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Biomarkers: challenges or pitfalls for patients
Liesbeth LemmensDigestive oncology
University hospitals Leuven
BIOMARKERS
PANCREAS
NURSES
GASTRIC COLORECTAL
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
MolecularPten
depletionmRNA
Would be, can be, maybe…
Simple?
Nucleus
Encyclopedia: 46 booksChromosomes
Sentences (genes) written with a code (DNA) Alphabet 4 letters
organism’s entire set of genes = the genome
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
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.
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
SCREENINGDETECT DISEASE
BIOMARKER
STAGE DISEASE
MONITOR PROGRESSION/RECURRENCE
DETERMINE TOXICITY
DETERMINE TREATMEN
T
PREDICT RESPONSE
TO TREATMENT
Role
Personalised ‘matched targeted therapy’
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!
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
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?
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
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
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?
• Changes over time
– Same lab – same units/values
Before During After
Changes over time!
Staging Sign of response Sign of recurrence
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
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
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)
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
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?
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?
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