Genetic Variations in the PI3K/PTEN/AKT/mTOR Pathway are Associated with Clinical Outcomes in Esophageal Cancer Patients Treated with Chemoradiotherapy

1
Genetic Variations in the PI3K/PTEN/AKT/mTOR
Pathway are Associated with Clinical Outcomes in
Esophageal Cancer Patients Treated with
Chemoradiotherapy

• Michelle Hildebrandt, Ph.D.InstructorDepartment
  of Epidemiology

2
Outline

• Pathway
• Experimental Details
• Results
• Conclusions
• Future Directions

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PI3K/PTEN/AKT/mTOR Pathway
4
Downstream Processes
Manning and Cantley, Cell (2007)
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Major Effectors

• PI3K
• PTEN
• AKT
• mTOR

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PI3K and PTEN

• Sensor of cellular environment
• PI3K activated by receptors at membrane
• RTK and GPCR
• Transmitted through
  PIP2/3
• PIP3 on
• PIP2 off
• PTEN removes
  activation signal

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AKT

• Major adaptor protein
• 3 isoforms (AKT1/2/3)
• AKT1 and AKT2 most important for this pathway in
  cancer

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mTORmammalian Target Of Rapamycin (FRAP1)

• Involved in regulation of translation

Y Mamane, et al, Oncogene (2006)
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Importance in Cancer

• Balance between cell survival and apoptosis
• Activated ? Survival
• This pathway is often constitutively active in
  MANY cancers
• Gene amplifications
• Activating mutations
• Silencing of PTEN ? no regulation

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Chemotherapy Response

• In lung and ovarian cell lines
• Overexpression of PIK3CA and reduced PTEN
  activity results in cisplatin resistance
• Cisplatin resistance associated with AKT
  overexpression
• Inhibition of AKT increases efficacy of
  paclitaxel
• Inhibition of mTOR increases cisplatin efficacy
• Increased AKT activity found to increase response
  to 5-FU

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Esophageal Cancer

• Estimated gt16,000 new EC cases each year in the
  US
• Rate of adenocarcinoma increasing rapidly
• Mirror rates of obesity ? gastroreflux
• Surgery is standard treatment
• Multimodal approaches are often used
• 5-year survival rate of 25-28

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Esophageal Cancer

• Phosphorylation of AKT increased during
  progression from Barretts to EC
• PI3K/PTEN/AKT/mTOR Pathway is activated in EC

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The Question

• For EC patients treated with a taxane,
  fluoropyrimidine and/or platinum agent
• Is genetic variation within the
  PI3K/PTEN/AKT/mTOR pathway associated with
  variation in clinical outcomes?

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Experimental DetailsPatient Characteristics

• 186 Caucasian patients with resectable
  adenocarcinoma or squamous cell carcinoma
• Recruited between 1985 and 2003 at MDACC
• Concurrent chemoradiotherapy followed by surgery,
  or induction chemotherapy followed by concurrent
  chemoradiotherapy and then surgery

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Experimental DetailsPatient Characteristics
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Experimental DetailsPatient Characteristics

• Study endpoints were
• Overall Survival
• Recurrence
• Pathologic Response to Therapy
• Adjusted all analyses for
• Age at diagnosis, gender, smoking status, alcohol
  consumption, clinical stage, histological tumor
  type, tumor location, pathological stage and
  histological viability, radiation dosage,
  chemoradiotherapy sequence, and chemotherapy
  regimens

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Experimental DetailsTreatment Information

• Stratified analyses by chemotherapeutic regimen
• Any of the three
• Fluoropyrimidine any
• Platinum compound any
• Taxane any

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Experimental DetailsSNP Selection

• tagged SNP Selection
• Based on HapMap data from CEPH population
• Gene 5 Kb flanking
• LD tagged SNPs r2 gt 0.8, MAF gt 0.1
• tagger and LDselect

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Experimental DetailsSNP Selection
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Results

• 16 SNPs, 4 treatment groups, 3 clinical outcomes

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ResultsRecurrence Risk in Patients Treated with
Any of the Three

• Three SNPs associated with recurrence
• AKT1rs2498804
• AKT2rs892119
• Increased risk of recurrence
• All treatment groups
• PTENrs12357281
• Decreased risk of recurrence
• Except for platinum compound any

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ResultsRecurrence Risk in Patients Treated with
Any of the Three
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ResultsRecurrence-free Survival by AKT2rs892119
A Any Three B 5-FU C Platinum agent D Taxane
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ResultsRecurrence Risk by Unfavorable Genotype

• AKT1rs2498804 and AKT2rs892119

Consistent across all strata Fluoropyrimidine -
HR 6.36 Platinum Agent - HR 10.73 Taxane -
HR 83.37
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ResultsGene-Gene Interactions in Patients
Treated with a Taxane

• 7 SNPs associated with Recurrence

p-value
95 CI
HR
AKT1rs2498804
0.003
2.40 - 83.02
14.10
GT TT
AKT1rs1130214
0.016
1.55 - 76.98
10.94
TT
AKT2rs892119
0.006
1.62 - 16.88
5.23
AG GG
FRAP1rs2295080
0.035
1.19 -128.38
12.35
TT
PIK3CArs7621329
0.015
1.60 - 80.88
11.38
TT
PIK3CArs6443624
0.031
1.20 - 42.36
7.13
CC
PTENrs12357281
0.008
0.006 - 0.458
0.05
CG GG
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ResultsSurvival Tree Analysis for Recurrence
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ResultsSurvival in Patients Treated with Any of
the Three

• Both FRAP1 (mTOR) SNPs significant
• Consistent except for platinum compound group

Taxane
Platinum Compound
Fluoropyrimidine
Any of the Three
p-value
HR
p-value
HR
p-value
HR
p-value
HR
 
FRAP1rs11121704
0.005
7.03
0.091
2.77
0.003
3.82
0.004
3.53
TT
 
FRAP1rs2295080
0.003
8.28
0.073
2.66
0.0004
4.66
0.001
4.19
TT
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ResultsSurvival in Patients Treated with a Taxane

• AKT1 and AKT2 SNPs

p-value
95 CI
HR
AKT1rs1130214
1(reference)
GG
0.222
0.73 - 3.94
1.69
GT
0.014
1.56 - 51.17
8.92
TT
0.157
0.79 - 4.19
1.82
GT TT
AKT2rs892119
1(reference)
AA
0.014
1.27 - 8.40
3.27
AG
0.065
0.89 - 43.88
6.25
GG
0.006
1.43 - 8.78
3.54
AG GG
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ResultsPathologic Response to Therapy

• AKT2rs892119

Taxane
Platinum Compound
Fluoropyrimidine
Any of the Three
p-value
OR
p-value
OR
p-value
OR
p-value
OR
1 (reference)
 
1 (reference)
1 (reference)
 
1 (reference)
AA
0.042
3.68
0.105
2.18
0.018
2.68
0.023
2.54
AG
 
 
GG
0.026
4.12
0.059
2.46
0.008
2.98
0.010
2.81
AG GG
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ResultsPathologic Response to Therapy

• AKT1rs3803304 in patients treated with Any of
  the Three
• HR 0.50 (0.25 0.99), p-value 0.049
• FRAP1rs11121704 in taxane group only
• HR 2.76 (1.04 7.37), p-value 0.042

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Conclusions

• Genetic variation within this important pathway
  is important
• AKT2rs892119 in particular
• Tags 5 SNPs
• Results suggest increased signaling
• Functional SNP?

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Conclusions

• PTEN variation had expected opposite effect
• Counteracts other effects
• Differences between treatment groups
• Many more in taxane group ? sample size?
• Less in platinum compound group

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Future Directions

• Analyze SNPs in a control group undergoing
  surgery alone
• Same in other cancers treated with these agents?
• Functional studies ? mechanism

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Thank You!
Xifeng Wu Jafer Ajani Julie Izzo Mien-Chie
Huang Esophageal Study Participants
Wu Laboratory