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!