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…
Where do we go wrong?
Challenge or pitfall
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?
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!
