C.L.A.U.D.I.A.

Introduction:

Dr. Rafael Molina started in 2000 a protocol for the use of tumor markers in helping in the diagnosis, histological diagnosis, and therapy monitoring in patients with cancer. In 2007 the group obtained a grant to evaluate the tumor marker utility in the diagnosis and histological diagnosis of lung cancer. Results of these studies were published in 2009 and a final report including 3200 patients was published in 2016.

Objectives:

1) Help in the diagnosis and differential diagnosis in patients with suspicious signs of lung cancer (hemoptysis, lung nodules, thoracic pain, persistent cough) using a panel of tumor markers

2) Help in the histological classification of patients with lung cancer

Molina R, Marrades R, Auge JM et al. Am J Respir Crit Care Med. 2016 Feb 15;193(4):427-37c

Tumor Markers:

Initially the programme evaluated 6 tumor markers, CEA, CA 15.3, CYFRA 21.1, SCC, NSE and ProGRP, and the determination of all them were necessary.

Today it is possible to use a programme that take in account the results of tumor markers used and reevaluate them according to clinical, radiological or analytical information that may modified the markers interpretation. Programme may work with at least one tumor marker, but evidently if we use all six tumor markers it is possible to obtain the best results.

The initial results has been modified with the addition of CA 125 and CA 72.4. However, Inclusion of these biomarkers do not increase the efficiency of the programme, increasing less than 2% sensitivity and loosing more than 8% specificity. CA 19.9 may increase around 5% sensitivity, but loosing 6% of specificity. However these false positive results, using serial determination, it is not a problem and false positive results may be identified.

Programme:

The main objective is help in the differential diagnosis taking in account the possible false positive results.

Program include relevant information including well known sources of false positive results, are renal failure or liver diseases, laboratory test that may suggest it, or other factors that may produce false positive results. Inclusion of these data is not mandatory but improve the programme efficiency.

Program also suggest actions to do to be sure if a result is indicating cancer or not or is a false positive result.

Specificity using six tumor markers in a single determination is around 87% .Taking in account relevant information requested, specificity may be increased until 90%. However the most important criteria in tumor marker evaluation is follow-up. Serial tumor marker determination will increase significantly specificity, until 99%.

BIBLIOGRAPHY

REFERENCES related to this topic from members of the team or collaborators.

Muley Th, Zhang X*, Holdenrieder S, Korse CM , Zhi X,Molina R, y cols. Progastrin-releasing peptide as a biomarker for clinical response in small-cell lung cancer. Lung Cancer. In press

Parra Robert M,Molina V, Miro S, Filella X, AUge JM, Molina R. Relationship between CA 19.9 and the Lewis phenotype: Options to improve diagnostic efficiency. Anticancer Res. In press

Holdenrieder S, Molina R, Qiu L, Zhi X, Rutz S, Engel C, Kasper-Sauer P, Dayyani F, Korse CM. Technical and clinical performance of a new assay to detect squamous cell carcinoma antigen levels for the differential diagnosis of cervical, lung, and head and neck cancer.Tumour Biol. 2018 Apr;40(4):1010428318772202. doi: 10.1177/1010428318772202. PMID:29701125

Filippou PS, Ren AH, Korbakis D, Dimitrakopoulos L, Soosaipillai A, Barak V, Frenkel S, Pe’er J, Lotem M, Merims S, Molina R, Blasutig I, Bogdanos DP, Diamandis EP. Exploring the potential of mucin 13 (MUC13) as a biomarker for carcinomas and other diseases. Clin Chem Lab Med. 2018 May 16. pii: /j/cclm.ahead-of-print/cclm-2018-0139/cclm-2018-0139.xml. doi: 10.1515/cclm-2018-0139. [Epub ahead of print]. PMID:29768245

Trape J. Sant F, Franquesa J, Montesinos J. Arnau A, Sala M, Bernadich O, Martin E, Perich D, Perez C, Lopez J, Ros, Esteve E, Perez R, Aligue J, Gurt G, Catot S, Domenech M, Bosch J, Badal JM, Bonet M, Molina R, Ordei, J. Evaluation of two strategies for the interpretation of tumour markers in pleural effusions. Respiratory research, 2017;18 ISSN 1465-9921, ISSN 1465-993X

Molina R, Marrades RM, Augé JM, Escudero JM, Viñolas N, Reguart N, Ramirez J, Filella X, Molins L, Agusti A.Assessment of a Combined Panel of Six Serum Tumor Markers for Lung Cancer.Am J Respir Crit Care Med. 2016 193 - 4, pp. 427 - 437. AMER THORACIC SOC, 15/02/2016. ISSN 1073-449X, ISSN 1535-497

Catharina M. Korse, Stefan Holdenrieder, Xiu-yi Zhi, Xiaotong Zhang d, Ling Qiud, Andrea Geistanger,Marcus-Rene Lisy, Birgit Wehnl, Daan van den Broek, José M. Escudero, Jens Standopb, Mu Hu, Rafael Molina.Multicenter evaluation of a new progastrin-releasing peptide (ProGRP) immunoassay across Europe and China. Clinica Chimica Acta 438 (2015) 388–395

Trapé J, Gurt G, Franquesa J, Montesinos J, Arnau A, Sala M, Sant F, Casado E, Ordeig JM, Bergos C, Vida F, Sort P, Isava Á, González M, Molina R. Diagnostic Accuracy of Tumor Markers CYFRA21-1 and CA125 in the Differential Diagnosis of Ascites..Anticancer Res. 2015 Oct;35(10):5655-60.

Rafael Molina, Xavier Filella, J. M. Augé, J. M. Escudero. Clinical value of tumor markers Current status and future prospects III. Roche Diagnostics International Ltd CH-6343 Rotkreuz Switzerland www.cobas.com. 2013

Trapé J, Montesinos J, Catot S, Buxó J, Franquesa J, Sala M, Domenech M, Sant F, Badal JM, Arnau A. A prognostic score based on clinical factors and biomarkers for advanced non-small cell lung cancer. Int J Biol Markers. 2012 8;27:e257-62.[PubMed PMID: 22815214].

Trapé J, Molina R, Sant F, Montesinos J, Arnau A, Franquesa J, Blavia R, Martín E, Marquilles E, Perich D, Pérez C, Roca JM, Doménech M, López J, Badal JM. Diagnostic accuracy of tumour markers in serous effusions: a validation study. Tumour Biol. 2012 Oct;33(5):1661-8.PMID: 22678976 [PubMed - indexed for MEDLINE]

Molina R, Bosch X, Augé JM, Filella X, Escudero JM, Molina V, Solé M, López-Soto A. Utility of serum tumor markers as an aid in the differential diagnosis of patients w ith clinical suspicion of cancer and in patients w ith cancer of unknown primary site. Tumour Biol. 2012 Apr;33(2):463-74.PMID: 22161237 [PubMed - indexed for MEDLINE].

Escudero JM, Auge JM, Filella X, Torne A,, Pahisa J, Molina R The utility of serum Human Epididymis protein (HE4) in patients with malignant and non malignant diseases: comparison with CA 125. Clin Chem 2011 Nov;57(11):1534-44.

Molina R, Alvarez E, Aniel Quiroga A, Borque M, Candas B, Leon A, Poyatos RM, Gelabert M. Evaluation of chromogranin A determined by three different procedures in patients with benign diseases, neuroendocrine tumors and other malignancies. Tumor Biol 2011; 32:13-22

Molina R, Holdenreider S, Auge JM, Schalhorn A, Hatz R, Stieber P. Diagnostic relevance of circulating biomarkers in patients with lung cancer. Cancer BioMark 2010; 6:163-178. (Review).

Molina R, Auge JM, Bosch X, Escudero JM, Vinolas N, Marrades R et al. Usefulness of serum tumor markers, including progastrin-releasing peptide, in patients with lung cancer: correlation with histology. Tumour Biol 2009;30:121-9.

Molina R, Auge JM, Escudero JM, Marrades R, Vinolas N, Carcereny E et al. Mucins CA 125, CA 19.9, CA 15.3 and TAG-72.3 as tumor markers in patients with lung cancer: comparison with CYFRA 21-1, CEA, SCC and NSE. Tumour Biol 2008;29:371-80.

Molina R, Barak V, van Dalen A, Duffy MJ, Einarsson R, Gion M, Goike H, Lamerz R, Nap M, Döletormos G, Stieber P. Tumor markers in breast cancer. European Group on Tumor Markers (EGTM) recommendations. Internal Medicine, 2007-2008, 15-16: 31-32.

Stieber P, Hatz R, Holdenrieder S, Molina R, Nap M, von Pawel J, Schalhorn A, Schneider J, Yamaguchi K. National Academy of Clinical Biochemistry Guidelines for the use of tumor markers in lung cancer. In NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic - Lung Cancer (Section 3P). 2006; published online at www.nacb.org/lmpg/ tumor_LMPG_draft_PDF.stm

Molina R, Auge JM, Filella X, Vinolas N, Alicarte J, Domingo JM, BallestaAM. Pro-gastrin-releasing peptide (proGRP) in patients with benign and malignant diseases: comparison with CEA, SCC, CYFRA 21-1 and NSE in patients with lung cancer. Anticancer Res. 2005 May-Jun;25(3A):1773-8. PMID: 16033098 [PubMed - indexed for MEDLINE]

Fuentes R, Bover I, Rifa J, Moreno V, Canals E, Marquez A, Barreiro E, Borras J, Molina R, Viladiu P. Factors influencing survival in a prospective cohort of patients with non-small cell lung cancer: an updated assessment.Clin Oncol (R Coll Radiol). 2004 Dec;16(8):583-4. No abstract available. PMID: 15630857 [PubMed - indexed for MEDLINE]

Molina R, Filella X, Auge JM. ProGRP: a new biomarker for small cell lung cancer. Clin Biochem. 2004 Jul;37(7):505-11. Review. PMID: 15234231 [PubMed - indexed for MEDLINE]

Molina R, Auge JM, Alicarte J, Filella X, Vinolas N, Ballesta AM. Pro-gastrin-releasing peptide in patients with benign and malignant diseases.

Tumour Biol. 2004 Jan-Apr;25(1-2):56-61. PMID: 15192313 [PubMed - indexed for MEDLINE]

Trape J, Molina R, Sant F. Clinical evaluation of the simultaneous determination of tumor markers in fluid and serum and their ratio in the differential diagnosis of serous effusions.Tumour Biol. 2004 Sep-Dec;25(5-6):276-81. PMID: 15627892 [PubMed - indexed for MEDLINE]

Molina R, Filella X, Auge JM, Fuentes R, Bover I, Rifa J, Moreno V, Canals E, Vinolas N, Marquez A, Barreiro E, Borras J, Viladiu P. Tumor markers (CEA, CA 125, CYFRA 21-1, SCC and NSE) in patients with non-small cell lung cancer as an aid in histological diagnosis and prognosis. Comparison with the main clinical and pathological prognostic factors.Tumour Biol. 2003 Aug-Sep;24(4):209-18. PMID: 14654716 [PubMed - indexed for MEDLINE]

Vinolas N, Molina R, Galan MC, Casas F, Callejas MA, Filella X, Grau JJ, Ballesta AM, Estape J. Tumor markers in response monitoring and prognosis of non-small cell lung cancer: preliminary report.Anticancer Res. 1998 Jan-Feb;18(1B):631-4. PMID: 9584045 [PubMed - indexed for MEDLINE]

Molina R, Agusti C, Mane JM, Filella X, Jo J, Joseph J, Gimenez N, Estape J, Ballesta AM. CYFRA 21-1 in lung cancer: comparison with CEA, CA 125, SCC and NSE serum levels. Int J Biol Markers. 1994 Apr-Jun;9(2):96-101. PMID: 7523548 [PubMed - indexed for MEDLINE]

Molina R, Agusti C, Filella X, Jo J, Joseph J, Gimenez N, Ballesta AM. Study of a new tumor marker, CYFRA 21-1, in malignant and nonmalignant diseases. Tumour Biol. 1994;15(6):318-25. PMID: 7997803 [PubMed - indexed for MEDLINE]

Molina R, Filella X, Bruix J, Mengual P, Bosch J, Calvet X, Jo J, Ballesta AM. Cancer antigen 125 in serum and ascitic fluid of patients with liver diseases. Clin Chem. 1991 Aug;37(8):1379-83. PMID: 1868598 [PubMed - indexed for MEDLINE]

Molina R, Filella X, Torres MD, Ballesta AM, Mengual P, Cases A, Balague A. SCC antigen measured in malignant and nonmalignant diseases. Clin Chem. 1990 Feb;36(2):251-4. PMID: 2302769 [PubMed - indexed for MEDLINE]

Molina R, Santabarbara P, Filella X, Mengual P, Ballesta AM, Balague A. Relationship of CA 125 and CA 19.9 with lung carcinoma histological subtype: preliminary study. Int J Biol Markers. 1989 Oct-Dec;4(4):215-20. PMID: 2560789 [PubMed - indexed for MEDLINE]

A.M. Ballesta, R. Molina, X. Filella, M. Nolla, J.L. Marín, M. Elena, A. Balagué.

SCC Antigen in lung diseases: Preliminary results. In: Kato H, de Bruihn HWA, Ebert W, Heberman RB, Johnson JT, eds. SCC antigen in the measurement of Squamous cell carcinoma. Excerpta Medica, Princenton, 1987:180-185

P. Santabárbara, R. Molina, A.M. Ballesta, J. Estapé, A. Balagué.

Preliminary results of PHI and CEA in lung cancer. In: Peeters H ed. Protides of the biological fluids. 31, Pergamon Press, Oxford, 1984: 953-957.