Biomarkers: challenges or pitfalls for patients

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

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

3. Where do we go wrong? Challenge or pitfall

4. Simple? Encyclopedia: 46 booksChromosomes Nucleus 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 ± 30000 genes 25000 human proteins • 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,…

8. Role SCREENING DETECT DISEASE STAGE DISEASE MONITOR PROGRESSION/ RECURRENCE BIOMARKER PREDICT RESPONSE TO TREATMENT DETERMINE TOXICITY DETERMINE TREATMENT 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 eachcell): geneticbiomarker • Colon • FAP (< 2% of all CRC) – youngage! • HNPCC - “Lynch-syndrome”( 5% of all CRC) • Juvenilepoliposis 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 Before During After Staging Sign of response Sign of recurrence Changes over time!

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 andeffectiviness of response • RECIST – criteria: measure response • FDG PET scan: identify tumor metabolicactivity (usingradioactive 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!