Michelle A T Hildebrandt 1 , Scott M Lippman , Carol J Etzel , Edward Kim , J Jack Lee , Fadlo R Khuri , Margaret R Spitz , Reuben Lotan , Waun Ki Hong , Xifeng Wu Show Affiliations »
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PURPOSE: The development of second primary tumors (SPT) or recurrence alters prognosis for curatively treated head and neck squamous cell carcinoma (HNSCC) patients . The 13-cis-Retinoic acid (13-cRA ) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated whether genetic variants in the PI3K/PTEN/AKT/mTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence , while also predicting response to 13-cRA chemoprevention. EXPERIMENTAL DESIGN: A total of 137 pathway single-nucleotide polymorphisms were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA . Risk models were created based on epidemiology, clinical, and genetic data. RESULTS: Twenty-two genetic loci were associated with increased SPT/recurrence risk , with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54 × 10(-4)) dose-response relationship for SPT/recurrence risk , with patients carrying four to five high-risk genotypes having a 3.76-fold [95% Confidence Interval (CI), 1.87-7.57] increase in risk in the placebo group (n = 215). Patients carrying four to five high-risk loci showed the most benefit from 13-cRA chemoprevention, with a 73% reduction in SPT/recurrence (95% CI, 0.13-0.58) compared with those with the same number of high-risk genotypes who were randomized to receive placebo . Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables. CONCLUSIONS: These results show that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step toward personalized chemoprevention for HNSCC patients. ©2012 AACR.
RCT Entities: Population
Interventions
Outcomes
PURPOSE: The development of second primary tumors (SPT) or recurrence alters prognosis for curatively treated head and neck squamous cell carcinoma (HNSCC ) patients . The 13-cis-Retinoic acid (13-cRA ) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated whether genetic variants in the PI3K/PTEN /AKT /mTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence, while also predicting response to 13-cRA chemoprevention. EXPERIMENTAL DESIGN: A total of 137 pathway single-nucleotide polymorphisms were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA . Risk models were created based on epidemiology, clinical, and genetic data. RESULTS: Twenty-two genetic loci were associated with increased SPT/recurrence risk, with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54 × 10(-4)) dose-response relationship for SPT/recurrence risk, with patients carrying four to five high-risk genotypes having a 3.76-fold [95% Confidence Interval (CI), 1.87-7.57] increase in risk in the placebo group (n = 215). Patients carrying four to five high-risk loci showed the most benefit from 13-cRA chemoprevention, with a 73% reduction in SPT/recurrence (95% CI, 0.13-0.58) compared with those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables. CONCLUSIONS: These results show that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step toward personalized chemoprevention for HNSCC patients . ©2012 AACR.
Entities: Chemical
Disease
Gene
Mutation
Species
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Year: 2012
PMID： 22577058 PMCID： PMC3404728 DOI： 10.1158/1078-0432.CCR-11-3271
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531