European Journal of Internal Medicine
Volume 18, Issue 3 , Pages 175-184 , May 2007

Role of tumor markers in patients with solid cancers: A critical review

  • Michael J. Duffy

      Affiliations

    • Corresponding Author InformationNuclear Medicine Laboratory, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. Tel.: +353 1 2094378; fax: +353 1 2696018.

Received 16 December 2005 ,Revised 3 November 2006 ,Accepted 15 December 2006.

References 

  1. Duffy MJ. Clinical uses of tumor markers: a critical review. Crit Rev Clin Lab Sci. 2001;38:225–262
  2. Thomas CMG, Sweep CGJ. Serum tumor markers: past, state of the art and future. Int J Biol Markers. 2001;16:73–86
  3. Roulston JE. Limitations of tumor markers in screening. Br J Surg. 1990;77:961–962
  4. Woods WG, Tuchman M, Robison LL, Bernstein M, Leclerc JM, Brisson LC, et al. A population-based study on the usefulness of screening for neuroblastoma. Lancet. 1996;348:1682–1687
  5. Regan LS. Screening for hepatocellular carcinoma in high-risk individuals, a clinical review. Arch Intern Med. 1989;149:1741–1744
  6. Daniele B, Bencivenga A, Megna AS, Tinessa V. Alfa-fetoprotein and ultrasonagraphy screening for hepatocellular carcinoma. Gastroenterology. 2004;127:S108–S112[suppl]
  7. Jacobs I, Skates SJ, MacDonald N, et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet. 1999;353:1207–1210
  8. Bell R, Petticrew M, Sheldon T. The performance of screening tests for ovarian cancer: results of a systematic review. Br J Obstet Gynaecol. 1998;105:1136–1147
  9. de Koning HJ, Schroder FH. PSA screening for prostate cancer. Ann Oncol. 1998;9:1293–1296
  10. Hernandez J, Thompson IM. Prostate-specific antigen: a review of the validation of the most commonly used cancer biomarker. Cancer. 2004;101:894–904
  11. Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. J Urol. 1994;151:1283–1290
  12. Carter HB, Morrell CH, Pearson JD, Brant LJ, Plato CC, Metter EJ, et al. Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease. Cancer Res. 1992;52:3323–3328
  13. Duffy MJ. PSA as a marker for prostate cancer. Ann Clin Biochem. 1996;33:511–519
  14. Bunting PS. Screening for prostate cancer with prostate specific antigen: beware of the biases. Clin Chim Acta. 2002;315:71–97
  15. Zappa M, Ciatto S, Bonardi R, Mazzotta A. Overdiagnosis of prostate carcinoma by screening: an estimate of the Florence Screening Pilot Study. Ann Oncol. 1998;9:1297–1300
  16. Ford ME, Havstad SL, Demers R, Johnson CC. Effect of false-positive prostate cancer screening results on subsequent positive cancer screening behavior. Cancer Epidemiol Biomarkers Prev. 2005;14:190–194
  17. Roddam AW, Duffy MJ, Hamdy FC, Milford Ward A, Patnick J, Price C, et al. Use of PSA isoforms for the detection of prostate cancer in men with a PSA level of 2–10 ng/ml: systematic review and meta-analysis. Eur Urol. 2005;48:386–399
  18. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level <4 ng per millilitre. N Engl J Med. 2004;350:2239–2246
  19. Carter HB. Prostate cancers in men with low PSA levels, must we find them?. N Engl J Med. 2004;350:2292–2294
  20. Price C, Allard J, Davies G, Dawnay A, Duffy MJ, France M, et al. Pre- and post-analytical factors that may influence use of serum prostate specific antigen and its isoforms in a screening programme for prostate cancer. Ann Clin Biochem. 2001;38:188–216
  21. Ilic D, O'Connor D, Green S, Wilt T. Screening for prostate cancer (Review). The Cochrane Collaboration. J Wiley and Sons Ltd.; 2006;Issue 4
  22. De Koning HJ, Auvinen A, Berenguer Sanchez A, Calais da Silva F, Ciatto S, Denis L, et al. Large-scale randomised prostate cancer screening trials: program performances in the European randomised screening for prostate cancer trial and the prostate, lung, colorectal and ovary cancer trial. Int J Cancer. 2002;97:237–244
  23. Gohagan JK, Prorok PC, Kramer BS, Hayes RB, Joyce E. The prostate, lung, colorectal and ovarian cancer screening trial of the National Cancer Institute. Cancer. 1995;75(Suppl 7):1869–1873
  24. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society Guidelines for the Early Detection of Cancer. CA Cancer J Clin. 2006;56:11–25
  25. US Preventive Services Task Force . Screening for prostate cancer: recommendations and rationale. Ann Intern Med. 2002;137:915–916
  26. Semjonow A, Albrecht W, Bialk P, Gerl A, Lamerz R, Schmid H-P, et al. Tumor markers in prostate cancer: EGTM recommendations. Anticancer Res. 1999;19:2785–2820
  27. Gamble AR, Bell JA, Ronan JE, Pearson D, Ellis IO. Use of tumor markers to identify primary site of metastatic cancer. Br Med J. 1993;306:295–298
  28. Savage P. Tumor markers of unknown primary origin: a clinical perspective. Ann Clin Biochem. 2006;43:1–2
  29. NCCN Practice Guidelines in Oncology, v.1.2005, Occult Primary. http://www.nccn.org/professionals/physician_gls/PDF/occult.pdf Accessed 1 Nov, 2006.
  30. Briasoulis E, Tolis C, Bergh J, Pavlidis N. ESMO minumum clinical recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP). Ann Oncol. 2005;16(Suppl 1):i75–i76
  31. Bosl GJ, Geller NL, Cirrincione C, Nisselbaum J, Vugrin D, Whitmore WF, et al. Serum tumor markers in patients with metastatic germ cell tumors of the testis. A 10-year experience. Am J Med. 1983;75:29–35
  32. Jacobs IJ, Rivera H, Oram DH, Bast RC. Differential diagnosis of ovarian cancer with tumour markers CA 125, CA 15-3, and TAG-72-3. Br J Obstet Gynaecol. 1993;100:1120–1124
  33. Schutter EM, Kenemans P, Sohn C, Kristen P, Crombach G, Westermann R, et al. Diagnostic value of pelvic examination,ultrasound and serum CA 125 in post-menopausal women with a pelvic mass. Cancer. 1994;74:1398–1406
  34. Duffy MJ, Bonfrer JM, Kulpa J, Rustin GJS, Soletormos G, Torre GC, et al. CA 125 in ovarian cancer: European Group on Tumor Markers (EGTM) guidelines for clinical use. Int J Gynecol Cancer. 2005;15:679–691
  35. Earle CC, Schrag D, Neville BA, Yabroff KR, Topor M, Fahey A, et al. Effect of surgeon specialty on processes of care and outcome for ovarian cancer patients. J Natl Cancer Inst. 2006;98:172–180
  36. ACOG Committee Opinion . The role of the generalist obstetrician–gynecologist in the early detection of ovarian cancer. Obstet Gynecol. 2002;100:1413–1416
  37. Bosl GJ, Motzer RJ. Testicular germ-cell cancer. N Engl J Med. 1977;337:242–251
  38. von Eyben FE. Laboratory markers and germ cell tumors. Crit Rev Clin Lab Sci. 2003;40:377–427
  39. Gori S, Porrozzi S, Roila F, Gatta G, De Giorgi U, Marangolo M. Germ cell tumors of the testis. Crit Rev Oncol Haematol. 2005;53:141–164
  40. Lonning PE. Study of suboptimum treatment response: lessons from breast cancer. Lancet Oncol. 2003;4:177–185
  41. Duffy MJ. Estrogen receptors: role in breast cancer. Crit Rev Clin Lab Med. 2006;43:325–347
  42. Ross JS, Fletcher JA, Linette GP, Clark E, Ayers M, Symmans WF, et al. The HER-2/neu and protein in breast cancer 2003: biomarker and target of therapy. Oncologist. 2003;8:307–325
  43. Duffy MJ. Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clin Chem. 2002;48:1194–1197
  44. Diblasio CJ, Kattan MW. Use of nomograms to predict the risk of disease recurrence after definitive local therapy for prostate cancer. Urology. 2003;62(Suppl 6B):9–18
  45. Kattan MW, Eastham JA, Stapleton AMF, Wheeler M, Scardino PT. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst. 1998;90:766–711
  46. Duffy MJ. CEA as a marker for colorectal cancer: is it clinically useful. Clin Chem. 2001;47:624–630
  47. Sener SF, Imperato SF, Chmiel J, Fremgen A, Sylvester JA. The use of cancer registry data to study preoperative carcinoembryonic antigen level as an indicator of survival in colorectal cancer. CA A Cancer J Clin. 1989;39:50–56
  48. Board RE, Bruijns CTPH, Pronk AE, Ryder WD, Wilkinson PM, Welch R, et al. Stage- and CA 125-related survival in patients with epithelial ovarian cancer treated at a cancer center. Int J Gynecol Cancer. 2006;16(suppl 1):18–24
  49. Fayers PM, Rustin G, Wood R, Nelstrop A, Leonard RC, Wilkinson P, et al. The prognostic value of serum CA 125 in patients with advanced ovarian carcinoma: an analysis of 573 patients by the Medical Research Council Working Party on Gynaecological Cancer. Int J Gynecol Cancer. 1993;3:285–292
  50. Pujol JL, Molinier O, Ebert W, Daures JP, Barlesi F, Buccheri G, et al. CYFRA 21-1 is a prognostic determinant in non-small cell lung cancer: results of a meta-analysis in 2063 patients. Br J Cancer. 2004;90:2097–2105
  51. International Germ Cell Cancer Collaborative Group. International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol. 1997;15:594–603
  52. Seki K, Matsui H, Sekiya S. Advances in the clinical laboratory detection of gestational trophoblastic disease. Clin Chim Acta. 2004;349:1–13
  53. Lee KL, Ma JF, Shortliffe LD. Neuroblastoma: management, recurrence and follow-up. Urol Clin North Am. 2003;30:881–890
  54. UICC (International Union Against Cancer) . In:  Sobin LH,  Wittekind Ch editor. TNM classification of malignant tumors. 6th ed.. New York: Wiley–Liss; 2002;
  55. Lamerz R, Albrecht W, Bialk P, Dati F, Duffy MJ, Gerl A, et al. Tumor markers in germ cell cancers: EGTM recommendations. Anticancer Res. 1999;19:2795–2798
  56. Huddart RA, Purkalne G. ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of mixed or non-seminomatous germ cell tumors (NSGCT). Ann Oncol. 2004;16(Suppl 1):i37–i39
  57. Pilar Laguna M, Pizzocaro G, Klepp O, Algaba F, Kisbenedek L, Leiva O, et al. EAU guidelines on testicular cancer. Eur Urol. 2001;40:102–110
  58. Benson AB, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, et al. American Society of Clinical Oncology Recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22:3408–3419
  59. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ, et al. Meeting highlights: International Expert Consensus on the primary therapy of early breast cancer 2005. Ann Oncol. 2005;16:1569–1583
  60. Molina R, Barak V, van Dalen A, Duffy MJ, Einarsson R, Gion M, et al. Tumor markers in breast cancer: European Group of Tumor Markers (EGTM) recommendations. Tumor Biol. 2005;26:281–293
  61. Mirza AN, Mirza NQ, Vlastos G, Singletary E. Prognostic factors in mode-negative breast cancer. A review of studies with sample size more than 200 and follow-up more than 5 years. Ann Surg. 2002;235:10–26
  62. Janicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Sweep F, et al. For the German Chemo No Study Group Randomized adjuvant chemotherapy trial in high-risk node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst. 2001;93:913–920
  63. Look MP, van Putten WLJ, Duffy MJ, Harbeck N, Christensen U, Thomssen C, et al. Pooled analysis of prognostic impact of tumor biological factors uPA and PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst. 2002;94:116–128
  64. Harbeck N, Kates RE, Schmitt M. Clinical relevance of invasion factors urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 for individualised therapy in primary breast cancer is greatest when used in combination. J Clin Oncol. 2002;20:1000–1007
  65. Harbeck N, Kates RE, Look MP, Meijer-van Gelder M, Klijn JGM, Kruger A, et al. Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (N=3424). Cancer Res. 2002;62:4617–4622
  66. Simon R. Development and validation of therapeutically relevant multi-gene biomarker classifiers. J Natl Cancer Inst. 2005;97:866–867
  67. Duffy MJ. Predictive markers in breast and other cancers. Clin Chem. 2005;51:494–503
  68. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER-2 for metastatic breast cancer that overexpressed HER-2. N Engl J Med. 2001;344:783–792
  69. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER-2-positive breast cancer. N Engl J Med. 2005;353:1673–1684
  70. Piccart-Gebhart MJ, Proctor M, Leyland-Jones B, Goldhirch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER-2-positive breast cancer. N Engl J Med. 2005;353:1659–1684
  71. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139
  72. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib. Science. 2004;304:1497–1500
  73. Chan SK, Gullick WJ, Hill ME. Mutations of the epidermal growth factor receptor in non-small cell lung cancer, search and destroy. Eur J Cancer. 2006;42:17–23
  74. Joensuu H. Gastrointestinal stromal tumors (GIST). Ann Oncol. 2006;17(Suppl 10):280–286
  75. De Giorgi U, Verweij J. Imatinib and gastrointestinal tumors: where do we go from here?. Mol Cancer Ther. 2005;4:495–501
  76. Anonymous . Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. J Clin Oncol. 1996;14:2843–2877
  77. Bast RC, Ravdin P, Hayes DF, Bates S, Fritsche H, Jessup JM, et al. 2000 Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865–1878
  78. Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in 2 large breast cancer databases. J Clin Oncol. 2003;21:1973–1979
  79. Dowsett M, Cuzick J, Wale C, Howell T, Houghton J, Baum M. Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status. J Clin Oncol. 2005;23:7512–7517
  80. The Breast International Group (BIG) 1–98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353:2747–2757
  81. Slamon D, Pegram M. Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol. 2001;28(Suppl 3):13–19
  82. Arteaga CL. Epidermal growth factor dependence in human tumors: more than just expression?. Oncologist. 2002;7(Suppl 4):31–39
  83. Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res. 2005;11:397–405
  84. Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U. Epidermal growth factor receptor gene mutations and increased copy number predict gefitinib sensitivity in patients with recurrent non-small cell lung cancer. J Clin Oncol. 2005;23:6829–6837
  85. Hirsch FR, Varella-Garcia M, McCoy J, McCoy J, West H, Xavier AC, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridisation associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol. 2005;23:6838–6845
  86. Duffy MJ. Serum tumor markers in breast cancer: are they of clinical value. Clin Chem. 2006;52:345–351
  87. Rustin GJS. Use of CA 125 to assess response to new agents in ovarian cancer trials. J Clin Oncol. 2003;21:187s–193s
  88. Fisher PM, Hancock BW. Gestational trophoblastic disease and their treatment. Cancer Treat Rev. 1997;23:1–16
  89. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol. 1994;152:1821–1825
  90. D'Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH. Surrogate end point for prostate-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst. 2003;95:1376–1383
  91. Sherman SI. Thyroid carcinoma. Lancet. 2003;361:501–511
  92. Spencer CA, LoPresti JS, Fatemi S, Nicloff JT. Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid. 1999;9:435441
  93. FIGO Oncology Committee (Ngan HYS) . FIGO staging for gestational trophoplastic neoplasia 2000. Int J Gynecol Obstet. 2002;77:285–287
  94. Bruinvels DJ, Stiggelbout AM, Kievit J, van Houwelingen HC, Habbema DF, van de Velde CH. Follow-up of colorectal cancer: a meta-analysis. Ann Surg. 1994;219:174–182
  95. Rosen M, Chan L, Beart RW, Vukasin P, Anthone G. Follow-up of colorectal cancer: a meta analysis. Dis Colon Rectum. 1998;41:1116–1126
  96. Renehan AG, Egger M, Saunders MP, O'Dwyer ST. Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. Br Med J. 2002;324:813–816
  97. Figueredo A, Rumble RB, Maroun J, Earle CC, Cummings B, McLeod R, et al. Follow-up of patients with curatively resected colorectal cancer: a practice guideline. BMC Cancer. 2003;3:26–39
  98. Jeffery GM, Hickey BE, Hider P. Follow-up strategies for patients treated for nonmetastatic colorectal cancer (Cochrane Review). In: The cochrane library issue 2. Chichester, UK: John Wiley and Sons, Ltd.; 2004;
  99. Duffy MJ, van Dalen A, Haglund C, Hansson L, Klapdor R, Lamerz R, et al. Clinical utility of biochemical markers in colorectal cancer: European Group on Tumor Markers (EGTM) guidelines. Eur J Cancer. 2003;39:718–727
  100. NCCN Practice Guidelines in Oncology, v.2.2006, Thyroid Carcinoma http://www.nccn.org/professionals/physician_gls/PDF/thyroid.pdf Accessed 1 November 2006.
  101. Cheung K, Graves CRL, Robertson JFR. Tumour marker measurements in the diagnosis and monitoring of breast cancer. Cancer Treat Rev. 2000;26:91–102
  102. Robertson JFR, Jaeger W, Syzmendera JJ, Selby C, Coleman R, Howell A, et al. The objective measurement of remission and progression in metastatic breast cancer by use of serum tumor markers. Eur J Cancer. 1999;35:47–53
  103. Rustin GJS, Nelstrop AE, McClean P, et al. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol. 1996;14:1545–1551
  104. Gronlund B, Hagdall C, Hilden J, Engelholm SA, Hogdall EVS, Hansen HH. Should CA 125 response criteria be preferred to response evaluation criteria in solid tumors (RECIST) for prognostication during second-line chemotherapy of ovarian cancer. J Clin Oncol. 2004;22:4051–4058
  105. Horwich A, Peckham MJ. Transient tumor marker elevation following chemotherapy for germ cell tumors of the testis. Cancer Treat Rep. 1986;70:1329–1331
  106. Yasasever V, Dincer M, Camlica H, Karalogly D, Delay N. Utility of CA 15-3 and CEA in monitoring breast cancer patients with bone metastasis: special emphasis on “spiking “ phenomena. Clin Biochem. 1997;30:53–56
  107. Sorbye H, Dahl O. Transient CEA increase at start of oxaliplatin combination therapy for metastatic colorectal cancer. Acta Oncol. 2004;43:495–498
  108. Diamandis EP, van der Merwe D-E. Plasma protein profiling by mass spectrometry for cancer diagnosis: opportunities and limitations. Clin Cancer Res. 2005;11:963–965
  109. Duffy MJ, Kelly ZD, Culhane A, O'Brien S, Gallagher WM. DNA microaaray-based gene expression profiling in cancer: aiding cancer diagnosis, assessing prognosis and predicting response to therapy. Curr Pharmacogenomics. 2005;3:289–304
  110. Brennan D, O'Brien S, Fagan A, Culhane AC, Higgins DG, Duffy MJ, et al. Application of DNA microarray technology in determining breast cancer prognosis and therapeutic response. Expert Opin Biol Ther. 2005;5:1069–1083
  111. Van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–536
  112. van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009
  113. van't Veer LJ. Molecular strategies improve therapeutic decisions. Eur J Cancer. 2006;4:2–3
  114. Negm RS, Verma M, Srivastava S. The promise of biomarkers in cancer screening and detection. Trends Mol Med. 2002;8:288–293
  115. Rai AJ, Chan DW. Cancer proteomics: serum diagnostics for tumor marker discovery. Ann N Y Acad Sci. 2004;1022:286–294

PII: S0953-6205(07)00004-0

doi: 10.1016/j.ejim.2006.12.001

European Journal of Internal Medicine
Volume 18, Issue 3 , Pages 175-184 , May 2007

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