Mitosis trumps T stage and proposed international association for the study of lung cancer/american thoracic society/european respiratory society classification for prognostic value in resected stage 1 lung adenocarcinoma.

INTRODUCTION: We investigated whether a group of pathologists could reproducibly apply the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification for lung adenocarcinoma to a cohort of stage 1 tumors and whether this architectural classification and/or other parameters could demonstrate survival advantage. METHODS: A total of 145 cases of 7 edition of tumor, node, metastasis stage 1 adenocarcinoma were retrospectively reviewed for predominant architectural pattern, including cribriform pattern, nuclear grade, mitotic index, and necrosis. The parameters were assessed for reproducibility and survival and using multivariate analysis, compared with stage, age, and sex. RESULTS: The majority of tumors had a mixed architecture with the acinar pattern being the most common predominant architecture. Micropapillary and cribriform architecture were the least frequent patterns. This study demonstrated that a group of five pathologists could reproducibly apply the IASLC/ATS/ERS classification. Although there were insufficient cribriform-predominant adenocarcinomas for assessment, when the percentage of all cribriform was combined with other architectures, it was associated with a worse prognosis. The majority of the parameters assessed demonstrated significance with univariate analysis but only mitotic index, as assessed by the highest count/10 high-power fields remained significant with multivariate analysis. CONCLUSION: In this study of resected stage 1 primary lung adenocarcinoma, we found mitotic index to be the only independent prognostic marker. It was more closely associated with outcome than either pathologic T stage or IASLC/ATS/ERS architecture-based classification. Further validation of concordance and reproducibility in reporting mitotic index, as well as validation of prognostic significance, needs to be undertaken in independent data sets.

Genomic medicine in non-small cell lung cancer: paving the path to personalized care.

Lung cancer is the commonest cause of cancer-related mortality and non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer. The prognosis of NSCLC remains poor across all stages, despite advances in staging techniques and treatments. The findings of recent high-throughput mRNA microarray studies have shown potential in refining current NSCLC diagnosis, classification, prognosis and treatment paradigms. Emerging microarray studies of microRNA, DNA copy number and methylation profiles are also providing novel insights into the biology of NSCLC. Currently there are several challenges, such as the reproducibility and cost of microarray platforms that will need to be addressed prior to the implementation of these genomic technologies to routine thoracic oncology practice. In addition, genomic tests (such as prognosis and prediction gene expression signatures) will need to be validated in well designed prospective studies that aim to answer clinically relevant questions. If successful, the integration of microarray-based genomic information with existing clinicopathological models may enhance the ability of clinicians to match the most effective treatment to an individual patient. Such a strategy may improve survival and reduce treatment-related morbidity in NSCLC patients.

Expression profiling defines a recurrence signature in lung squamous cell carcinoma.

Lung cancer remains the leading cause of cancer death worldwide. Overall 5-year survival is approximately 10-15% and despite curative intent surgery, treatment failure is primarily due to recurrent disease. Conventional prognostic markers are unable to determine which patients with completely resected disease within each stage group are likely to relapse. To identify a gene signature associated with recurrent squamous cell carcinoma (SCC) of lung, we analyzed primary tumor gene expression for a total of 51 SCCs (Stages I-III) on 22 323 element microarrays, comparing expression profiles for individuals who remained disease-free for a minimum of 36 months with those from individuals whose disease recurred within 18 months of complete resection. Cox proportional hazards modeling with leave-one-out cross-validation identified a 71-gene signature capable of predicting the likelihood of tumor recurrence and a 79-gene signature predictive for cancer-related death. These two signatures were pooled to generate a 111-gene signature which achieved an overall predictive accuracy for disease recurrence of 72% (77% sensitivity, 67% specificity) in an independent set of 58 (Stages I-III SCCs). This signature also predicted differences in survival [log-rank P=0.0008; hazard ratio (HR), 3.8; 95% confidence interval (CI), 1.6-8.7], and was superior to conventional prognostic markers such as TNM stage or N stage in predicting patient outcome. Genome-wide profiling has revealed a distinct gene-expression profile for recurrent lung SCC which may be clinically useful as a prognostic tool.

CYP1A1 Ile462Val and MPO G-463A interact to increase risk of adenocarcinoma but not squamous cell carcinoma of the lung.

Common polymorphisms in genes encoding phase I and phase II enzymes are considered to modify lung cancer risk due to changes in enzyme activity. Candidates include genetic variants of glutathione S-transferases (GSTM1, GSTT1 and GSTP1) and myeloperoxidase (MPO). We performed a large case-control study of these candidate genes in 1103 patients with non-small cell lung cancer (NSCLC) and 627 controls without NSCLC. Associations between deletion genotypes of GSTM1 and GSTT1 and between single nucleotide polymorphisms (SNPs) of GSTP1 Ile105Val and MPO G-463A were first tested by adjusted logistic regression. Then we analysed gene-gene interactions, also incorporating our published data on the Ile462Val SNP in the phase I enzyme, cytochrome P450 CYP1A1. The homozygous GSTP1 105Val genotype was significantly under-represented in NSCLC compared with controls (OR = 0.73; 95%CI 0.53-1.00; P = 0.050), especially in females (OR = 0.57; 95%CI 0.34-0.98; P = 0.04). The GSTT1-null genotype was significantly over-represented in adenocarcinomas (OR = 1.41; 95%CI 1.06-1.90; P = 0.02) but not in squamous cell carcinomas (OR = 1.03; 95%CI 0.76-1.41; P = 0.84). There was weak risk reduction associated with GSTM1 null in heavy smokers (OR = 0.71; 95%CI 0.54-0.94; P = 0.02), but neither GSTM1 nor MPO genotypes affected the overall risk of NSCLC. The MPO and CYP1A1 risk genotypes interacted to increase the overall risk of NSCLC (OR = 2.88; 95%CI 1.70-5.00; P < 0.001). The data are consistent with the concept that multiple genes of modest effect interact to confer genomic-based susceptibility to lung cancer.

Risk of non-small cell lung cancer and the cytochrome P4501A1 Ile462Val polymorphism.

OBJECTIVE: The Ile462Val substitution in the cytochrome P450 1A1 gene (CYP1A1) results in increased enzymatic activity. Preliminary data suggesting a link between this polymorphism and lung cancer risk in Caucasians are inconsistent, reflecting small sample sizes and the relatively low frequency of the variant. METHODS: The data set consisted of 1050 primary non-small cell lung cancer cases and 581 controls, a large homogenous population designed specifically to address previous inconsistencies. Patients were genotyped using a PCR-RFLP technique. RESULTS: Carriers of the valine allele, CYP1A1*2C, (Ile/Val or Val/Val genotypes) were significantly over-represented in non-small cell lung cancer compared to controls (OR=1.9; 95% CI=1.2-2.9; p=0.005) when adjusted for confounders, particularly in women (OR=4.6; 95% CI=1.7-12.4; p=0.003). The valine variant was statistically significantly over-represented in cases of lung cancer younger than the median age (64 years) (OR=2.5; 95% CI=1.3-4.8; p=0.005) and cases with less than the median cumulative tobacco-smoke exposure (46 pack-years) (OR=2.4; 95% CI=1.3-4.7; p=0.007). CONCLUSIONS: These new data establish an association between the CYP1A1 Ile462Val polymorphism and the risk of developing non-small cell lung cancer, especially among women.