Back to Search
Start Over
Genetic Variants in the PI3K/PTEN/AKT/mTOR Pathway Predict Head and Neck Cancer Patient Second Primary Tumor/Recurrence Risk and Response to Retinoid Chemoprevention
Genetic Variants in the PI3K/PTEN/AKT/mTOR Pathway Predict Head and Neck Cancer Patient Second Primary Tumor/Recurrence Risk and Response to Retinoid Chemoprevention
- Source :
- Clinical Cancer Research. 18:3705-3713
- Publication Year :
- 2012
- Publisher :
- American Association for Cancer Research (AACR), 2012.
-
Abstract
- 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. Clin Cancer Res; 18(13); 3705–13. ©2012 AACR.
- Subjects :
- Oncology
Cancer Research
medicine.medical_specialty
Antineoplastic Agents
Protein Serine-Threonine Kinases
Biology
Placebo
Polymorphism, Single Nucleotide
Ribosomal Protein S6 Kinases, 90-kDa
Disease-Free Survival
Article
Phosphatidylinositol 3-Kinases
Risk Factors
Internal medicine
Genotype
medicine
Humans
PTEN
Isotretinoin
PI3K/AKT/mTOR pathway
Randomized Controlled Trials as Topic
Tumor Suppressor Proteins
Head and neck cancer
PTEN Phosphohydrolase
Cancer
Neoplasms, Second Primary
medicine.disease
Head and neck squamous-cell carcinoma
Clinical trial
Treatment Outcome
ROC Curve
Head and Neck Neoplasms
Immunology
Carcinoma, Squamous Cell
Insulin Receptor Substrate Proteins
biology.protein
Neoplasm Recurrence, Local
Signal Transduction
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....9ad538c0432b18b447d0e0d9a660161b
- Full Text :
- https://doi.org/10.1158/1078-0432.ccr-11-3271