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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.Instructor
Department of Epidemiology
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Outline
• Pathway• Experimental Details• Results• Conclusions• Future Directions
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PI3K/PTEN/AKT/mTOR Pathway
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Downstream Processes
Manning and Cantley, Cell (2007)
mTOR
TERT
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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 >16,000 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 Barrett’s 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 > 0.8, MAF > 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– AKT1:rs2498804– AKT2:rs892119
• Increased risk of recurrence• All treatment groups
– PTEN:rs12357281• Decreased risk of recurrence• Except for platinum compound + any
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0.0270.13 - 0.880.34 CG + GG
1 / 0GG
0.0270.13 - 0.890.3422 / 7CG
1(reference)95 / 49CC
PTEN:rs12357281
0.0011.64 - 6.663.30 AG + GG
0.2800.49 - 12.012.423 / 2GG
0.0011.66 - 7.283.4825 / 23AG
1(reference)95 / 33AA
AKT2:rs892119
0.0341.06 - 4.602.21 GT + TT
0.0371.07 - 9.613.218 / 7TT
0.0680.95 - 4.372.0463 / 30GT
1(reference)50 / 20GG
AKT1:rs2498804
p-value95% CIHR*No Recurrence /
Recurrence
ResultsRecurrence Risk in Patients Treated with Any of the Three
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ResultsRecurrence-free Survival by AKT2:rs892119
A: Any Three
B: 5-FU
C: Platinum agent
D: Taxane
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p-value95% CIHR*No Recurrence /
Recurrence
< 0.0012.34 - 18.186.5215 / 172
0.0241.15 - 7.192.8769 / 271
1 (reference)36 / 130
# of Unfavorable Genotypes
ResultsRecurrence Risk by Unfavorable Genotype
• AKT1:rs2498804 and AKT2:rs892119
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
0.0080.006 - 0.4580.05CG + GG
PTEN:rs12357281
0.0311.20 - 42.36 7.13CC
PIK3CA:rs6443624
0.0151.60 - 80.8811.38TT
PIK3CA:rs7621329
0.0351.19 -128.3812.35TT
FRAP1:rs2295080
0.0061.62 - 16.885.23AG + GG
AKT2:rs892119
0.0161.55 - 76.9810.94TT
AKT1:rs1130214
0.0032.40 - 83.0214.10GT + TT
AKT1:rs2498804
p-value95% CIHR*
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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
TaxanePlatinum
CompoundFluoropyrimidineAny of the
Three
0.0038.280.0732.660.00044.660.0014.19TT
FRAP1:rs2295080
0.0057.030.0912.770.0033.820.0043.53TT
FRAP1:rs11121704
p-valueHR*p-valueHR*p-valueHR*p-valueHR*
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ResultsSurvival in Patients Treated with a Taxane
• AKT1 and AKT2 SNPs
0.0061.43 - 8.783.54AG + GG
0.0650.89 - 43.886.25GG
0.0141.27 - 8.403.27AG
1(reference)AA
AKT2:rs892119
0.1570.79 - 4.191.82GT + TT
0.0141.56 - 51.178.92TT
0.2220.73 - 3.941.69GT
1(reference)GG
AKT1:rs1130214
p-value95% CIHR*
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ResultsPathologic Response to Therapy
• AKT2:rs892119
p-valueOR*p-valueOR*p-valueOR*p-valueOR*
TaxanePlatinum CompoundFluoropyrimidineAny of the Three
0.0264.120.0592.460.0082.980.0102.81AG + GG
GG
0.0423.680.1052.180.0182.680.0232.54AG
1 (reference) 1 (reference)1 (reference) 1 (reference)AA
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ResultsPathologic Response to Therapy
• AKT1:rs3803304 in patients treated with Any of the Three– HR*: 0.50 (0.25 – 0.99), p-value: 0.049
• FRAP1:rs11121704 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…
• AKT2:rs892119 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 WuJafer Ajani
Julie Izzo
Mien-Chie Huang
Esophageal Study Participants
Wu Laboratory