1. Biomarkers: challenges or pitfalls for patients Liesbeth Lemmens Digestive oncology University hospitals Leuven

2. BIOMARKERS PANCREAS NURSES GASTRICCOLORECTAL KRAS BRAF MSI CEA – CA19,9 MUTATION PREDICTIVE PROGNOSTIC DNA PROTEIN HER2 HEREDITARY HCC OESOPHAGAL PERSONALIZED MEDICINE GENE MATCHED TARGETED THERAPY GENOME snps Tumor marker Molecular Pten depletion mRNA Would be, can be, maybe…

3. Where do we go wrong? Challenge or pitfall

4. Simple? Nucleus Encyclopedia: 46 booksChromosomes Sentences (genes) written with a code (DNA) Alphabet 4 letters organism’s entire set of genes = the genome

5. Molecular biology The basic: –DNA sequences inform the creation of RNA molecules → inform the production of proteins → determine the functions of the cell –proteins serve the most vital functions in the body enzymes, hormones, growth factors, antibodies,… Proteins can serve as markers

6. Definition A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention NIH Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin PharmacolTher 2001;69:89-95.

7. Biomarkers DNA, RNA, proteins,… Changes: –Presence or absence –Chromosomes, immune system –Gene defect, gene (over) expression –Mutations, translocations, depletions,,,, Objective presence/absence in/on: –Tissue: tumor cells – Fluid: blood, urine, bone marrow,… ± 30000 genes 25000 human proteins

8. SCREENING DETECT DISEASE BIOMARKER STAGE DISEASE MONITOR PROGRESSION/ RECURRENCE DETERMINE TOXICITY DETERMINE TREATMENT PREDICT RESPONSE TO TREATMENT Role Personalised ‘matched targeted therapy’

9. CHARACTERISTICS OF A BIO-TUMOR - MARKER Not enough for diagnosis –Normal production Eg HCG → pregnancy –Non-cancerous diseases can also cause elevation Eg AFP → hepatitis B –Every person is different –Consider person’s history Eg CEA → smoking ➥ Combination of tests is needed! → → pathologist and lab needed!

10. Screening: detect disease Hereditary (present in each cell): genetic biomarker –Colon FAP (< 2% of all CRC) – young age! HNPCC - “Lynch-syndrome”( 5% of all CRC) Juvenile poliposis coli (JPS) Peutz-Jeghersyndrome –Pancreas (5-10%) BRCA 2-gen mutation Sporadic –Colon: FOBT

11. Stage disease CA19.9 - blood –Pancreatic cancer –Nl: ≤ 37 U/ml –High(er) level = advanced disease –BUT: also elevated in IBD, pancreatitis, thyroid disease Alpha Fetoprotein (AFP) - blood –Diagnosis/guide HCC –Nl ≤ 10 ng/ml (1billionth of 1gr) BUT: Chronic hepatitis elevated! Hep. B + HCC: AFP > 4000 ng/ml –Response to treatment: Surgery: nl level of AFP Predict prognosis?

12. Predictive and prognostic markers Predictive biomarkers –Measured before treatment to identify who will or will not benefit from a particular treatment ER, HER2, KRAS Prognostic biomarkers –Measured before treatment to indicate long-term outcome for patients untreated or receiving standard treatment –Used to identify who does not require more intensive treatment

13. Predictive markers Predict if treatment is likely to work or not –HER2 (tumor tissue) Expression present at time of diagnosis Breast (poor prognosis) and gastric cancer (more agressive) Response to targeted therapy trastuzumab –KRAS (tumor tissue) Mutation present at time of diagnosis Constitutive activation of down stream signalling Within gene codon12,13 and 61 BRAF, NRAS,PIK3CA

15. Determine response/recurrence Determine response to treatment –Level may predict answer during treatment Eg CEA ↓ after 8 weeks chemotherapy: response –Cancer can be very sensitive to chemotherapy: Eg release of large amount of marker Detecting recurrence –After surgery HCC Eg AFP → elevated → recurrence?

16. Changes over time –Same lab – same units/values BeforeDuringAfter Changes over time! Staging Sign of responseSign of recurrence

17. Determine response /recurrence CEA - blood –CRC, breast, lung,… –Nl 3-5 ng/ml –BUT: increased in smoking, colitis, COPD 5-HIAA – 24h urine –Elevated levels of hormone serotonin → Neuroendocrine tumor ileum, lung, pancreas –BUT: alteration by certain drugs (paracetamol) and serotonin–rich foods ( pineapple, banana, kiwi fruit, plums, tomato, aubergine, walnuts, dates and avocado) Challenge or pitfall

18. Determine toxicity Single nucleotide polymorphisms (SNPS) –DNA sequence variation –Influence on metabolism of drugs –Mutation → more or less drug (over/under dosing) – toxicity Mutation (inherited) – UGT1A1 + irinotecan: severe (life-treath) neutropenia- diarrhea – Deficiency of DPD + 5FU: severe reactions Challenge or pitfall

19. Imaging biomarkers For screening, diagnosis, treatment and effectiviness of response RECIST – criteria: measure response FDG PET scan: identify tumor metabolic activity (using radioactive glucose) Somatostatin receptor scintigraphy: Expression of receptors (NET)

20. Targeting NETs Somatostatin receptors highly expressed by NETs –Targeting SST receptors can provide symptom and disease control New targets could change treatment paradigm : –mTOR, PI3K, VEGF inhibitors –Other antiangiogenic agents High potential for combinations PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

21. Others…. Skin toxicity and EGFR-inhibitor therapy –More skin toxicity → better response to treatment Hypomagnesemia and EGFR-inhibitor therapy – More → better response to treatment? Hypertension and anti-angiogenesis therapy –More → better response to treatment?

22. Personalized medicine Challenge or pitfalls –What do you want to know? –DNA-card? Ethical? –Quality of life? Biomarker –Identification depends on excellence? –Prevention of disease –Cost? –Self testing?

23. Conclusions ‘Perfect’ biomarker: –Only found in case of cancer –For all people –Identify the type of cancer –Tumor load –Treatment BUT: no biomarker(s) found so far Expertise and share!