Biomarkers: challenges or pitfalls for patients

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Biomarkers challenges or pitfalls for patients

• Liesbeth Lemmens
• Digestive oncology
• University hospitals Leuven

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Would be, can be, maybe
GENOME
PREDICTIVE
HEREDITARY
PROTEIN
MSI
NURSES
snps
PANCREAS
KRAS
Pten
Molecular
BIOMARKERS
PERSONALIZED MEDICINE
PROGNOSTIC
GENE
Tumor marker
GASTRIC
COLORECTAL
BRAF
DNA
MUTATION
HCC
depletion
mRNA
HER2
MATCHED TARGETED THERAPY
OESOPHAGAL
CEA CA19,9
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Where do we go wrong?
Challenge or pitfall
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Simple?
Encyclopedia 46 booksChromosomes
Nucleus
Sentences (genes) written with a code (DNA)
Alphabet 4 letters
organisms entire set of genes the genome
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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
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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 20016989-95.
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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
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Role
SCREENING DETECT DISEASE
STAGE DISEASE
MONITOR PROGRESSION/ RECURRENCE
BIOMARKER
PREDICT RESPONSE TO TREATMENT
DETERMINE TOXICITY
DETERMINE TREATMENT
Personalised matched targeted therapy
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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 persons history
• Eg CEA ? smoking

? Combination of tests is needed! ? pathologist
and lab needed!
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Screening detect disease

• Hereditary (present in each cell) genetic
  biomarker
• Colon
• FAP (lt 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

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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 gt 4000 ng/ml
• Response to treatment
• Surgery nl level of AFP

Predict prognosis?
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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

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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

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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?

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• Changes over time
• Same lab same units/values

Before
During
After

Staging
Sign of response
Sign of recurrence
Changes over time!
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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 serotoninrich foods (pineapple, banana, kiwi
  fruit, plums, tomato, aubergine, walnuts, dates
  and avocado)

Challenge or pitfall
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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
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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)

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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
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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?

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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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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!