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PROGNOSTIC VALUE OF BIOLOGIC MARKERS. Prof. Dr. Abdurrahman ŞENYİĞİT University of Dicle Department of Chest Diseases Diyarbakir-TURKEY. MAY-2009. SEP-2009. NOV- 2009. NOV- 2009. NOV 2009. MARCH-2010. APRIL-2010 (Preop).

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slide1

PROGNOSTIC VALUE OF BIOLOGIC MARKERS

Prof. Dr. Abdurrahman ŞENYİĞİT

University of Dicle

Department of Chest Diseases

Diyarbakir-TURKEY

slide9

There is some evidence that MM patients respond better to therapy if it is delivered early in the disease

Robinson BWS. Lung Cancer 2005

There is no effective cure (including surgery) for mesothelioma, and no evidence

that early detection alters outcome.

Sherpereel A, et al. Curr Opin Pulm Med 2007

introduction
INTRODUCTION
  • Mesothelioma is a universally fatal malignancy and its incidence is rising in European countries.
  • As asbestos is still widely used in developing countries, mesothelioma will remain a major problem for the coming decades.
  • In Europe, the incidence is 20 per million.
  • The annual incidence of MPM in Southeast of Turkey was found to be 42.9 per million.

Senyigit A, et al. Respiration 2000 Sherpereel A, et al. Curr Opin Pulm Med 2007

Scherpereel A. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J. 2010

what is the role of thoracoscopy for the diagnosis
What is the role of thoracoscopy for the diagnosis?
  • When a mesothelioma is suspected on clinical or radiological data, thoracoscopy is the best method to obtain the diagnosis.

ERS/ATS Task Force. Scherpereel A. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J. 2010

mesothelial markers
MESOTHELIAL MARKERS
  • The incidence of MM was 32-fold higher and 5.5-fold higher in the asbestosis population and benign pleural disease cohorts, respectively, as compared with the general Finnish population.
  • Millions of subjects with previous exposure to asbestos are at risk of developing mesothelioma. Currently, no tests exist to predict disease development. Thus many workers live with this constant anxiety, often heightened by media publicity of the deadly nature of mesothelioma and personal knowledge of colleagues who have developed the disease.
  • A biomarker that may predict disease development would have a great impact on public health.

Sherpereel A, et al. Curr Opin Pulm Med 2007Pass HI, et al. Semin Thorac Cardiovasc Surg 2009

mesothelial markers1
MESOTHELIAL MARKERS
  • The ideal biomarker for mesothelioma should therefore be capable of capturing all subtypes of mesothelioma; differentiate mesothelioma from benign pleural diseases and metastatic pleural malignancies (usually from breast or lung carcinomas); reflect disease severity or tumor load (thus allow tracking of treatment response); and predict development of mesothelioma in subjects exposed to asbestos.
  • Many candidate markers (e.g., hyaluronic acid, Cyfra 21-1, tissue plasminogen activator, etc) have been proposed but none was sufficiently accurate for clinical application.
  • Three potential markers for mesothelioma are mesothelin, megakaryocyte potentiating factor (MPF) and osteopontin.

Creaney F. J Thorac Oncol 2008

Sherpereel A, et al. Curr Opin Pulm Med 2007

soluble mesothelin or soluble mesothelin related peptides
SOLUBLE MESOTHELIN OR SOLUBLE MESOTHELIN RELATEDPEPTIDES
  • Mesothelin is a differentiation marker of mesothelial cells and is a cell surface glycoprotein.
  • The mesothelin gene produces 4 protein products:
    • megakaryocyte potentiating factor (MPF),
    • mesothelin variant 1,
    • mesothelin variant 2,
    • Soluble mesothelin-related protein (SMRP).
  • Mesothelin is expressed by normal mesothelial cells; however, it is highly overexpressed in cancers, such as MM, pancreatic, or ovarian carcinoma and 49-fold increased over normal peritoneum.

Pass HI. Semin Thorac Cardiovasc Surg 2009

slide18
SMRP
  • SMRP testing is clinically available and provides reasonable diagnostic sensitivity and specificity when applied to serum or pleural fluid.
  • The role of SMRP in predicting mesothelioma development in subjects exposed to asbestos has raised interest.

Sherpereel A, et al. Curr Opin Pulm Med 2007

slide19
SMRP
  • As a diagnostic tool
  • As a disease monitoring tool
  • As a screening tool for at-risk populations
smrp as a diagnostic tool
SMRP:As a diagnostic tool
  • Robinson et al were the first toinvestigate the SMRP in the serum of MM patients. They published that 37(84%) of 44 patients with MM had raised concentrations ofSMRP.
  • SMRP was elevatedin 1/30 lung cancers, 0/28 non-asbestos-exposed individuals,and 7/40 asbestos patients.
  • It was reported that SMRP levels were elevated in MPM compared with healthy asbestos-exposed and nonexposed individuals, and with various benign and malignant conditions of the lung and pleura.
  • SMRP levels were shown to correlate with tumor size. In the epithelial subtype of MPM, higher amounts of SMRP were measured compared with sarcomatoid MPM.
  • Anecdotically, the authors also reported on decreasing values in response to therapy and a trend towards increasing SMRP levels in patients with tumor progression.
  • In addition, they provided data which showed that SMRP might be helpful for screening asbestos-exposed individuals for early detection of mesothelioma.

Robinson BWS, et al. Lancet 2003

smrp as a diagnostic tool1
SMRP:As a diagnostic tool

1. A study comparing 3 cohorts of individuals (healthy subjects, patients with previous asbestos exposure and no pleural disease, and patients with previous asbestos exposure and benign pleural disease) to those with MM reported a specificity and sensitivity of 72% for the diagnosis of MM using an SMRP cut-off of 0.55 nM/L.

2. The largest North American SMRP study

  • Mean serum SMRP levels were higher in MM compared with lung cancer, and
  • stage I MM SMRP levels were significantly higher than those in asbestos-exposed individuals.
  • Stage II-IV SMRP serum levels were significantly higher than those for stage I MM.
  • SMRP was also noted to be consistently higher in effusion compared to serum.

Pass HI. Semin Thorac Cardiovasc Surg 2009

smrp as a diagnostic tool2
SMRP:As a diagnostic tool
  • Two large studies have evaluated the usefulness of SMRP levels in pleural fluids from patients with mesothelioma and from controls with other pleural diseases.
    • SMRP levels in pleural fluid were significantly higher than (and correlated to) corresponding serum measurements, consistent with the belief that circulating SMRP originates from pleural mesothelioma. The sensitivity and specificity of SMRP levels in pleural fluid were 77% and 76% in a multicenter study from France, and 67% and 98%, respectively, in a Western Australian cohort of 234 patients

Sherpereel A, et al. Curr Opin Pulm Med 2007

slide24

Fig 1. Serum SMRP levels for groups studied. (Adeno adenocarcinoma; LCa lung carcinoma; MPM malignant pleural mesothelioma.)

Pass HI, et al. Ann Thorac Surg 2008

slide25

Fig 2. Soluble mesothelin-related peptide (SMRP) level for differing malignant pleural mesothelioma (MPM) histologies.

Pass HI, et al. Ann Thorac Surg 2008

slide26

Fig 3. SMRP levels based on the radiographic characteristics of age- and sex-matched normal controls, not exposed to asbestos compared with asbestos exposed controls.

Pass HI, et al. Ann Thorac Surg 2008

slide27

Fig 5. SMRP levels for asbestos-exposed individuals and various malignant pleural mesothelioma (MPM) stages.

Pass HI, et al. Ann Thorac Surg 2008

slide28

Fig 7. Pleural effusion serum SMRP levels for MPM, benign, and other malignancies.

Pass HI, et al. Ann Thorac Surg 2008

slide29
SMRP
  • Schneider investigated the diagnostic and prognostic value of SMRP in sera from patients with newly diagnosed MPM (n 100), MPM patients at tumor relapse (n 29), primary lung cancer (n 139), and benign asbestosis (n 75).

Schneider J, et al. J Thorac Oncol 2008

slide31

FIGURE 1. SMRP concentrations in serum samples from patients with MPM in relation to tumor stages. There were no significant statistical differences between the individual stages.

Schneider J, et al. J Thorac Oncol 2008

slide32

FIGURE 3. Box and Whisker plot of SMRP serum concentrations in untreated MPM (MPM/pre) compared with MPM at relapse/progression after an initial therapy (MPM/progressive disease) (p 0.001,two-sided Mann-Whitney U test). Horizontal line indicates the best statistical diagnostic cutoff (1.35 nM) (y axis in logarithmic scale).

Schneider J, et al. J Thorac Oncol 2008

slide33

THE PROGNOSTIC VALUE OF SMRP

Schneider J, et al. J Thorac Oncol 2008

smrp as a disease monitoring tool
SMRP:As a disease monitoring tool
  • Serum SMRP levels parallelled tumor growth. Preliminary data suggested that serum levels of SMRP may be helpful in monitoring patient response to therapy.
  • Levels also paralleled surgical status, failing with resection and rising again with progression. Therefore, Measuring serum SMRP may be a good marker of the effectiveness of surgical debulking procedures.

Robinson BWS, et al. Lung Cancer 2005

Sherpereel A, et al. Curr Opin Pulm Med 2007

smrp as a screening tool for at risk populations
SMRP:AS A SCREENING TOOL FOR AT-RISK POPULATIONS
  • Robinson et al.measured SMRP levels in the stored serum of 40 subjects exposed to asbestos and
    • found elevated SMRP levels in seven, of whom three eventually developed mesothelioma (and one developed lung cancer) within 5 years.
    • Conversely, none of the 33 subjects with normal serum levels of SMRP developed mesothelioma after 8 years of follow-up.
    • High serum SMRP levels preceding clinical disease presentation could reflect the presence of small foci of mesothelioma that were not detectable.

Robinson BWS, et al. Lancet 2003

slide36
SMRP
  • The mesothelin biomarker represents the best available serum biomarker for mesothelioma. An elevated mesothelin level is highly suggestive of malignancy, and particularly of mesothelioma.

Creaney F. J Thorac Oncol 2008

slide38

Figure 1 Forest plot of estimates of sensitivity and specificity for mesothelin assays in the diagnosis of malignant mesothelioma. The point estimates of sensitivity and specificity from each study are shown as solid circles. Error bars are 95% confidence intervals.Numbers indicate the reference numbers of studies cited in the reference list.

Luo L. Respiratory Medicie 2009

smrp a meta analysis study
SMRPA META-ANALYSIS STUDY
  • In the present meta-analysis, the results indicate that high specificity 0.89 (95% CI 0.88-0.90); sensitivity, however, was only 0.64 (95% CI 0.61-0.68), showing that sensitivity estimates were quite low, and were more variable than specificity.
  • These data suggest that SMRP determination might be somehow helpful in confirming (ruling in) MM.

In conclusion, serum SMRP determination plays a role in the diagnosis of malignant mesothelioma. The results of SMRP assays should be interpreted in parallel with clinical findings and the results of conventional tests.

Luo L., et al. Respiratory Medicie 2009

osteopontin
OSTEOPONTIN
  • Osteopontin is a pluripotent extracellular cell adhesion protein, important in cancer progression as well as in bone matrix formation and in immune responses.
  • High levels of OPN are known to correlate with tumorinvasion, progression, or metastases.

Sherpereel A, et al. Curr Opin Pulm Med 2007

osteopontin1
OSTEOPONTIN
  • Osteopontin is expressed in many malignancies and elevated serum osteopontin levels have been reported in ovarian, colon, breast, prostate and lung cancers as well as in tuberculosis.
  • Serum osteopontin levels are higher in patients with mesothelioma compared with healthy subjects exposed to asbestos. Serum levels of osteopontin, however, have little discriminatory value in distinguishing mesothelioma from metastatic pleural carcinomas or benign asbestos pleural diseases.

Sherpereel A, et al. Curr Opin Pulm Med 2007

osteopontin2
OSTEOPONTIN
  • Although serum levels of osteopontin discriminate between mesothelioma patients and healthy controls,levels of osteopontin alone are unlikely to be of clinical value in mesothelioma diagnosis.
  • In addition, some common nonmalignant, nonpleural effusion associated conditions including coronary artery disease, interstitial pneumonia, and other benign pulmonary disease can result in increased levels of osteopontin in the serum.

Creaney F. J Thorac Oncol 2008

osteopontin3
OSTEOPONTIN
  • Serum levels of osteopontin as a prognostic factor in mesothelioma
    • Circulating osteopontin levels are inversely related to survival. High serum osteopontin levels have also been linked to advanced staging and poor prognosis in many cancers, including breast, prostate, colon, pancreatic, esophageal and lung tumors.

Sherpereel A, et al. Curr Opin Pulm Med 2007

megakaryocyte potentiating factor
MEGAKARYOCYTE POTENTIATING FACTOR
  • MPF is secreted by cells of several mesothelioma cell lines, as well as by pancreatic cancer cells. In vitro, MPF stimulates megakaryocyte colony formation.
  • Serum MPF levels were elevated in 91% of patients with mesothelioma compared with.
  • MPF levels returned to normal in patients after surgery for their peritoneal mesothelioma, suggesting that MPF may be useful in following the response of mesothelioma to treatment.

Sherpereel A, et al. Curr Opin Pulm Med 2007

smrp osteopontin and mpf
SMRP, OSTEOPONTIN AND MPF

Biomarker concentrations in serum. Biomarker concentrations were determined at least in duplicate by ELISA and individual patient values are plotted on the graph.

A, MPF; B, osteopontin; and C, mesothelin.

Creaney J. J Thorac Oncol 2008

other serum markers
OTHER SERUM MARKERS
  • Other serum markers are elevated in MM, including
    • Cytokeratin Fragment 19 (CYFRA 21-1)
    • Cancer Antigen 125 (CA125),
    • Hyaluronic acid.

Roe OD, et al. Lung Cancer 2008

other serum markers hyaluronic acid
OTHER SERUM MARKERSHYALURONIC ACID
  • The studies revealed that hyaluronic acid levels in serum were elevated in patients with MM and were significantly higher than levels seen in healthy volunteers of the same age or in malignant tumors of nonmesothelial origin.
  • Patients with asbestosis did not exhibit increased serum hyaluronan.
  • Further studies revealed that during the clinical course of the disease, serum hyaluronate increases only at an advanced stage of the cancer, rendering serum hyaluronate determination of little value for early detection of MM.

Pass HI. Semin Thorac Cardiovasc Surg 2009

other serum markers hyaluronic acid1
OTHER SERUM MARKERSHYALURONIC ACID
  • Hyaluronic acid (HA) has been proposed as a putative diagnostic marker for mesothelioma but high serum levels have been described only in advanced stage mesothelioma. Moreover a significant proportion of mesothelioma do not secrete HA. However high pleural levels of HA (higher than 100 µg/L) have been considered to be specific for MPM diagnosis.

Grigoriu b, et al. Clinical Biochemistry 2009

slide49

Results: Using a serum HA cut-off of 100 μg/L, 8 patients/33 (24.2%) were positive in the Mets group versus 20/76 (26.3%) in the MPM group and only 1/27 BPLAE patients. The area under ROC curve for serum HA in MPM versus Mets or BPLAE groups was only 0.617 while it

was 0.755 for mesothelin. In pleural fluid, both markers had similar diagnostic values

In conclusion, serum mesothelin had a better diagnostic valuethan serum hyaluronic acid and therefore may be considered asthe reference biological marker in MPM diagnosis. In pleural effusion, bothmarkers were equally effective in diagnosing MPM.

Grigoriu b, et al. Clinical Biochemistry 2009

vascular endothelial growth factor vegf
VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
  • VEGF is known to be an important regulator of angiogenesis and has critical roles in endothelial cell proliferation, vascular permeability, and angiogenesis in several inflammatory lesions.

Amati M. Mutation Research. 2008

slide52

FIGURE 3. Survival of MPM subjects according to serum

VEGF levels. Estimates of the probability of survival were calculated using the Kaplan-Meier method and compared using the log-rank test.

Yasimatsu A. J Thorac Oncol 2010

conclusion
CONCLUSION
  • Biological markers such as soluble mesothelin related peptides and osteopontin are currently studied.
  • The proposed markers have insufficient accuracy to replace cytohistology as the gold standard for diagnosis for mesothelioma.
  • Because of the sensitivity and specificity of available biological markers, and because of the prevalence of the disease, the number of false-positive tests would be several times higher than true-positive subjects identified if screening was proposed to all asbestos-exposed subjects. Therefore, biological markers cannot be presently proposed as screening tools.
  • The usefulness of biological markers should be further evaluated in selected highly exposed populations included in voluntary surveillance protocols.
  • Studies are therefore ongoing to identify new mesothelioma-specific markers.