TY - JOUR
T1 - PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy
AU - Pu, Xia
AU - Hildebrandt, Michelle A.T.
AU - Lu, Charles
AU - Lin, Jie
AU - Stewart, David J.
AU - Ye, Yuanqing
AU - Gu, Jian
AU - Spitz, Margaret R.
AU - Wu, Xifeng
N1 - Funding Information:
This research was supported in part, by National Cancer Institute (NCI) grants R01 CA111646, P50 CA070907 , and R01 CA055769 . MATH is supported by an NCI Cancer Prevention Research Fellowship training grant R25T CA57730 . The study sponsors have no involvement in any aspects of the preparation of this manuscript.
PY - 2011/1
Y1 - 2011/1
N2 - Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related deaths. The effect of the PI3K/PTEN/AKT/mTOR signaling pathway on cancer treatment, including NSCLC, has been well documented. In this study, we analyzed associations between genetic variations within this pathway and clinical outcomes following platinum-based chemotherapy in 168 patients with stage IIIB (wet) or stage IV NSCLC. Sixteen tagging SNPs in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) of this pathway and identified SNPs associated with development of toxicity and disease progression. We observed significantly increased toxicity for patients with PIK3CA:rs2699887 (OR: 3.86, 95% CI: 1.08-13.82). In contrast, a SNP in PTEN was associated with significantly reduced risk for chemotherapeutic toxicity (OR: 0.44, 95% CI: 0.20-0.95). We identified three SNPs in AKT1 resulting in significantly decreased risks of distant progression in patients carrying at least one variant allele with HRs of 0.66 (95% CI: 0.45-0.97), 0.52 (95% CI: 0.35-0.77), and 0.62 (95% CI: 0.42-0.91) for rs3803304, rs2498804, and rs1130214, respectively. Furthermore, these same variants conferred nearly 2-fold increased progression-free survival times. The current study provides evidence that genetic variations within the PI3K/PTEN/AKT/mTOR signaling pathway are associated with variation in clinical outcomes of NSCLC patients. With further validation, our findings may provide additional biomarkers for customized treatment of platinum-based chemotherapy for NSCLC.
AB - Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related deaths. The effect of the PI3K/PTEN/AKT/mTOR signaling pathway on cancer treatment, including NSCLC, has been well documented. In this study, we analyzed associations between genetic variations within this pathway and clinical outcomes following platinum-based chemotherapy in 168 patients with stage IIIB (wet) or stage IV NSCLC. Sixteen tagging SNPs in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) of this pathway and identified SNPs associated with development of toxicity and disease progression. We observed significantly increased toxicity for patients with PIK3CA:rs2699887 (OR: 3.86, 95% CI: 1.08-13.82). In contrast, a SNP in PTEN was associated with significantly reduced risk for chemotherapeutic toxicity (OR: 0.44, 95% CI: 0.20-0.95). We identified three SNPs in AKT1 resulting in significantly decreased risks of distant progression in patients carrying at least one variant allele with HRs of 0.66 (95% CI: 0.45-0.97), 0.52 (95% CI: 0.35-0.77), and 0.62 (95% CI: 0.42-0.91) for rs3803304, rs2498804, and rs1130214, respectively. Furthermore, these same variants conferred nearly 2-fold increased progression-free survival times. The current study provides evidence that genetic variations within the PI3K/PTEN/AKT/mTOR signaling pathway are associated with variation in clinical outcomes of NSCLC patients. With further validation, our findings may provide additional biomarkers for customized treatment of platinum-based chemotherapy for NSCLC.
KW - AKT
KW - Chemotherapy
KW - Clinical outcomes
KW - Lung cancer
KW - Platinum-agents
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U2 - 10.1016/j.lungcan.2010.04.008
DO - 10.1016/j.lungcan.2010.04.008
M3 - Article
C2 - 20447721
AN - SCOPUS:78651359460
SN - 0169-5002
VL - 71
SP - 82
EP - 88
JO - Lung Cancer
JF - Lung Cancer
IS - 1
ER -