Aakre, Jeremiah A.

Abstract To identify the genetic factors that influence overall survival in never smokers who have non–small cell lung carcinoma (NSCLC), we conducted a consistency meta-analysis study using genome-wide association approaches for overall survival in 327 never smoker patients with NSCLC from The University of Texas MD Anderson Cancer Center (Houston, TX) and 293 cases from the Mayo Clinic (Rochester, MN). We then conducted a two-pronged validation of the top 25 variants that included additional validation in 1,256 patients with NSCLC from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a P value of 10−6. Two variants of these 25 were also significant in the Taiwanese population: rs6901416 [HR, 1.44; 95% confidence interval (CI), 1.01–2.06] and rs10766739 (HR, 1.23; 95%CI, 1.00–1.51). These loci resulted in a reduction of median survival time of at least eight and five months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung tissue. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biologic mechanism for a subset of these observed associations. Cancer Res; 73(13); 4028–38. ©2013 AACR.

AbstractBackgroundThis study evaluated the impact of tumor regression grading (TRG) and other pathologic variates in a cohort of rectal carcinoma patients treated with neoadjuvant chemoradiotherapy (CRT). The value of a grading less than pCR for predicting survival is unknown. Tumor budding has not been systematically studied in rectal cancer after neoadjuvant therapy.MethodsPathologic risk factors for survival were evaluated on surgical specimens of 237 patients with stages I, II, and III rectal cancer treated between 1996 and 2006. All patients underwent preoperative CRT followed by surgical resection 6–8 weeks later. TRG, tumor grade, budding, venous invasion, radial margin, and nodal status were evaluated. The prognostic value of TRG categories was calculated with Cox regression models and validated with resampling methods.ResultsTRG of <25% occurred in 61 (25.7%) and a complete response in 39 (16.4%) of the resected specimens. TRG of <25% was shown to be a statistically significant predictor for cancer‐specific survival (CSS) and recurrence‐free survival (RFS) compared to TRG ≥25% (P = 0.013). Tumor budding was present in 24 (10.1%) of the patients and was negatively associated with CSS (P = 0.013). Lymph node involvement was observed in 83 (35.0%) patients. TRG and nodal status (P < 0.001) were the most significant predictors associated with outcome.ConclusionPartial pathologic response ≥25% was a superior predictor compared to pCR for improved survival after preoperative CRT. CSS and RFS were adversely affected by the presence of lymph node metastases.

Abstract Purpose: Variations in genes related to biological activity of anticancer drugs could influence treatment responses and lung cancer prognosis. Genetic variants in four biological pathways, that is, glutathione metabolism, DNA repair, cell cycle, and epidermal growth factor receptor (EGFR), were systematically investigated to examine their association with survival in advanced stage non–small cell lung cancer (NSCLC) treated with chemotherapy. Experimental Design: A total of 894 tagging single-nucleotide polymorphisms (SNP) in 70 genes from the four pathways were genotyped and analyzed in a 1,076-patient cohort. Association with overall survival was analyzed at SNP and whole-gene levels within all patients and major chemotherapy agent combination groups. Results: A poorer overall survival was observed in patients with genetic variations in GSS (glutathione pathway) and MAP3K1 (EGFR pathway; HR = 1.45; 95% CI = 1.20–1.77 and HR = 1.25; 95% CI = 1.05–1.50, respectively). In the stratified analysis on patients receiving platinum plus taxane treatment, we observed a hazardous effect on overall survival by the MAP3K1 variant (HR = 1.38; 95% CI = 1.11–1.72) and a protective effect by RAF1 (HR = 0.64; 95% CI = 0.50–0.82) in the EGFR pathway. In patients receiving platinum plus gemcitabine treatment, RAF1 and GPX5 (glutathione pathway) genetic variations showed protective effects on survival (HR = 0.54; 95% CI = 0.38–0.77; HR = 0.67; 95% CI = 0.52–0.85, respectively); in contrast, NRAS (EGFR pathway) and GPX7 (glutathione pathway) variations showed hazardous effects on overall survival (HR = 1.91; 95% CI = 1.30–2.80; HR = 1.83; 95% CI = 1.27–2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis. Conclusion: Common genetic variations in genes of EGFR and glutathione pathways may be associated with overall survival among patients with advanced stage NSCLC treated with platinum, taxane, and/or gemicitabine combinations. Clin Cancer Res; 17(11); 3830–40. ©2011 AACR.

Abstract Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-186.