancreatic adenocarcinoma using haptoglobin and serum amyloid A in a panel screen. World J Surg. 2009;33:716–22.CrossRefPubMedPubMedCentral Firpo MA, Gay DZ, Granger SR, Scaife CL, DiSario JA, Boucher KM, et al. Improved diagnosis of pancreatic adenocarcinoma using haptoglobin and serum amyloid A in a panel screen. World J Surg. 2009;33:716–22.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Dobryszycka W. Biological functions of haptoglobin—new pieces to an old puzzle. Eur J Clin Chem Clin Biochem. 1997;35:647–54.PubMed Dobryszycka W. Biological functions of haptoglobin—new pieces to an old puzzle. Eur J Clin Chem Clin Biochem. 1997;35:647–54.PubMed
26.
Zurück zum Zitat Kelly P, Paulin F, Lamont D, Baker L, Clearly S, Exon D, et al. Pre-treatment plasma proteomic markers associated with survival in oesophageal cancer. Br J Cancer. 2012;106:955–61.CrossRefPubMedPubMedCentral Kelly P, Paulin F, Lamont D, Baker L, Clearly S, Exon D, et al. Pre-treatment plasma proteomic markers associated with survival in oesophageal cancer. Br J Cancer. 2012;106:955–61.CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Ultraviolet B irradiance and vitamin D status are inversely associated with incidence rates of pancreatic cancer worldwide. Pancreas. 2010;39:669–74.CrossRefPubMed Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Ultraviolet B irradiance and vitamin D status are inversely associated with incidence rates of pancreatic cancer worldwide. Pancreas. 2010;39:669–74.CrossRefPubMed
28.
Zurück zum Zitat Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103:703–11.CrossRef Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103:703–11.CrossRef
29.
Zurück zum Zitat Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96:252–61.CrossRefPubMedPubMedCentral Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96:252–61.CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Blanke CD, Beer TM, Todd K, Mori M, Stone M, Lopez C. Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. Investig New Drugs. 2009;27:374–8.CrossRef Blanke CD, Beer TM, Todd K, Mori M, Stone M, Lopez C. Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. Investig New Drugs. 2009;27:374–8.CrossRef
31.
Zurück zum Zitat Alkhateeb A, Zubritsky L, Kinsman B, Leitzel K, Campbell-Baird C, Ali SM, et al. Elevation in multiple serum inflammatory biomarkers predicts survival of pancreatic cancer patients with inoperable disease. J Gastrointest Cancer. 2014;45:161–7.CrossRefPubMed Alkhateeb A, Zubritsky L, Kinsman B, Leitzel K, Campbell-Baird C, Ali SM, et al. Elevation in multiple serum inflammatory biomarkers predicts survival of pancreatic cancer patients with inoperable disease. J Gastrointest Cancer. 2014;45:161–7.CrossRefPubMed
32.
Zurück zum Zitat Sawaki A, Kanemitsu Y, Mizuno N, Takahashi K, Nakamura T, Ioka T, et al. Practical prognostic index for patients with metastatic pancreatic cancer treated with gemcitabine. J Gastroenterol Hepatol. 2008;23:1292–7.CrossRefPubMed Sawaki A, Kanemitsu Y, Mizuno N, Takahashi K, Nakamura T, Ioka T, et al. Practical prognostic index for patients with metastatic pancreatic cancer treated with gemcitabine. J Gastroenterol Hepatol. 2008;23:1292–7.CrossRefPubMed
33.
Zurück zum Zitat Tanaka T, Ikeda M, Okusaka T, Ueno H, Morizane C, Hagihara A, et al. Prognostic factors in Japanese patients with advanced pancreatic cancer treated with single-agent gemcitabine as first-line therapy. Jpn J Clin Oncol. 2008;38:755–61.CrossRefPubMed Tanaka T, Ikeda M, Okusaka T, Ueno H, Morizane C, Hagihara A, et al. Prognostic factors in Japanese patients with advanced pancreatic cancer treated with single-agent gemcitabine as first-line therapy. Jpn J Clin Oncol. 2008;38:755–61.CrossRefPubMed
34.
Zurück zum Zitat Stocken DD, Hassan AB, Altman DG, Billingham LJ, Bramhall SR, Johnson PJ, et al. Modelling prognostic factors in advanced pancreatic cancer. Br J Cancer. 2008;99:883–93.CrossRefPubMedPubMedCentral Stocken DD, Hassan AB, Altman DG, Billingham LJ, Bramhall SR, Johnson PJ, et al. Modelling prognostic factors in advanced pancreatic cancer. Br J Cancer. 2008;99:883–93.CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Pant S, Martin LK, Geyer S, Wei L, Van Loon K, Sommovilla N, et al. Baseline serum albumin is a predictive biomarker for patients with advanced pancreatic cancer treated with bevacizumab: a pooled analysis of 7 prospective trials of gemcitabine-based therapy with or without bevacizumab. Cancer. 2014;120:1780–6.CrossRefPubMedPubMedCentral Pant S, Martin LK, Geyer S, Wei L, Van Loon K, Sommovilla N, et al. Baseline serum albumin is a predictive biomarker for patients with advanced pancreatic cancer treated with bevacizumab: a pooled analysis of 7 prospective trials of gemcitabine-based therapy with or without bevacizumab. Cancer. 2014;120:1780–6.CrossRefPubMedPubMedCentral
Metadaten
Titel
Assessing novel prognostic serum biomarkers in advanced pancreatic cancer: the role of CYFRA 21-1, serum amyloid A, haptoglobin, and 25-OH vitamin D3
verfasst von
Michael Haas
Christoph Kern
Stephan Kruger
Marlies Michl
Dominik P. Modest
Clemens Giessen
Christoph Schulz
Jobst C. von Einem
Steffen Ormanns
Rüdiger P. Laubender
Stefan Holdenrieder
Volker Heinemann
Stefan Boeck
Publikationsdatum
01.04.2015
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 4/2015
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2885-x

Weitere Artikel der Ausgabe 4/2015

Tumor Biology 4/2015 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.