The October 2012 Journal of Thoracic Oncology presents two papers of interest to pathologists.
The first study is a paper by Yanagawa et al. that correlates PTEN expression with gene copy number, P53 expression, EGFR and KRAS mutations in surgically resected NSCLCs and examines the relationship between PTEN status, clinicopathologic characteristics and survival.
Recall that PTEN functions as a lipid phosphatase that negatively regulates the PI3K/AKT anti-apoptotic and proliferation pathway, which is a key downstream component of the EGFR pathway. Loss of PTEN is most commonly due to promoter hypermethylation, while homozygous deletion and nonsense mutations with LOH seem to be uncommon.
PTEN expression was examined by immunohistochemistry in a tissue microarray constructed from 152 patients with a median follow-up time of 2.3 years. The study consisted of 62% adenocarcinomas, 29% squamous cell carcinomas and 9% of tumors called “other.” Since this is a study of surgically resected patients, there is obviously an overrepresentation of stage one tumors compared to all patients typically diagnosed with lung cancer. Smokers comprised 79% of the study population. EGFR mutations were found in 15% and KRAS mutations and 22%. The authors defined loss of PTEN as complete absence of cytoplasmic staining in tumor cells.
Loss of PTEN was found in 63 out of 152 cases (41.4%). No significant differences were found between loss of PTEN and smoking, EGFR mutations, KRAS mutations, or p53 expression.
Patients with loss of PTEN expression had significantly worse disease-free survival compared with patients with retained PTEN expression (HR 1.76, log-rank p=0.038) but the prognostic effect was related directly to tumor histology: loss of PTEN was significantly associated with shorter DFS in adenocarcinoma only (HR 2.72, log-rank p=0.002). This association was also significant in multivariate analysis controlling for sex, age, histology and stage.
Recent data suggest that loss of PTEN may contribute to EGFR TKI resistance in NSCLC. PIK3CA mutations only account for 2% to 4% of NSCLC but loss of PTEN would result in constitutive activation of the PI3K pathway. This study suggests that lung adenocarcinomas selected for PTEN status may be susceptible to PI3KCA inhibitors that are currently under investigation.
My next post will discuss the other interesting paper in JTO this month.
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