Clinical Outcome In NSCLC Patients Research Articles

594P The treatment pattern and clinical outcome in NSCLC patients with MET alteration: A retrospective real-world analysis in China

594P The treatment pattern and clinical outcome in NSCLC patients with MET alteration: A retrospective real-world analysis in China

Early Monitoring Drug Resistant Mutation T790M with a Two-Dimensional Simultaneous Discrimination Nanopore Strategy.

With the aim of detecting low frequency of drug resistant mutation T790M against wild-type sequences, we reported a two-dimensional signal analysis strategy by combining a three locked nucleic acids (LNAs)-modified probe (LP15-3t) and an α-HL nanopore. The specific hybridization of the LP15-3t probe with the T790M generated unique long two-level signals, including characteristic blocking current and characteristic dwell time. Due to the significant dwell time difference (114.2-fold) and the blocking current difference ranging from 81% to 96%, this two-dimensional signal analysis strategy can simultaneously distinguish T790M sequences with a sensitivity of 0.0001% against wild-type sequences. The LOD of T790M was 0.1 pM. This high discrimination capability would have great potential in the detection of rare mutation sequences and the early monitoring of clinical outcome of NSCLC patients with TKI drug resistance.

Decreased Preoperative Estimated Glomerular Filtration Rate Was Related With Poor Prognosis of NSCLC Patients.

(1) Background:The coexistence of chronic kidney disease (CKD) and cancer is common due to the increased incidence of cancer in patients with CKD. Glomerular filtration rate is the optimal way to measure kidney function. To date, little is known about the role preoperative renal function plays in the prognosis of NSCLC patients.(2) Methods:The study enrolled 140 patients who had been newly diagnosed NSCLC and received potential radical surgery for treatment from 2009 January to 2012 December. The detailed characteristics were collected including gender, age, smoking and drinking habits, KPS score, hemoglobin levels, tumor size, pathology type, differentiation, pTNM stage and serum creatinine before surgery. Univariate and multivariate analyses of overall survival (OS) and disease-free survival (DFS) were performed using Kaplan-Meier method and Cox model.(3) Results:The univariate analysis identified that the pTNM stage (p < 0.001), eGFR level (p = 0.006), and adjuvant treatment (p = 0.007) were prognostic factors for OS, while drinking habit (p = 0.032), pTNM stage (p = 0.002) and eGFR level (p = 0.006) were the prognostic factors for DFS. Further multivariate analysis found that pTNM stage (HR = 2.091, 95% CI 1.424-3.071; p < 0.001) and eGFR level (HR = 1.890, 95% CI 1.424-3.071; p = 0.004) were independent factors associated with OS. The pTNM stage (HR = 1.735, CI 1.215-2.479; p = 0.002) and eGFR (HR = 1.793, CI 1.193-2.696; p = 0.005) were independent factors associated with DFS. Further subgroup analyses found that in female patients/ no smoking patients/ patients younger than 60 years, better eGFR level was significantly associated with better OS and DFS.(4) Conclusions:Decreased preoperative eGFR was associated with poor clinical outcome of NSCLC patients.

Abstract 4549: Pemetrexed enhances anti-tumor efficacy of PD1 pathway blockade by promoting intra tumor immune response via immunogenic tumor cell death and T cell intrinsic mechanisms

Abstract Background: Recently, pemetrexed and carboplatin in combination with PD–1 antibody (pembrolizumab) demonstrated markedly improved clinical outcome in NSCLC patients (KEYNOTE–021G trial) suggesting a positive interaction between pemetrexed–based chemotherapy and immunotherapy. However, the role of pemetrexed in modulating antitumor immune response is largely unknown. The objective of this study was to characterize the effects of pemetrexed on intra–tumor immune response in monotherapy and combination with carboplatin or PD–1 pathway blockade in preclinical models. Methods: Mice bearing syngeneic MC38 or Colon26 tumors were treated with pemetrexed with or without carboplatin or anti–mouse PD–L1 antibody (178G7). Immune cell subsets and immune–related changes in mouse tumor tissue and T cells were assessed by flow cytometry and gene expression analysis (Quantigene Plex and nanoString nCounter assays). Effects of pemetrexed on immunogenic cell death in tumor cells and mitochondrial respiration in T cells were evaluated by HMGB1 ELISA and Agilent Seahorse XF analysis, respectively. Results: In MC38 tumors, pemetrexed monotherapy demonstrated a trend towards an increased frequency of intratumoral leukocytes and total and cycling (Ki67+) T cells accompanied by immune–related gene expression changes indicative of enhanced antigen presentation, T cell infiltration and/or activation and down–modulation of the myeloid cell compartment. Immune gene expression signature induced by pemetrexed was largely unaffected by carboplatin. In both MC38 and Colon26 tumor cells, in vitro treatment with pemetrexed induced a robust release of HMGB1 indicative of immunogenic cell death. Proliferation of primary human T cells stimulated with CD3/CD28 was inhibited by pemetrexed in a dose–dependent manner. At clinically relevant concentrations pemetrexed also enhanced T cell activation phenotype exemplified by an increased frequency of CD137+, GITR+ and PD–L1+ T cells as well as upregulation of multiple interferon gamma–induced genes, and increased mitochondrial respiration. In both MC38 and Colon26 models, treatment with pemetrexed and 178G7 demonstrated a combination benefit compared to either monotherapy, and nCounter profiling of Colon26 tumors followed by Ingenuity Pathway Analysis revealed that improved antigen presentation, enhanced T cell and cytokine signaling and an engagement of CD4+ T cell–mediated immunity might underlie this combination effect. Conclusions: Pemetrexed promotes intra–tumor T cell–mediated immune response through immunogenic tumor cell death and increased activation and metabolic fitness of T cells leading to an enhanced anti–tumor efficacy in combination with PD–L1 antibody. Citation Format: Ruslan Novosiadly, David Schaer, Nelusha Amaladas, Erik Rasmussen, Zhao Hai Lu, Andreas Sonyi, Carmine Carpenito, Yanxia Li, Shuang Luo, Andrew Capen, Catalina Meyer, Xiaodong Huang, Jason Manro, Gregory Donoho, Thompson Doman, Gerald Hall, Sandaruwan Geeganage, Michael Kalos. Pemetrexed enhances anti-tumor efficacy of PD1 pathway blockade by promoting intra tumor immune response via immunogenic tumor cell death and T cell intrinsic mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4549.

MiR-30a-5p enhances paclitaxel sensitivity in non-small cell lung cancer through targeting BCL-2 expression.

BCL-2 is a novel direct target of miR-30a-5p. miR-30a-5p enhances NSCLC paclitaxel sensitivity in vitro and in vivo. miR-30a-5p sensitizes NSCLC cells to paclitaxel by inducing apoptosis through BCL-2 inhibition. miR-30a-5p negatively correlates with BCL-2 and predicts a favorable clinical outcome in NSCLC patients.

P3.02c-083 Treatment Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center: Topic: IT Biomarkers

It has been suggested that certain patients could be primed to respond to anti-programmed cell death-1 (PD-1) therapy due to heightened baseline “immunocompetence,” but data supporting this is limited as is our ability to measure it. The experience with ipilumumab suggests that immune related adverse events (irAEs) experienced by melanoma patients may predict improved clinical outcomes (Weber et al, J Clin Oncol 2012). We retrospectively analyzed NSCLC patients from a single center on the KEYNOTE-001 trial and evaluated the association between treatment related adverse events (trAE) and clinical outcomes. We performed a retrospective analysis of the 97 NSCLC patients treated on KEYNOTE-001 at UCLA with either 2 mg/kg Q3W or 10 mg/kg Q2/3W of pembrolizumab (data cut-off 3/2016). Investigators reported AEs and graded according to CTCAE v4.0, labeling them as unlikely, possibly, or probably treatment related. AEs labeled as possibly/probably related were considered trAEs. The initial scan was at 9 weeks and subsequent scans were every 9 weeks. Investigator assessed irRC was the radiographic assessment used for clinical decisions at individual sites. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared using the log-rank test. 10% (85/826) of AEs reported on trial were considered trAEs. The most frequent trAEs were rash (29%), fatigue (9%), and pneumonitis (8%). The occurrence of a trAE was associated with higher objective response rate (ORR) (OR=0.1509, P=0.0009), PFS (HR=0.3004, P<0.0001) and OS (HR=0.4391, P<0.0001). To assess whether the shorter duration of follow-up in those progressing earlier biased this analysis, additional analyses were performed. The relationship remained, particularly for longitudinal outcomes, when assessed only in patients that continued on trial >9 weeks. This was true both when including trAEs over the entire trial duration (ORR: OR=0.1839, P=0.005; PFS: HR=0.3525, P<0.0001; OS: HR=0.4526, P=0.0008) or when including only trAEs occurring within the first 9 weeks (ORR: OR=0.4063, P=0.1047; PFS: HR=0.5568, P=0.0211; OS: HR=0.6404, P=0.0465). Neither number of prior lines of therapy nor age, gender, or smoking history predicted frequency of trAE occurrence. This single center, retrospective analysis, revealed that a trAE predicted for improved clinical outcome with pembrolizumab. When controlling for the inherent bias of asymmetric follow-up, these associations remained. Although this analysis has the weakness of being conducted at a single center representing less than 20% of patients on trial, the strength is that a limited number of investigators assessed if an event was an AE and was treatment related.

Abstract 2263: Prognostic significance of REV3like and TYMS gene expression in blood samples from non-small cell lung patients treated with platinum-based chemotherapy plus pemetrexed

Abstract BACKGROUND: Pemetrexed is an effective antineoplastic agent as monotherapy (second line and maintenance setting) or in platinum-based combination regimes (first-line). Pemetrexed inhibits three key enzymes in the folate metabolic pathway: thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). As a consequence, pemetrexed interferes with the synthesis of both pyrimidine and purine, thereby effectively inhibiting both DNA and RNA synthesis. The aim of this study was to investigate the impact of the PBMC (peripheral blood mononuclear cells) expression levels of AEG1, BRCA1, REV3like, ant TYMS mRNA in the clinical outcome in NSCLC patients treated with Pemetrexed-based therapy. MATERIAL AND METHODS: This is a prospective, observational cohort study, of consecutively selected patients. We included patients with non-squamous NSCLC, stage IV, treated with platinum-based chemotherapy plus Pemetrexed. Blood samples from each patient were collected at the beginning of treatment. Quantitative reverse transcription (qRT)-PCR was performed with the use of the TaqMan gene expression assay (Applied Biosystems) according to the manufacturer's instructions. Amplifications were carried out on the Applied Biosystem 7500 RT-PCR system, and relative gene expression values were calculated by the ΔΔCt method (Sequence Detection System 2.0.5). Results from analysis, done in triplicate, are expressed relative to expression levels of GAPDH. RESULTS: We here present preliminary results of 16 patients included in the study: median age was 63.4 (range 52-82); 12 were males. Histological subtypes were 13 adenocarcinomas, and 3 large cell carcinomas. Pemetrexed was combined with Carboplatin in 9 patients and Cisplatin in 7 patients. Best response obtained was partial response in 7 patients, stable disease in 3 patients, and progression in 5 patients. We found significant differences in the REV3like expression levels between patients with PR&amp;SD and patients with PD (0.69 ± 0.14 vs 0.44 ± 0.07; P = 0.003). In addition there were statistically significant differences in disease free survival (3 ± 0.74 vs 13 ± 1.89, P = 0.035; 12 ± 2.32 vs 3 ± 2.19, P = 0.003, months), and overall survival (10 ± 5.21 vs not reached, P = 0.026; not reached vs 12 ± 2.38, P = 0.007, months) between patients with mRNA levels of REV3like and TYMS under mean value of the cohort and patients with levels over mean value of the our cohort. CONCLUSIONS: This study supports the value of the PBMC expression profiling of the REV3like and TYMS genes in the prognosis of NSCLC treated with platinum-based chemotherapy plus Pemetrexed. Citation Format: Maria Teresa Agullo-Ortuño, C.Vanessa Díaz-García, José A. López-Martín, Elena Prieto-García, Santiago Ponce, Jon Zugazagoitia, Lara Iglesias-Docampo, Ana B. Enguita, Luis Paz-Ares, Juan A. Nuñez-Sobrino. Prognostic significance of REV3like and TYMS gene expression in blood samples from non-small cell lung patients treated with platinum-based chemotherapy plus pemetrexed. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2263.

The Dissociation of Gefitinib Trough Concentration and Clinical Outcome in NSCLC Patients with EGFR Sensitive Mutations.

Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. Ctrough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of Ctrough was 173.9 ng/ml (P25–P75, 130.5–231.2 ng/ml), and cutoff value 200 ng/ml was determined by X-Tile. The PFS between Ctrough < 200 ng/ml and Ctrough ≥ 200 ng/ml groups were not significantly different (17.3 VS 14.8 months; p = 0.258). Ctrough was not significantly associated with rash, diarrhea and hepatotoxicity. Non-smokers enjoyed longer PFS than smokers (18.7 VS 9.3 months; p = 0.025). The results showed that, for NSCLC patients with EGFR sensitive mutations, the PFS in lower trough concentration group were not inferior to that in higher trough concentration group and dose reduction is a rational suggestion for adjustment of dose regimen for aforementioned patients. More clinical trials are warranted to explore the precision dose schedule of gefitinib.

Effect of chemotherapy on the myeloid-derived suppressor cells percentages in the peripheral blood of advanced non-small cell lung cancer patients (TUM6P.965)

Abstract In our previous study, high levels of one granulocytic (G-MDSC) and two monocytic (M-MDSCs) subpopulations of immunosuppressive MDSCs were found and their overexpression was correlated with worse prognosis in NSCLC patients. Using flow cytometry, the impact of chemotherapy on the percentages and functionality of M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin- and CD14+CD15+CD11b+ CD33+HLA-DR-Lin-) and G-MDSC (CD14-CD15+CD11b+CD33+HLA-DR-Lin-) was evaluated in the peripheral blood of patients (n=141) prior to chemotherapy and after the 3rd and 6th cycle of treatment. The M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin-) percentages were found significantly decreased post chemotherapy compared to baseline, whereas chemotherapy had no effect on CD14+CD15+CD11b+CD33+HLA-DR-Lin- M-MDSCs. In contrast, the production of iNOS by M-MDSCs was significantly increased compared to the baseline. Both G-MDSC levels and their ROS expression were not affected by chemotherapy. In addition, both subtypes of MDSCs, when co-cultured with CD3+ T cells, were able to significantly suppress IFN-γ secretion by T cells. Finally, the M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin-) percentages were found significantly decreased in patients that did not develop progressive disease during or after treatment completion, compared to patients with disease progression. Chemotherapy seems to have an impact on MDSC expression and functionality, hence targeting these cells may lead to a better clinical outcome in NSCLC patients.

TP53 is a Mutational Target in Non Small Cell Lung Cancer Patients and its Pro/Pro Variant is Potentially Contributing to Cancer Susceptibility

Background: TP53 is one of the most important tumor suppressor genes, regulating various cellular processes and playing a pivotal role in preventing a cell to become malignant. P53 mutant protein containing arginine or proline at codon 72 shows different biological and biochemical activity. So, the aim of the present study was to find out the role of mutated P53 gene with different codon 72 variants on the clinical outcome of patients suffering from NSCLC. Materials and methods: A case control study of 100 NSCLC patients and 100 cancer free healthy controls was performed. TP53 codon 72 polymorphism and mutations at exon 5 and 8 were analyzed in NSCLC patients using AS–PCR and survival curves were plotted using Kaplan–Meier analysis. Results: A statistically significant difference was observed in the frequencies of P53 codon 72 variants between cases and healthy controls (p<0.003) with a strong association of risk of developing NSCLC with homozygous Pro/ Pro genotype, OR 5.3 ( 95% CI 1.8-15.3, p<0.001).TP53 mutations at exon 5/8 occurred in 78% of the cases and Pro/Pro genotype of codon 72 was associated with increased number of P53 mutations, OR 4.7(95% CI 0.5-44.8): Pro/Pro homozygotes,16 of 17 (94.1%); Arg/Pro heterozygotes, 45 of 61 (73.8%); and Arg/Arg homozygotes, 17 of 22 (77.3%). Codon 72 Pro/Pro homozygotes were associated with poor overall survival and the Pro/Pro genotypes with P53 mutations also predicted decreased overall survival .The median survival time for patients with wild type P53 and mutated P53 with Arg/Arg and Pro/Pro codon 72 genotypes were 14.5, 11.5 and 4.0 months respectively (p=0.003). Conclusion: Pro/Pro variant of P53 codon 72 was associated with increased number of P53 mutations, and was associated with adverse clinical outcome of NSCLC patients of north India.

Abstract B11: EGFR polymorphism as a predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI

Abstract Background: Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of efficacy for EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR gene were associated with clinical outcome in NSCLC patients treated with EGFR-TKI. Methods: A polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one and single nucleotide polymorphisms in the promoter region (SNP -216 GG or GT) were evaluated in 71 NSCLC patients by PCR-RFLP and DNA sequencing. Genetic polymorphisms were correlated with clinical outcomes of EGFR-TKIs. Results: SNP-216G/T polymorphisms were associated with the efficacy of EGFR-TKI. The response rate for the SNP-216G/T was significantly higher than that for the GG (62.5% vs. 27.4%, P=0.044). SNP-216G/T genotype was also associated with longer progression-free survival compared with GG genotype (16.7 months vs. 5.1 months, P=0.005). However, Genotypes for the CA-SSR1 was not associated with the efficacy of EGFR-TKI. Conclusions: SNP-216G/T polymorphism is potential predictor for clinical outcome in NSCLC patients treated with EGFR-TKI.

CYP1A1*2A polymorphism as a predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI and its combined effects with EGFR intron 1 (CA)n polymorphism

BackgroundMutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of efficacy for EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR and cytochrome P450, family 1, member A1 (CYP1A1) genes were associated with clinical outcome in NSCLC patients treated with EGFR-TKI. MethodsGenotypes for the intron 1 (CA)n repeat and R497K polymorphisms in the EGFR gene and the *2A (3801 T→C) and *2C (2455 A→G) polymorphisms in CYP1A1 gene were evaluated in 115 NSCLC patients by PCR-RFLP and DNA sequencing. Genetic polymorphisms were correlated with clinical outcomes of EGFR-TKIs. From a subgroup of patients whose tumour tissues were available, associations between somatic EGFR mutations, EGFR expression, and genomic polymorphisms were also analysed. ResultsEGFR intron 1 (CA)n and CYP1A1*2A polymorphisms were independent predictive factors (p=0.046, p=0.011, respectively) and the latter was also a prognostic factor (p=0.001) for patients treated with EGFR-TKIs. We also observed a strong synergistic effect from two genotypes. Specifically, patients with both the T/T allele of the CYP1A1 gene and shorter intron 1 CA repeats (⩽16 CA) of the EGFR gene showed an improved response (p=0.002) compared with patients with the T/C or C/C allele and longer intron 1 CA repeats (both alleles >16 CA). In contrast, for R497K and CYP1A1*2C, no relationship was observed with clinical outcome for patients treated with EGFR-TKIs (p=0.573; p=0.629, respectively). Both SNPs in the CYP1A1 gene showed a correlation with EGFR somatic mutations. ConclusionsThe findings of this study suggest that the CYP1A1*2A polymorphism is a predictor for clinical outcome in NSCLC patients treated with EGFR-TKI therapy, and combining analysis of both CYP1A1*2A and EGFR intron 1 (CA)n polymorphisms may be useful for predicting treatment outcome in NSCLC patients treated with EGFR-TKIs.

Genetic variants in angiogenesis pathway associated with clinical outcome in NSCLC patients (pts) treated with bevacizumab in combination with carboplatin and paclitaxel: Subset pharmacogenetic analysis of ECOG 4599

8032 Background: E4599 was a randomized phase III study which demonstrated a survival advantage in advanced NSCLC pts treated with bevacizumab (bev) + carboplatin/paclitaxel (BPC) versus carboplatin/paclitaxel alone (PC). Recent studies have shown certain germline polymorphisms (SNPs) are associated with clinical outcome in advanced breast cancer pts treated with paclitaxel plus bev and in advanced colorectal cancer pts treated with first line 5-FU or capecitabine in combination with oxaliplatin and bev. A study also found 2 SNPs in WNK1 gene were associated with bev-induced hypertension. We tested the hypothesis that SNPs involved in angiogenesis pathway (VEGF, EGF, EGFR, IL-8, KDR, ICAM1, FGFR4), DNA repair pathway (ERCC1, XPD, XRCC1, GSTP1) and WNK1 may predict clinical outcome in a subset of pts enrolled on E4599. Methods: Of 878 pts enrolled, samples from 146 pts were available for the current pharmacogenetic study and only 133 of the samples (67 PC, 66 BPC) came from eligible pts. PCR-RFLP assays were performed on genomic DNA extracted from sera of pts. The Kaplan-Meier method was used to estimate time-to-event distributions. Multivariable Cox models adjusted for gender, PS, stage, adrenal, liver and bone mets were separately fitted for each SNP to obtain estimates of hazard ratios. Results: Median OS for the 133 patients was 10.3 mos (8.2–15.6) for PC and 13.0 mos (10.2–16.6) for BPC. Median PFS was 4.6 mos (3.6–5.6) for PC &amp; 6.5 mos (5.4–8.3) for BPC. Pts with mutant homozygote CC genotype for ICAM1 T469C had significantly higher tumor response rate (39%) than heterozygote CT (13%) and homozygote TT (20%) genotype (Fisher's test, p=0.04). Tests for whether treatment effect differs by genotype via interaction terms in the Cox models were statistically significant (p&lt;0.05) for VEGF G-634C, ICAM1 T469C and WNK1-rs11064560 for OS, and for ICAM1 T469C, EGF A-61G and CXCR2 C785T for PFS. Conclusions: Although exploratory, our preliminary results suggest germline SNPs in angiogenesis pathway may predict response, PFS and OS in NSCLC pts treated with BPC. Prospective trials based on these correlative studies are warranted. [Table: see text]

Elevated circulating level of osteopontin is associated with advanced disease state of non-small cell lung cancer

Osteopontin (OPN) plays important roles in tumor progression and metastasis through binding to OPN receptors such as alpha(v)beta(beta) integrin and CD44, and its overexpression in tumor is associated poor clinical outcome of NSCLC patients. Circulating OPN levels, measured by ELISA in 130 NSCLC cases that had not been treated for cancer at the time of sampling, were analyzed according to clinical, pathologic parameters and single nucleotide polymorphisms (SNPs) in the OPN gene promoter. Advanced disease states had higher circulating levels of OPN (T4 versus T1-3, N3 versus N0-2, and M1 versus M0, P=.029, .001, and .001, respectively, Kruskal-Wallis H-test), reflected by higher level of OPN in stage IV than stage I-III (P=.029, Kruskal-Wallis H-test). Among the clinical and pathological parameters including age, gender, smoking status, histologic subtypes and grade of differentiation, smoking status influences circulating OPN level showing higher level of OPN in ex-smokers than current and non-smokers (P=.038, Kruskal-Wallis H-test). Variation at nucleotide (nt) -443 of the OPN gene promoter had no influence on circulating OPN levels, however, patients with G/G at nt -156 showed higher concentrations of OPN than those with G/GG or GG/GG (P=.003, Kruskal-Wallis H-test). A patient with G/G at nt -156 was more frequently diagnosed with advanced stage (IIIB-IV) than with early stage (I-IIIA) NSCLC (P=.048, Mantel-Haenszel-test). In multivariate analysis, stage is the only independent factor influencing circulating level of OPN. Although circulating level of OPN in the patients with bone metastasis was higher than in those without bone metastasis (P=.028, Mann-Whitney U-test), there was no difference in the OPN levels between bone metastasis group and non-bone metastasis group. Given that the elevated levels of OPN is associated with advanced stages of NSCLC, elucidating OPN regulatory mechanisms may contribute to the development of a new therapeutic modality for NSCLC.