road-map for translation of cancer risk biomarkers into...
TRANSCRIPT
Road-map for translation of
Cancer Risk biomarkers into
clinical practice, individual
risk assessment and
prevention.
Stefano Bonassi, PhD, ERT
Department of Human Sciences and Quality of Life
Promotion San Raffaele University, and Unit of Clinical
and Molecular Epidemiology IRCCS San Raffaele Pisana;
Rome, Italy
Porto, Portugal 27 February 2020
2
A biomarker is any
substance, structure or
process that can be
measured in the body or
its products and
influence or predict the
incidence of outcome or
disease (AIRC, 1997)
3
A biomarker is any
substance, structure or
process that can be
measured in the body or
its products and
influence or predict the
incidence of outcome or
disease (AIRC, 1997)
Genetic background
+Exposure to Environmental Carcinogens
Cancer
BIOLOGICAL EVENT:e.g., symmetrical translocationin the target organ
BIOMARKER:Unstable aberrations in PBL
BIOMARKER:Micronucleated cells in PBL
Genetic background Environmental agents
Cancer
+
BMK Early detection, diagnosis
BMK Prevention
MN and Haematological Cancer
MN and Oral Cancer, Head and Neck Cancers
MN and Colorectal Cancer
MN and Cervical Cancer
MN and Bladder Cancer
MN and Lung Cancer
MN and Prostate Cancer
MN and Breast Cancer
MN and Skin Cancer
Bonassi & Fenech, Micronuclei and Their Association with Infertility, Pregnancy
Complications, Developmental Defects, Anaemias, Inflammation, Diabetes, Chronic Kidney
Disease, Obesity, Cardiovascular Disease, Neurodegenerative Diseases and Cancer
The Micronucleus Assay in Toxicology. Chapter 4. Royal Society of Chemistry, 2019
Meta-analysis of 22
epidemiological
studies of 32P-
postlabeling DNA
adducts and lung
cancer risk in
bronchial cells
according to
smoking habits.
(Ceppi et al., 2017)
Reverse causality occurs
when the probability of the
outcome is causally related
to the exposure being
studied.
Past Present
Cancer
cases
Biomarker
+
Biomarker
-
Hagmar et al., Cancer Res, 1998
European Study Group on Cytogenetic
Biomarkers and Health - ESCH
Chromosomal
aberration
frequency in
lymphocytes
predicts the
risk of cancer:
results
from a pooled
cohort study of
22 358
subjects in 11
countries
Bonassi et al.,
Carcinogenesis, 2008
Country Subject
s
Cancer
Cases
Person
Years
Period of
Test
CA frequency
mean (sd)
Croatia 1,320 24 11,148 1982-2000 3.5 (2.3)
Hungary 840 46 6,823 1978-2001 1.9 (2.1)
Lithuania 812 24 7,478 1981-2002 3.3 (2.0)
Slovakia 2,994 55 27,135 1985-2001 2.1 (1.7)
Poland 456 22 5,012 1981-2001 1.5 (1.8)
Cekia 11,991 363 114,712 1975-1999 2.4 (1.8)
Sweden 756 48 12,740 1970-1987 1.8 (1.8)
Norway 471 48 7,936 1970-1988 1.5 (1.3)
Denmark 197 6 2,456 1987 1.8 (1.5)
Finland 557 39 10,189 1974-1988 2.3 (2.1)
Total incidence 20,394 675 205,629 1970-2002 2.4 (1.9)
Italy 1,964 99 31,818 1965-1995 3.6 (4.2)
Total 22,358 774 237,447 1965-2002 2.5 (2.2)
Bonassi et al., Carcinogenesis, 2008
CA
frequency
Cases RR 95% CI p
LOW 152 1.0 -
MEDIUM 240 1.31 1.07-1.64 0.006
HIGH 283 1.41 1.16-1.78 <0.001
All cancers (140-208)
Bonassi et al., Carcinogenesis, 2008
WWW.HUMN.ORG
Link with the disease
Numerical and structural chromosomal instability is one of
the main hallmarks of cancer and MN assays are amongst
the best validated biomarkers of this disease.
Mechanism
The role of MN in cancer has been further supported by
recent studies showing that chromosomes entrapped in MN
are shattered and massively rearranged leading to the
localised hypermutation state often seen in cancer.
Link with the exposure
Furthermore, MN assays are internationally endorsed
methods for determining the mutagenic and carcinogenic
potential of chemicals in vivo and in vitro.
(Bonassi & Fenech, The Micronucleus Assay in Toxicology. Chapter 4.
2019)
Belgium a) 146 0 599 3.9 (2.3)Bulgaria 208 4 1,264 41.1 (28.6)Croatia 202 4 1,841 59.0 (41.5)Italy a, b) 2,654 56 25,47 64.6 (4.2)Japan 833 146 7,935 52.2 (14.6)Poland 205 11 1,839 14.3 (10.0)Slovakia 926 10 7,735 12.1 (6.1)Sweden 677 31 10,440 4.1 (2.7)Taiwan 203 2 1,443 13.0 (11.1)Yugoslavia 676 4 4,408 11.6 (9.3)
Total 6,730 268 62,980 15.5 (21.0)
a) Mortality Follow up;b) Incidence data were available for 253 subjects (1,460 person-years, 7 cancer cases):
Country Sbj. Cases PY MN ‰
Cases Subjects RR* 95% CI
MN frequency
Low 51 1,313 1 Ref.Medium 91 1,433 1.84 1.28-2.66High 77 1,435 1.53 1.04-2.25
* adjusted for age, gender, smoking habit, occupational exposure, and laboratory.
CytotoxicActivity of PBL
Cases RR 95% CI p
HIGH 45 1.0 -
MEDIUM 41 1.70 1.15-2.50 <0.01
LOW 68 1.59 1.09-1.32 <0.01
All cancers (140-208)
Imai et al., Lancet 2000
Natural Cytotoxic activity of PBL and cancer
incidence (11 years FU study of a general
population)
The hCOMET cohort
Overall Mortality
LogRank test p<0.02
Total Cancer Incidence
Covariate Hazard
Ratio
95% CI P
value
Tail Intensity
2 Tertile (Medium)
3 Tertile (High)
1.11
1.06
0.78-1.57
0.76-1.48
0.55
0.75
Sex
Males 1.16 0.83-1.60 0.38
Age
5 years increase 1.10 1.08-1.11 0.001
Smoking habit
Current smoker 1.41 1.02-1.94 0.039
Genotoxic exposure
Exposed 3.73 2.08-6.69 0.001
hCOMET cohort: Cox Regression analysis
What now besides mechanistic implications ?
Surrogate endpoint of cancer at individual level, i.e., Clinical trials, Chemoprevention, Individual Risk Assessment, etc.
Cancer Risk prediction in groups exposed to genotoxins, mutagens, or bearing a susceptible genotype or phenotype.
1 2
To establish a biomarker as a Cancer Risk
Biomarker useful for individual risk assessment
some basic requirements have to be addressed:
Mechanisms known/
Association with the
disease established
Measurement of the
biomarker valid,
reproducible, repeatable,
standardized
The predictive link with
the disease is well
established and
quantitatively strong
enough to be effective at
individual level
An early identification of
individual at risk because
of altered levels of the
biomarker may contribute
to modify the prognosis
of the disease
Chromosomal
Instability/DNA
damage
Total
Cholesterol
Cancer CHD
Slide Source:
Lipids Online Slide Librarywww.lipidsonline.org
Relative Risks of CHD by Quintiles of LDL-C and HDL-C in ARIC Men
*Adjusted for age and race.
4.50
2.85
1.80
1.15
0.75
LDL-C (mg/dL)
Rela
tive R
isk o
f CH
D* 1.00
0.60
0.35
0.20
0.15
Adapted from Sharrett AR et al. Circulation 2001;104:1108-1113.©2001 Lippincott Williams & Wilkins. www.lww.com
Rela
tive R
isk o
f CH
D*
HDL-C (mg/dL)
90.9
110.2
130.0 168.2
149.3 187.5
28.6
36.3
44.1 59.6
51.8
Framingham Heart Study TG Levels and Relative Risk of CHD
Castelli WP. Ann Epidemiol 1992;2:23-28.
0.0
0.5
1.0
1.5
2.0
2.5
3.0
50 100 150 200 250 300 350 400Triglycerides (mg/dL)
Rela
tive R
isk
Men
Women
Total Cholesterol Distribution: CHD vs Non-CHD Population
35% of CHD
Occurs in People
with TC<200 mg/dL
150 200
Total Cholesterol (mg/dL)
250 300
No CHD
CHD
Framingham Heart Study—26-Year Follow-up
Road-map for translation of
Risk biomarkers into clinical
practice, individual risk
assessment and prevention.
Lesson learned
from the
Cholesterol story !
32
1° LEVEL
To discriminate between groups of subjects affected /healthy
• Provide useful hints and mechanistic insight and may indicate
potential therapeutic target.
Possible use of Biomarkers of DNA damage in individual
risk assessment/clinics
33
1° LEVEL
To discriminate between groups of subjects affected /healthy
• Provide useful hints and mechanistic insight and may indicate
potential therapeutic target.
2° LEVEL
From population to individuals
• geno/fenotipic susceptibility to cancer and other NCD’s
• Subject with risk of adverse events (safety)
• Enrichment designs (es HerB2)
• Early identification of responders
Possible use of Biomarkers of DNA damage in individual
risk assessment/clinics
Our systematic review indicates a potential
usefulness of the buccal micronucleus assay in the
prescreening and follow up of patients at risk for oral
and head and neck cancer.
Clinical application of micronucleus test in exfoliated
buccal cells: A systematic review and metanalysis,
Bolognesi et al., Mutat Res Review, 2015
Our systematic review indicates a potential
usefulness of the buccal micronucleus assay in the
prescreening and follow up of patients at risk for oral
and head and neck cancer.
A main limitation of the assay, which needs to be
addressed in the perspective of a practical
application, is the large variability in the MN
frequency observed across the laboratories in
patients as well as in control groups. The main
source for this variability is related to the different
experimental protocols and scoring criteria applied
Clinical application of micronucleus test in exfoliated
buccal cells: A systematic review and metanalysis,
Bolognesi et al., Mutat Res Review, 2015
Clinical and Genomic safety of treatment with Gingko
Biloba: A Randomized Clincal Trial. Bonassi et al.,
BMC Complementary and Alternative Medicine, 2018
37
1° LEVEL
To discriminate between groups of subjects affected /healthy
• Provide useful hints and mechanistic insight and may indicate
potential therapeutic target.
2° LEVEL
From population to individuals
• geno/fenotipic susceptibility to cancer and other NCD’s
• Subject with risk of adverse events (safety)
• Enrichment designs (es HerB2)
• Early identification of responders
3° LEVEL
Validate the use of Biomarkers in real life
Cohort studies, Intervention studies
Randomized Clnical Trials
Possible use of Biomarkers of DNA damage in individual
risk assessment/clinics
Gould AL et al. Circulation. 1998;97:946-952.
Clinical Benefits of Cholesterol Reduction• A meta-analysis of 38 trials demonstrated
that for every 10% reduction in Total
Cholesterol
–CHD mortality decreased by 15%
(P<0.001)
– total mortality decreased by 11%
(P<0.001)
• Decreases were similar for all treatment
modalities
• Cholesterol reduction did not increase non-
CHD mortality
Thank you