Phosphorylated Akt Expression in Early-Stage NSCLC
Phosphorylated Akt Expression in Early-Stage NSCLC
Aims: To determine the prognostic significance of pAkt expression in order to identify high-risk stage IB patients with non-small cell lung cancer (NSCLC) in an exploratory study.
Methods: We identified 471 consecutive patients with stage IB primary NSCLC according to the American Joint Commission on Cancer 6th edition tumour-node-metastasis (TNM) staging system, who underwent surgical resection between 1990 and 2008. Patients who received neoadjuvant or adjuvant treatments were excluded. Pathology reports were reviewed, and pathological characteristics were extracted. Expression of phosphorylated Akt (pAkt) in both cytoplasmic and nuclear locations was assessed by immunohistochemistry, and clinicopathological factors were analysed against 10-year overall survival using Kaplan–Meier and Cox proportional hazards model.
Results: 455 (96.6%) cancers were adequate for pAkt immunohistochemical analysis. The prevalence of pAkt expression in the cytoplasm and nucleus of the cancers was 60.7% and 43.7%, respectively. Patients whose cancers expressed higher levels of cytoplasmic pAkt had a trend towards longer overall survival than those with lower levels (p=0.06). Conversely, patients whose cancers expressed higher levels of nuclear pAkt had a poorer prognosis than those with lower levels of expression (p=0.02). Combined low cytoplasmic/high nuclear expression of pAkt was an independent predictor of overall survival (HR=2.86 (95% CI 1.35 to 6.04); p=0.006) when modelled with age (HR=1.05 (95% CI 1.03 to 1.07); p<0.001), extent of operation (HR=2.11 (95% CI 1.48 to 3.01); p<0.001), visceral pleural invasion (HR=1.63 (95% CI 1.24 to 2.15); p<0.001), gender, tumour size, histopathological type and grade (p>0.05).
Conclusions: Level of expression of pAkt in the cytoplasm and nucleus is an independent prognostic factor that may help to select patients with high-risk disease.
Lung cancer is the most common and leading cause of cancer death worldwide, with an incidence of 1.6 million new cases annually and a mortality of 1.38 million in 2008. In early-stage non-small cell lung cancer (NSCLC), surgical resection remains the treatment of choice with adjuvant chemotherapy having a modest absolute survival benefit of 5% at 5 years in stage II–IIIA disease, while subgroup analyses were not significant in stage IB disease. Nevertheless, 45% of patients with resected stage IB disease will die of their cancer. Therefore, there is an urgent need to identify novel prognostic markers that can select patients with early-stage disease who are at high risk of recurrence. Numerous molecular prognostic markers have been examined in NSCLC, but to date none have moved into routine clinical practice.
Our aim was to identify a molecular prognostic marker for stage IB resected NSCLC; therefore, we undertook a literature search to establish which would be the most appropriate marker to assess in this study. Our criteria were (1) that there be more than one study of a molecular marker (ie, an independent validation study), (2) the marker had to be an independent predictor of outcome in multivariable analysis and (3) had to be implicated in the biology of lung cancer. It was preferable for the molecular marker to be assessable by immunohistochemistry so that it would be appropriate for routine hospital pathology implementation. Phosphorylated Akt (pAkt) not only fulfilled all our predetermined criteria but it is also a key mediator in numerous signalling pathways that are central to the balance of cell survival, proliferation and apoptosis. Furthermore, it is particularly important in the PI3K/Akt/mTOR signalling pathway, where major therapeutics are either already in clinical practice, such as epidermal growth factor tyrosine kinase inhibitors (gefitinib and erlotinib) and mTOR inhibitors (everolimus and temsirolimus), or in development, such as dual PI3K/mTOR, PI3K and Akt inhibitors.
There have been a number of studies that have demonstrated an association between overexpression of pAkt in NSCLC and a poorer prognosis. However, these studies included patients with heterogeneous stages of disease, different immunohistochemical protocols and pAkt antibodies against different phosphorylation sites, while others had small sample sizes, which were underpowered to demonstrate prognostic significance.
Given the potential role of pAkt as a prognostic marker, we aimed to examine the association between pAkt expression and outcome in a cohort of patients, who had resected early-stage node-negative NSCLC, in order to identify patients who are at high risk of recurrence and may potentially benefit from adjuvant chemotherapy.
Abstract and Introduction
Abstract
Aims: To determine the prognostic significance of pAkt expression in order to identify high-risk stage IB patients with non-small cell lung cancer (NSCLC) in an exploratory study.
Methods: We identified 471 consecutive patients with stage IB primary NSCLC according to the American Joint Commission on Cancer 6th edition tumour-node-metastasis (TNM) staging system, who underwent surgical resection between 1990 and 2008. Patients who received neoadjuvant or adjuvant treatments were excluded. Pathology reports were reviewed, and pathological characteristics were extracted. Expression of phosphorylated Akt (pAkt) in both cytoplasmic and nuclear locations was assessed by immunohistochemistry, and clinicopathological factors were analysed against 10-year overall survival using Kaplan–Meier and Cox proportional hazards model.
Results: 455 (96.6%) cancers were adequate for pAkt immunohistochemical analysis. The prevalence of pAkt expression in the cytoplasm and nucleus of the cancers was 60.7% and 43.7%, respectively. Patients whose cancers expressed higher levels of cytoplasmic pAkt had a trend towards longer overall survival than those with lower levels (p=0.06). Conversely, patients whose cancers expressed higher levels of nuclear pAkt had a poorer prognosis than those with lower levels of expression (p=0.02). Combined low cytoplasmic/high nuclear expression of pAkt was an independent predictor of overall survival (HR=2.86 (95% CI 1.35 to 6.04); p=0.006) when modelled with age (HR=1.05 (95% CI 1.03 to 1.07); p<0.001), extent of operation (HR=2.11 (95% CI 1.48 to 3.01); p<0.001), visceral pleural invasion (HR=1.63 (95% CI 1.24 to 2.15); p<0.001), gender, tumour size, histopathological type and grade (p>0.05).
Conclusions: Level of expression of pAkt in the cytoplasm and nucleus is an independent prognostic factor that may help to select patients with high-risk disease.
Introduction
Lung cancer is the most common and leading cause of cancer death worldwide, with an incidence of 1.6 million new cases annually and a mortality of 1.38 million in 2008. In early-stage non-small cell lung cancer (NSCLC), surgical resection remains the treatment of choice with adjuvant chemotherapy having a modest absolute survival benefit of 5% at 5 years in stage II–IIIA disease, while subgroup analyses were not significant in stage IB disease. Nevertheless, 45% of patients with resected stage IB disease will die of their cancer. Therefore, there is an urgent need to identify novel prognostic markers that can select patients with early-stage disease who are at high risk of recurrence. Numerous molecular prognostic markers have been examined in NSCLC, but to date none have moved into routine clinical practice.
Our aim was to identify a molecular prognostic marker for stage IB resected NSCLC; therefore, we undertook a literature search to establish which would be the most appropriate marker to assess in this study. Our criteria were (1) that there be more than one study of a molecular marker (ie, an independent validation study), (2) the marker had to be an independent predictor of outcome in multivariable analysis and (3) had to be implicated in the biology of lung cancer. It was preferable for the molecular marker to be assessable by immunohistochemistry so that it would be appropriate for routine hospital pathology implementation. Phosphorylated Akt (pAkt) not only fulfilled all our predetermined criteria but it is also a key mediator in numerous signalling pathways that are central to the balance of cell survival, proliferation and apoptosis. Furthermore, it is particularly important in the PI3K/Akt/mTOR signalling pathway, where major therapeutics are either already in clinical practice, such as epidermal growth factor tyrosine kinase inhibitors (gefitinib and erlotinib) and mTOR inhibitors (everolimus and temsirolimus), or in development, such as dual PI3K/mTOR, PI3K and Akt inhibitors.
There have been a number of studies that have demonstrated an association between overexpression of pAkt in NSCLC and a poorer prognosis. However, these studies included patients with heterogeneous stages of disease, different immunohistochemical protocols and pAkt antibodies against different phosphorylation sites, while others had small sample sizes, which were underpowered to demonstrate prognostic significance.
Given the potential role of pAkt as a prognostic marker, we aimed to examine the association between pAkt expression and outcome in a cohort of patients, who had resected early-stage node-negative NSCLC, in order to identify patients who are at high risk of recurrence and may potentially benefit from adjuvant chemotherapy.
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