gene-environment interaction

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Dr. Francesco Graziano
Dipartimento di Onco-Ematologia, SOC
Oncologia Azienda Ospedaliera Ospedali Riuniti
Marche Nord
VEGF inhibitors predictive markers and
biological insights
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ANTI ENDOTHELIAL CELLS - Angyostatin -
Endostatin - TNP 470 - Thalidomide
ANTI VEGF/VEGF-R Monoclonal Abs - Bevacizumab
(VEGF) - IMC-IC11 (VEGF-R2) - VEGF-trap (soluble
rec.) VEGF-R TKI - PTK787/ZK222 584 - SU11248 -
BAY43-9006 - AG013736 - ZD 6474 - CP-547, 632
MMPS INHIBITORS - Marimastat - Prinomastat
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Displaying the battlefield.
an example of what survival curves say in
metastatic colorectal cancer
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Bevacizumab and chemotherapy as initial treatment
for metastatic colorectal cancer
Cetuximab and chemotherapy as initial treatment
for metastatic colorectal cancer
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Cetuximab and chemotherapy as initial treatment
for metastatic colorectal cancer
Bevacizumab and chemotherapy as initial treatment
for metastatic colorectal cancer
The KRAS mutational status effect
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A KRAS effect in the Bevacizumab therapy?
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Predictive markers of benefit from anti-VEGF
agents
The Timeline of the Search
Baseline Dynamic markers
Baseline markers
Dynamic markers
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Focus on VEGF a central mediator of angiogenesis
There are at least 6 isoforms of VEGF-A arising
by alternative exon splicing. VEGF165 is
predominant
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Focus on microvessel density and VEGF-A
expression Baseline markers for differences in
the activity of anti-VEGF therapeutics?
Low MVD
Low VEGF
High VEGF
High MVD
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Summary of Results for baseline biomarkers
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Following the timeline Imaging in patients
treated with anti-VEGFWhat can we see?
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Imaging by DCE-MRI.(two compartments model)
Kinetic modeling of contrast agent distribution
is based on diffusion of solute across a
semipermeable membrane...the value of Ktrans at
any location will reflect local blood flow,
endothelial permeability, endothelial surface
area.
Ve
Vp
Ktrans
Plasma Extracellular extravascular space
Blood flow
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The Ktrans drop reflects the decrease in tumor
vascular permeability and/or flow and it is
consistent with vascular normalization
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A new option among baseline markers genetics
Polimorfismo
Mutazione
Proteina normale
Attivazione o silenziamento del gene
Proteina alterata
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A new option among baseline markers..polymorphism
s
Esone
5-UTR
3-UTR
Introne
promoter
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VEGF gene is highly polymorphic..is there a
predictive role for VEGF polymorphisms?
Promoter region
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Data from a randomized trial for the predictive
role of - VEGF/VEGFR-2 polymorphisms
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VEGF Polymorphisms and Predictive Value in
ECOG-2100 (Pac /- Bev Metastatic Breast Cancer)
Kaplan-Meier curve for overall survival (OS) in
experimental arm by genotype (A) vascular
endothelial growth factor (VEGF)-2578 C/A (B)
VEGF-1154 G/A

• Caveats
• Predictive for OS, but not PFS
• Small numbers

Schneider, et al. J Clin Oncol 2008
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PRO.Ve.TT.A - Background
Pts treated with first-line FOLFIRI and
bevacizumab
Pts treated with first-line FOLFIRI
BEVACIZUMAB GROUP N111
CONTROL GROUP N107
Investigated VEGF SNPs

• -2578 A/C (rs699947)
• -1498 C/T (rs833061)
• 405 C/G (rs2010963)
• 936 C/T (rs3025039)

Promoter region
5 Untranslated Region
3 Untranslated Region
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VEGF -1498 C/T variants and PFS
BEVACIZUMAB GROUP
CONTROL GROUP
-1498 T/T (N25) median PFS 8.6 months -1498 C/T
(N55) median PFS 8.2 months -1498 C/C (N27)
median PFS 8.0 months Logrank test p 0.662
-1498 T/T (N29) median PFS 7.5 months -1498 C/T
(N60) median PFS 10.5 months -1498 C/C (N22)
median PFS 12.8 months Logrank test p 0.0046
T/T
T/T
C/T
C/T
C/C
C/C
Loupakis et al. ECCO-ESMO 09
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VEGF -1498 C/T variants and PFS
-1498 T/T (N29) median PFS 7.5 months -1498 C-
(N82) median PFS 11.1 months HR 2.13
1.41-5.10 Logrank test p 0.0046
T/T
C/T C/C
Loupakis et al. ECCO-ESMO 09
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PRO.Ve.TT.A Statistical design
To detect a HR for PFS of 1.7 for -1498 T/T vs C-
variant

• Setting
• a-error 0.05
• ß-error 0.10
• -1498 T/T prevalence 25...

According to Schoenfeld design ? 199 events
required
Assuming a 25 of censored patients
265 patients should be included
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Hypertension as a result of VEGF inhibition
Hypertension as a surrogate marker for anti-VEGF
activity ?
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Data from a randomized trial for the predictive
role of Hypertension
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Grade 3/4 Hypertension Is Associated With
Improved Median OS in E2100 (taxol /- Bev in
Metastatic Breast Cancer)
Median OS 38.7 mo p0.002 25.3 mo
Schneider et al J Clin Oncol, 2008
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Data from other two randomized trials showed
association between hypertension and improved
clinical outcomes under treatment with Bevacizumab
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but
5,900 patients from 6 studies in metastatic cancer
AVF2107g(colorectal)
NO16966(colorectal)
AVADO(breast)
AVOREN(Renal cell)
RIBBON-1(breast)
AVAiL(NSCLC)
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Caveats in HT studiesCut-off values?Rapid
onset or slow increase?Effects of medical
management of hypertension?Differences among
diseases?
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Turnover of circulating endothelial cells as
surrogate marker of anti-VEGF activity?

Circulating Endothelial Progenitors (CEP)
CD133CD34VEGFR2
Neo-angiogenesis
Circulating Endothelial Cells (CEC)
CD146CD34CD45-
Neo-angiogenesis Damage?

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Analysis in 435 out of 755 patients in the
CAIRO-2 study
Which patients from the CAIRO-2?

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VEGF production seems important in the early
stages, while progression is accompanied by
altered production of other angiogenic factors

Analysis of Circulating Levels
VEGFPIGFPDGF bFGFIL-8
Progression?

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Circulating vascular endothelial growth factor
(VEGF) as a biomarker for bevacizumab-based
therapy in metastatic colorectal, non-small cell
lung, and renal cell cancers Analysis of phase
III studies.

Bernaards C et al Abstr 10519
Baseline VEGF levels in 1816 patients from
AVF2107g(colorectal)
AVAiL(NSCLC)
AVOREN(Renal cell)
Higher circulating VEGF levels were associated
with shortened PFS and overall survival
regardless of bevacizumab treatment The
distributions of circulating VEGF levels were
similar across the tumor types Measurement of
baseline circulating VEGF levels may be useful as
a prognostic biomarker, but not as a predictive
biomarker for bevacizumab-based treatment benefit
in metastatic colorectal, lung, and renal cell
cancers.

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Neither the baseline levels of VEGF nor those of
VEGFR2 were associated with differences in PFS or
OS, but

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Dynamic changes of cytokine levels




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In conclusion..where do we stand?
hypertension
VEGF polys
DCE-NMR
PDGF MMP-9 bFGF
IL-8