and The Hidden Tumor Orly & Mira Barak Tumor Markers DiaSorin

Transcription

1 and The Hidden Tumor Orly & Mira Barak Tumor Markers DiaSorin

2 CASE A Female,74 years old Acute symptoms: Stomach ache, Fullness Weight loss-7kg in 2 months Additional health status: asthma diabetes hypertension hypothyroidism y Clinical findings: Increased liver size and tenderness Laboratory findings: Cholestatic tests impairment and increased LDH Imaging findings: Infiltrated liver with metastatic pattern Is there any need for tumor markers?

3 Case A TUMOR MARKERS

4 CASE B male,87 years old Acute symptoms: Weakness Burning on urination Weight loss-15kg in last year TUMOR MARKERS Additional health status: dyslipidemia hypothyroidism Is there any need for tumor markers?

5 CASE C Male,73years old TUMOR MARKERS Acute symptoms: Shortness of breath after a long flight with diagnosis of PE and DVT Additional health status: Hypertension Hyperparathyroidism BPH with PSA 10ng/ml Colon polypectomy Is there any need for tumor markers?

6 and The Hidden Tumor Tumor markers- to do or not to do?

7 Intermediate summary Case A: tumor markers for tumor localization? l Case B: tumor markers as screen method to rule out malignancy? Case C: tumor markers as a diagnosis mean in a monitored patient with additional suspicion of paraneoplastic involvement (hypercoagulation)?

8 History Bence Jonce 1940-acid phosphatase h 1963-AFP 1965-CEA 1980-CA125 CA125, PSA 1980-oncogenes n g n and tumor suppressor r genes 2001-microarray,mass spectrophotometry, p bioinformatics

9 Hormones (hcg; calcitonin; gastrin; prolactin) Enzymes (acid phosphatase; alkaline phosphatase; PSA) Proteins & Glycoproteins (CA 125; CA 15.3; CA 19.9) Oncofetal antigens (CEA, AFP) Receptors (ER, PR, EGFR) Oncogenes (Ras; Myc; abl-bcr) b Tumor suppressor genes (BRCA1; p53; Rb)

10 TM are usually glycoproteins found in blood or excretions, indicating the presence, course and prognosis of a neoplastic process TM are not tissue or tumor specific TM are produced by benign and malignant tissue: the difference is only quantitative TM levels are dependent on synthesis, secretion, release, clearance of the molecule as well as are dependent on tumor size, metastases and angiogenesis

11 TM are not tissue or tumor specific

12 TM are produced by benign and malignant tissue: the difference is only yquantitative Tumor Markers Cancers What else? AFP (Alphafetoprotein) Liver, germ cell cancers of ovaries or testes Also elevated during pregnancy, cirrhosis CA 15-3 Breast and others including Also elevated in benign lung and ovaries breast conditions; CA 19-9 Pancreatic, sometimes colorectal l and bile ducts Also elevated in pancreatitis and inflammatory bowel disease CA 125 ovarian Also elevated with endometriosis, some other diseases and benign conditions; pregnancy, ascites CEA (Carcino- Colorectal, lung, breast, Elevated in other conditions embryonic antigen) thyroid, pancreatic, liver, cervix, and bladder such as hepatitis, COPD, colitis, pancreatitis and in cigarette smokers

13 There are no TM normal levels -the cut-off value is determined in 95% of blood donors and patients with benign diseases of similar origin. The cut-off values are irrelevant in cancer patients: the single relevant value is the level of TM obtained during monitoring of the patient in the same lab with the same kit, since the TM kinetics is more important than its absolute value. The kinetics of the TM can differentiate between a benign and malignant n process. An increase in the TM level within the reference range may be very significant. הערות לסמני סרטן כפי שמופיעות באוטולאב :(ng/ml ) CEA ב- 95 % מהבריאים פחות מ- 5.5 :(U/ml ) CA 15-3 ב- 95% מהנבדקים פחות מ- 30 :(U/ml ) CA 125 ב- 95% מהבריאים פחות מ- 35 :(U/ml ) CA19-9 ב- 99 % מהנבדקים פחות מ- 39 :(ng/ml)/ l ALPHA FETO PROTEIN (AFP) ב- 95% מהבריאים פחות מ- 7 :PSA בב- 95% מהנבדקים קטן ממ- 4 מעל 2.5 הערכת סיכון אישי :FPSA לשקול עם מדדים נוספים הערות כלליות לכל אחד מהסמנים לל אינו שולל או מאמת ממאירות במעקב השווה לערך קודם

14 Tumor marker utility grading system (TMUGS) Level of use explanation 0 no clinical use- do not use routinely +/- There is a clinical correlation- in research- do not use routinely There is clinical correlation-unknown if the TM use has any additional value or can influence mode of therapy- do not use routinely There is additional specific information, but it should be used only together with other diagnostic means for getting g clinical significance-use routinely only in specific cases Independent diagnostic tool for routine clinical use

15 Retrospective study on 8253 patients When TM are used? Which TM are used? What was the outcome? Follow-up Clinical suspicion

16 Appropriate TM? Guidelines?

17 NACB: Tumor Markers 2009 The National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic Draft Guidelines - Second Posting Although in certain circumstances tumor markers may aid in diagnosis, speculative measurement of panel of tumor markers ( fishing ) (f g) should be discouraged

18 TM usually have a mean lead time of 3-12 months in comparison to other diagnostic means Each TM has a specific in-vivo i t 1/2 The level l of the TM is influenced by its production in benign diseases and by adjacent tissues. The TM level is influenced also by individual factors, circadian rhythm, hormones, hemodynamic and iatrogenic factors. TM levels are influenced by the sample preparation and the kits used.

19 Mean lead time treatment (TM) CT- CT- CT- CT months

20 TREATMENT T 1/ T 1/2 < (TM) TIME

21 TM kineticsi TREATMENT INCREASE DECRESE DECREASE +/-INCREASE (TM) NO CHANGE TIME

22 Follow-up by TM Clinical course TM course Malignancy progression Partial remission Complete remission Increase by >25% Decrease by >50% Not defined by TM between two tests performed within 1 month Decrease not caused by production cessation or necrosis

23 Biological variation and total error marker Intraindividual Precision% Total error% cv% P<0.05 CEA CA CA MCA CA β 2 MG PSA

24 TM standardization TM International standard year source AFP IS 72/ Cord blood CEA IRP 73/ Liver metastases HCG IS75/ Purified β hcg nicked HCG & bhcg IRP75/ PSA IS/ :10 C :F F-PSA IS96/ Free purified CA125 CA15-3 CA19-9 CA72-4 none - -

25 Intermediate summary Case A: tumor markers for tumor Case A tumor markers for tumor localization?

26 CASE A Female,74 years old Acute symptoms: Stomach ache, Fullness Weight loss-7kg in 2 months Clinical findings: Increased liver size and tenderness Laboratory findings: Cholestatic tests impairment and increased LDH Imaging findings: Additional health status: asthma diabetes hypertension hypothyroidism A huge tumor in colonoscopy Infiltrated liver with metastatic pattern

27 CEA CA 125 CA15-3 CA602 CEA IgG supergene family Immunoglobulins T cell receptor Growth factor receptor N-CAM Core protein Biliary glycoprotein Non specific cross reacting agent Core chain CA 72-4 CA 546 Peripheral chain CA 19-9 CA 50

28 Lewis antigen and CA 19-9

29 Colorectal Cancer 10% 5% 3% 15% CEA CA % 29% CA 242

30 NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic Colorectal Cancer (Section 3C)

31 2003

32 Guideline recommendations for tumor markers use 2007 Colorectal Cancer: CEA Screening and diagnosing no staging / prognosis, detecting recurrence, monitoring therapy yes Use immediate postoperative-no

33 Intermediate summary Case A: tumor markers for tumor localization l -no follow-up- yes Case B: tumor markers as screen method to rule out malignancy?

34 CASE B male,87 years old Acute symptoms: Weakness Burning on urination Weight loss-15kg in last year Additional health status: dyslipidemia hypothyroidism

35 ...do you know? "Elementary, my dear Watson has not appeared in any of Sir Conan Doyle books, but in the first Sherlock Holmes film..

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37 Intermediate summary Case A: tumor markers for tumor localization li i - no Case B: tumor markers as screen method to rule out malignancy- only PSA: yes Case C: tumor markers as a diagnosis mean in a monitored patient with additional suspicion of paraneoplastic p involvement (hypercoagulation)?

38 CASE C Male, 73 years old Acute symptoms: Shortness of breath after a long flight with diagnosis of PE and DVT Additional health status: Hypertension Hyperparathyroidism BPH with PSA 10ng/ml Colon polypectomy Prostate cancer

39 The most wide spread tumor in men Prostate Cancer Histological found in 42% of men over 50y (NO tests >75y- task force) Low mortality rate, but in advanced disease-no cure The most useful TM, found almost exclusively l in the prostate, t but in all prostate diseases NCCN 2004-cut off 2.5 ng/ml Stamey 2004: the PSA era in USA is over- the test is all but useless Catalona 2005: PSA saves lives (17% diagnosed with PC- 84% will survive due to PSA early detection and treatment) # deaths(usa) Thompson 2005: no cut-off level effectively identifies men with the disease

40 Prostate Cancer Free PSA (uncomplexed form) 5-40% of PSA %f PSA more benign PSA Complexes (cpsa) PSA- -1-antichymotrypsin (ACT) (60-95% of PSA) PSA- -1-protease inhibitor (API) (1-2.5% of PSA) etc. No previous prostate manipulations Significant change-above the test total error

41 PSA parameters T-PSA age dependent ng/ml years <2.5 <49 <3.5 <59 <4.5 <6.5 <69 <79 low specificity in older F-PSA above 13% Variability of kits PSA velocity <0.75 ng/ml/year -3 years follow-up PSA density <0.15 ng/ml per gr tissue inaccuracy of TRUS

42 PSA biological roles Pro-PSA Activation (hk2) PSA Inhibitors (Zn, Serpins) Physiological substrate(s) Other competing proteases beneficial Cell differentiation Reduced cell growth rate Induction of apoptosis Antiangiogenic stimulus Reduced migration Effect Semen liquefaction harmful Resistance to tamoxifen Releases mitogens Stimulates cell growth Activates cytokines Promotes invasion Promotes metastasis

43 Guideline recommendations for tumor markers use 2009 Prostate Cancer: PSA Screening (with DRE), diagnosis, prognosis, monitoring yes % free PSA (PSA 4-10 ng/ml and DRE negative) diagnosis yes

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45 Trousseau s syndrome: multiple definitions and multiple mechanisms -hypercoagulability l syndrome associated with cancer -By its original definition, the diagnosis i of Trousseau s syndrome is made in retrospect, when the occult malignancy is found

46 Intermediate summary Case A: tumor markers for tumor localization li - no Case B: tumor markers as screen method to rule out malignancy- only PSA: yes Case C: tumor markers as a diagnosis mean in a monitored patient with additional suspicion of paraneoplastic involvement (hypercoagulation)?- yes

47 Other frequent questions: CA -125 in males and PSA in females: Possible, but not recommended Use of TM for follow-up of rare malignancies: mesothelioma (Mesothelioma, more precisely malignant mesothelioma, is a rare form of cancer that develops from the protective lining that covers many of the body's internal organs, the mesothelium. It is usually caused by exposure to asbestos. Possible, but not recommended Use of TM in samples other than serum (sputum, peritoneal wash, pleural effusion, cyst fluid etc.): No relative values Usually no possibility of follow-up

48 When to perform TM? -Before any treatment: surgery, chemotherapy, radiotherapy, hormonal therapy -After therapy:-2-10 days according to t 1/2 of the TM -each 3 months during the first two years after treatment and each half year for the next 3 years -before each treatment change -With each suspicion of recurrence -When restaging -2-4 weeks after a clinical unexpected significant increase in 4 weeks after a cl n cal unexpected s gn f cant ncrease n the marker level during monitoring

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50 What will be in the future?

51 MALDI, matrix-assisted laser desorption/ionization; TOF, time tme of flght flight During cancer development, cancer cells and/or the surrounding microenvironment generate proteins and peptides of different type and in different concentrations than normal cells. Can be analyzed by imaging-based mass spectrometry and the patterns compared with controls to identify cancer-specific changes that may prove to be clinically useful.

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