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1.  Genetic variations in the transforming growth factor-beta pathway as predictors of survival in advanced non-small cell lung cancer 
Carcinogenesis  2011;32(7):1050-1056.
The magnitude of benefit is variable for advanced non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy. The purpose of this study is to determine whether genetic variations in the transforming growth factor-beta (TGF-β) pathway are associated with clinical outcomes in NSCLC patients receiving first-line platinum-based chemotherapy. Five hundred and ninety-eight advanced-stage NSCLC patients who received first-line platinum-based chemotherapy with or without radiotherapy were recruited at the MD Anderson Cancer Center between 1995 and 2007. DNA from blood was genotyped for 227 single nucleotide polymorphisms (SNPs) in 23 TGF-β pathway-related genes to evaluate their associations with overall survival. In individual SNP analysis, 22 variants were significantly associated with overall survival, of which the strongest associations were found for BMP2:rs235756 [hazard ratio (HR) = 1.45; 95% confidence interval (CI), 1.11–1.90] and SMAD3:rs4776342 (HR = 1.25; 95% CI, 1.06–1.47). Fifteen and 18 genetic loci displayed treatment-specific associations for chemotherapy and chemoradiation, respectively, identifying a majority of the cases who would be predicted to respond favorably to a specific treatment regimen. BMP2:rs235753 and a haplotype in SMAD3 were associated with overall survival for both treatment modalities. Cumulative effect analysis showed that multiple risk genotypes had a significant dose-dependent effect on overall survival (Ptrend = 2.44 x 10−15). Survival tree analysis identified subgroups of patients with dramatically different median survival times of 45.39 versus 13.55 months and 18.02 versus 5.89 months for high- and low- risk populations when treated with chemoradiation and chemotherapy, respectively. These results suggest that genetic variations in the TGF-β pathway are potential predictors of overall survival in NSCLC patients treated with platinum-based chemotherapy with or without radiation.
doi:10.1093/carcin/bgr067
PMCID: PMC3128559  PMID: 21515830
2.  DNA Repair Capacity in Peripheral Lymphocytes Predicts Survival of Patients With Non–Small-Cell Lung Cancer Treated With First-Line Platinum-Based Chemotherapy  
Journal of Clinical Oncology  2011;29(31):4121-4128.
Purpose
Platinum-based regimens are the standard chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC). DNA repair capacity (DRC) in tumor cells plays an important role in resistance to platinum-based drugs. We have previously reported that efficient DRC, as assessed by an in vitro lymphocyte-based assay, was a determinant of poor survival in patients with NSCLC in a relatively small data set. In this larger independent study of 591 patients with NSCLC, we further evaluated whether DRC in peripheral lymphocytes predicts survival of patients with NSCLC who receive platinum-based chemotherapy.
Patients and Methods
All patients were recruited at The University of Texas MD Anderson Cancer Center and donated blood samples before the start of any chemotherapy. We measured DRC in cultured T lymphocytes by using the host-cell reactivation assay, and we assessed associations between DRC in peripheral lymphocytes and survival of patients with NSCLC who were treated with first-line platinum-based chemotherapy.
Results
We found an inverse association between DRC in peripheral lymphocytes and patient survival. Compared with patients in the low tertile of DRC, patients with NSCLC in the high tertile of DRC had significantly worse overall and 3-year survival (adjusted hazard ratio [HR], 1.33; 95% CI, 1.04 to 1.71; P = .023; and HR, 1.35; 95% CI, 1.04 to 1.76; P = .025, respectively). This trend was more pronounced in patients with early-stage tumors, adenocarcinoma, or squamous cell carcinoma.
Conclusion
We confirmed that DRC in peripheral lymphocytes is an independent predictor of survival for patients with NSCLC treated with platinum-based chemotherapy.
doi:10.1200/JCO.2010.34.3616
PMCID: PMC3675702  PMID: 21947825
3.  Genome-Wide Association Study of Prognosis in Advanced Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy 
Purpose
Genetic variation may influence chemotherapy response and overall survival in cancer patients.
Experimental design
We conducted a genome-wide scan in 535 advanced-stage non–small cell lung cancer (NSCLC) patients from two independent cohorts (307 from Nanjing and 228 from Beijing). A replication was carried out on an independent cohort of 340 patients from Southeastern China followed by a second validation on 409 patients from the Massachusetts General Hospital (Boston, MA).
Results
Consistent associations with NSCLC survival were identified for five single-nucleotide polymorphisms (SNP) in Chinese populations with P values ranging from 3.63 × 10−5 to 4.19 × 10−7 in the additive genetic model. The minor allele of three SNPs (rs7629386 at 3p22.1, rs969088 at 5p14.1, and rs3850370 at 14q24.3) were associated with worse NSCLC survival while 2 (rs41997 at 7q31.31 and rs12000445 at 9p21.3) were associated with better NSCLC survival. In addition, rs7629386 at 3p22.1 (CTNNB1) and rs3850370 at 14q24.3 (SNW1-ALKBH1-NRXN3) were further replicated in the Caucasian population.
Conclusion
In this three-stage genome-wide association studies, we identified five SNPs as markers for survival of advanced-stage NSCLC patients treated with first-line platinum-based chemotherapy in Chinese Han populations. Two of these SNPs, rs7629386 and rs3850370, could also be markers for survival among Caucasian patients.
doi:10.1158/1078-0432.CCR-12-1202
PMCID: PMC3723686  PMID: 22872573
4.  Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer 
The Oncologist  2012;17(12):1551-1561.
Thirteen tag SNPs at the CASP8 and CASP10 loci in patients with advanced NSCLC were genotyped in a two-stage analysis consisting of a discovery set and an independent validation set. These SNPs were evaluated for their association with toxicity outcomes with platinum-based chemotherapy.
Caspase-8 and caspase-10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase-8 (CASP8) and caspase-10 (CASP10) genes in relation to toxicity outcomes with first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum-based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including rs3769821, rs3769825, rs7608692, and rs12613347, were significantly associated with severe toxicity risk in some subgroups, such as in nonsmoking patients, patients with adenocarcinoma, and patients treated with cisplatin combinations. Consistent results were also found in haplotype analyses. Our results provide novel evidence that polymorphisms in CASP8 and CASP10 may modulate toxicity outcomes in patients with advanced NSCLC treated with platinum-based chemotherapy. If validated, the findings will facilitate the genotype-based selection of platinum-based chemotherapy regimens.
doi:10.1634/theoncologist.2011-0419
PMCID: PMC3528388  PMID: 22843554
CASP8; CASP10; Polymorphisms; Platinum-based chemotherapy; Toxicity; Non-small cell lung cancer; Association
5.  SIRT1 Expression Is Associated with the Chemotherapy Response and Prognosis of Patients with Advanced NSCLC 
PLoS ONE  2013;8(11):e79162.
Aim
The role of Sirtuin 1 (SIRT 1) in carcinogenesis is controversial. This study was to explore the association between the SIRT1 expression and the clinical characteristics, the responsiveness to chemotherapy and prognosis in Non-small cell lung cancer (NSCLC).
Methods
We enrolled 295 patients with inoperable advanced stage of NSCLC, namely, stage III (A+B) and IV NSCLC. All patients had received platinum-based chemotherapy after diagnosis and the chemotherapy response were evaluated. All patients were followed up for overall survival (OS) and progression free survival (PFS). In vitro, H292 cells were tranfected with SIRT1 small interfering RNA (siRNA). The cell biological behaviors and chemosensitivity to cisplatin treatment were studied. The in vivo tumorgenesis and metastasis assays were performed in nude mice.
Results
We found that the SIRT1 expressions were significantly associated with the tumor stage, tumor size and differentiation status. Patients with high SIRT 1 expressions had a significantly higher chance to be resistant to chemotherapy than those with low SIRT 1 expression. Patients with high expression of SIRT1 had significantly shorter OS and DFS than those with low expression. Cox analyses confirmed that the SIRT 1 expression was a strong predictor for a poor OS and PFS in NSCLC patients underwent Platinum-based chemotherapy. In vitro studies revealed that the reduced expression SIRT 1 by siRNA technique significantly inhibited cell proliferation, migration and invasion. More importantly, SIRT1 si-RNA significantly enhanced the chemosensitivity of H292 cells to cisplatin treatment. The in vivo tumorgenesis and metastasis assays showed that SIRT1 knockdown dramatically reduced the tumor volume and the metastatic ability in nude mice.
Conclusion
Collectively, our data suggest that the SIRT1 expression may be a molecular marker associated with the NSLCLC clinical features, treatment responsiveness and prognosis of advanced NSCLC.
doi:10.1371/journal.pone.0079162
PMCID: PMC3818418  PMID: 24223900
6.  Efficacy of platinum-based adjuvant chemotherapy in T2aN0 stage IB non-small cell lung cancer 
Background
Although overall survival for non-small cell lung cancer (NSCLC) has increased, survival rate for pathologically staged T2aN0M0 stage IB NSCLC remains low. Adjuvant chemotherapy is not a standard treatment for stage IB NSCLC. Our purpose was to determine the efficacy of platinum-based adjuvant chemotherapy in stage IB NSCLC.
Methods
We retrospectively reviewed the medical records of 119 stage IB patients who underwent lobectomy and mediastinal lymph node dissection. Among these, 60 patients underwent platinum-based adjuvant chemotherapy (adjuvant group) and 59 did not receive chemotherapy (observation group).
Results
Participants had a mean age of 62.12 ± 11.51 years and 73 (61.3%) were male. The median follow-up period was 49.04 months. Mean age was higher in the observation group whereas patients in the adjuvant group had larger tumors, more dissected lymph nodes, and better performance status. The 5-year overall survival was 64.7% in the observation group and 88.2% in the adjuvant group (p = 0.010). The 5-year disease-free survival was 51.3% in the observation group and 74.0% in the adjuvant group (p = 0.011). In multivariate analysis, only platinum-based adjuvant chemotherapy was a risk factor for overall survival [hazard ratio (HR) = 0.428, p = 0.049] and disease-free survival (HR = 0.57, p = 0.043). In subset analysis, patients with a larger tumor (greater than 3.2 cm), moderate to poor differentiation, and good performance status (Eastern Cooperative Oncology Group, 0) benefitted from platinum-based adjuvant chemotherapy.
Conclusions
Platinum-based adjuvant chemotherapy for surgically treated stage IB NSCLC might offer better survival than observation alone. A large-scale randomized clinical trial is needed to validate these findings.
doi:10.1186/1749-8090-8-151
PMCID: PMC3684513  PMID: 23759129
Lung cancer surgery; Adjuvant therapy; Statistics; Survival analysis
7.  CHFR protein expression predicts outcomes to taxane-based first line therapy in metastatic NSCLC 
Purpose
Currently, there is no clinically validated test for the prediction of response to tubulin-targeting agents in non-small cell lung cancer (NSCLC). Here, we investigated the significance of nuclear expression of the mitotic checkpoint gene checkpoint with forkhead and ringfinger domains (CHFR) as predictor of response and overall survival (OS) with taxane-based first-line chemotherapy in advanced stage NSCLC.
Methods
We studied a cohort of 41 patients (median age 63 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. CHFR expression by immunohistochemistry (score 0–4) was correlated with clinical outcome using Chi-Square test and Cox proportional models. A cutoff score of ‘3’ was determined by ROC-analysis for “low” CHFR expression. Results were validated in an additional 20 patients who received taxane based chemotherapy at Emory University Hospital and the Atlanta VAMC.
Results
High expression (score = 4) of CHFR is strongly associated with adverse outcomes: the risk for progressive disease (PD) after first-line chemotherapy with carboplatin-paclitaxel was 52% in patients with CHFR-high vs. only 19% in those with CHFR-low tumors (p=0.033). Median OS was strongly correlated with CHFR expression status (CHFR low: 9.9 months; CHFR high: 6.2 months; p =0.002). After multivariate adjustment, reduced CHFR expression remained a powerful predictor of improved OS (HR 0.24 (95% CI 0.1–0.58, p=0.002). In the validation set, low CHFR expression was associated with higher likelihood of clinical benefit (p=0.03) and improved OS (p=0.038).
Conclusions
CHFR expression is a novel predictive marker of response and OS in NSCLC patients treated with taxane-containing chemotherapy.
doi:10.1158/1078-0432.CCR-12-2995
PMCID: PMC3602233  PMID: 23386692
8.  Multicenter, Phase II Trial of Sunitinib in Previously Treated, Advanced Non–Small-Cell Lung Cancer 
Purpose
Aberrant vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) signaling have been shown to play a role in non–small-cell lung cancer (NSCLC) pathogenesis and are associated with decreased survival. We evaluated the clinical activity and tolerability of sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor that blocks the activity of receptors for VEGF and PDGF, as well as related tyrosine kinases in patients with previously treated, advanced NSCLC.
Patients and Methods
Patients with stage IIIB or IV NSCLC for whom platinum-based chemotherapy had failed received 50 mg/d of sunitinib for 4 weeks followed by 2 weeks of no treatment in 6-week treatment cycles. The primary end point was objective response rate (ORR); secondary end points included progression-free survival, overall survival, and safety.
Results
Of the 63 patients treated with sunitinib, seven patients had confirmed partial responses, yielding an ORR of 11.1% (95% CI, 4.6% to 21.6%). An additional 18 patients (28.6%) experienced stable disease of at least 8 weeks in duration. Median progression-free survival was 12.0 weeks (95% CI, 10.0 to 16.1 weeks), and median overall survival was 23.4 weeks (95% CI, 17.0 to 28.3 weeks). Therapy was generally well tolerated.
Conclusion
Sunitinib has promising single-agent activity in patients with recurrent NSCLC, with an ORR similar to that of currently approved agents and an acceptable safety profile. Further evaluation in combination with other targeted agents and chemotherapy in patients with NSCLC is warranted.
doi:10.1200/JCO.2007.13.9303
PMCID: PMC3559017  PMID: 18235126
9.  Survival Following Surgery with or without Adjuvant Chemotherapy for Stage I–IIIA Non-Small Cell Lung Cancer: An East Asian Population-Based Study 
The Oncologist  2012;17(10):1294-1302.
The survival impact of platinum-based adjuvant chemotherapy for Asian patients with stage I–IIIA non-small cell lung cancer is examined. The lower risk for death provided by adjuvant chemotherapy among the Asian population is comparable with that found in the literature based mainly on data from white patients.
Background.
Asian ethnicity is associated with a distinct molecular etiology, treatment response, and survival outcome among patients with non-small cell lung cancer (NSCLC). This study examines the survival impact of platinum-based adjuvant chemotherapy for Asian patients with stage I–IIIA NSCLC.
Methods.
This study recruited patients aged ≥18 years with histologically proven stage IA–IIIA NSCLC registered in the Taiwan Cancer Registry database in January 2004 to December 2007. Platinum-containing adjuvant chemotherapy had to be started within 90 days of the primary surgery. Kaplan–Meier survival curves, log-rank tests, and the Cox proportional hazards regression model were used to assess the influence of various risk factors on survival time.
Results.
This study included 2,231 patients with stage IA–IIIA NSCLC who underwent primary surgery with a clear surgical margin. The percentages of all causes of death were significantly lower for the chemotherapy group for both stage II and stage IIIA patients. Multivariate analysis identified platinum-based adjuvant chemotherapy as an independent prognostic factor for the overall survival outcome of stage II (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.39–0.94; p = .024) and IIIA (HR, 0.71; 95% CI, 0.52–0.96; p = .029) patients. Among these patients, those who received adjuvant chemotherapy had a superior overall survival outcome for both genders, for the subgroup of patients aged ≥70 years, and for those with adenocarcinoma.
Conclusion.
Platinum-based adjuvant chemotherapy should be considered in the treatment plan for Asian patients with resected stage II and stage IIIA NSCLC.
doi:10.1634/theoncologist.2012-0082
PMCID: PMC3481895  PMID: 22826374
Non-small cell lung cancer; Adjuvant chemotherapy; Asian ethnicity; Survival; Comparative effectiveness
10.  Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy †, ‡ 
Purpose
Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate SNPs/genes, we performed a genome-wide association study (GWAS) for cisplatin cytotoxicity using lymphoblastoid cell lines (LCLs), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.
Experimental Design
GWAS for cisplatin were performed with 283 ethnically diverse LCLs. 168 top SNPs were genotyped in 222 small cell and 961 non-small cell lung cancer (SCLC, NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells.
Results
Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the four top SNPs and 8 genes for which expression was correlated with three SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells.
Conclusions
This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer.
doi:10.1158/1078-0432.CCR-11-1133
PMCID: PMC3167019  PMID: 21775533
Lung cancer; cisplatin; pharmacogenomics; lymphoblastoid cell lines; GWAS
11.  XRCC3 Thr241Met Polymorphism and Clinical Outcomes of NSCLC Patients Receiving Platinum-Based Chemotherapy: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(8):e69553.
Introduction
X-ray repair cross-complementing protein 3 (XRCC3) is an essential gene involved in the double-strand break repair pathway. Published evidence has shown controversial results about the relationship between XRCC3 Thr241Met polymorphism and clinical outcomes of non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy.
Methods
A systematic review and meta-analysis was performed to evaluate the predictive value of XRCC3 Thr241Met polymorphism on clinical outcomes of advanced NSCLC receiving platinum-based chemotherapy. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were analyzed.
Results
A number of 11 eligible studies were identified according to the inclusion criteria. Carriers of the variant XRCC3 241Met allele were significantly associated with good response to platinum-based chemotherapy (ThrMet/MetMet vs. ThrThr: OR  = 1.509, 95% CI: 1.099–2.072, Pheterogeneity  = 0.618). The XRCC3 Thr241Met polymorphism was not associated with OS (MetMet vs. ThrThr, HR  = 0.939, 95% CI:0.651–1.356, Pheterogeneity  = 0.112) or PFS (MetMet vs. ThrThr, HR  = 0.960, 95% CI: 0.539–1.710, Pheterogeneity  = 0.198). Additionally, no evidence of publication bias was observed.
Conclusions
This systematic review and meta-analysis shows that carriers of the XRCC3 241Met allele are associated with good response to platinum-based chemotherapy in advanced NSCLC, while the XRCC3 Thr241Met polymorphism is not associated with OS or PFS.
doi:10.1371/journal.pone.0069553
PMCID: PMC3734199  PMID: 23940523
12.  Personalized medicine in metastatic non-small-cell lung cancer: promising targets and current clinical trials 
Current Oncology  2012;19(Suppl 1):S73-S85.
Non-small-cell lung cancer (nsclc) remains the leading cause of cancer-related death globally, with most patients presenting with non-curable disease. Platinum-based doublet chemotherapy has been the cornerstone of treatment for patients with advanced-stage disease and has resulted in a modest increase in overall survival (on the order of an incremental 2 months increased survival per decade) and quality of life. Improved knowledge of the molecular signalling pathways found in nsclc has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many nsclc patients. In this review, we present a summary of many of the currently investigated nsclc targets, discuss their current clinical trial status, and provide commentary as to the likelihood of their success making a positive impact for nsclc patients.
doi:10.3747/co.19.1132
PMCID: PMC3377759  PMID: 22787415
Lung cancer; clinical trials; novel targets; novel therapeutics
13.  Smoking and Prognostic Factors in an Observational Setting in Patients with Advanced Non-Small Cell Lung Carcinoma 
Journal of Cancer  2011;2:52-61.
Background: This prospective observational study estimated the effect of prognostic factors, particularly continued smoking during therapy, on survival in advanced non-small cell lung cancer (NSCLC) patients receiving gemcitabine-platinum. Further, prognostic factors were used to build a survival model to improve prognosis prediction in naturalistic clinical settings.
Methods: Eligibility criteria included: Stage IIIB/IV NSCLC, no prior chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. A Cox regression model was constructed and validated by randomizing patients into two datasets (Construction [C]:Validation [V]; 3:1 ratio). Country, disease stage, hypercalcemia, “N” factor, weight reduction, performance status, and superior vena cava obstruction were pre-defined variables forced into the model. Continued smoking was tested with adjustment for these variables.
Results: One thousand two hundred and fourteen patients (C=891 and V=323) were enrolled. The final predictive model, established in the Construction dataset, identified four significant (p≤0.05) and independent predictors of survival, which were disease stage, performance status, gemcitabine-platinum regimen, and T-stage. Smoking during therapy was not significantly associated with survival (Hazard Ratio [95% CI]: 0.955 [0.572, 1.596], p=0.8618; versus never smokers).
Conclusions: Although continued smoking during therapy was not significantly associated with shorter survival, the model developed in this study forms an evidence-based approach to assessing prognosis in advanced stage NSCLC.
PMCID: PMC3020361  PMID: 21234301
smoking; observational; NSCLC; prognostic factors; predictive modeling.
14.  The impact of both platinum-based chemotherapy and EGFR-TKIs on overall survival of patients with advanced non-small cell lung cancer 
Chinese Journal of Cancer  2014;33(2):105-114.
Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival (OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials—involving 11,456 adult patients in 32 arms—were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian (predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs (r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.
doi:10.5732/cjc.012.10274
PMCID: PMC3935012  PMID: 23816558
NSCLC; platinum-based doublet chemotherapy; correlation; EGFR-TKIs; overall survival
15.  Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer 
British Journal of Cancer  2009;101(9):1543-1548.
Background:
Sunitinib malate (SUTENT) has promising single-agent activity given on Schedule 4/2 (4 weeks on treatment followed by 2 weeks off treatment) in advanced non-small cell lung cancer (NSCLC).
Methods:
We examined the activity of sunitinib on a continuous daily dosing (CDD) schedule in an open-label, multicentre phase II study in patients with previously treated, advanced NSCLC. Patients ⩾18 years with stage IIIB/IV NSCLC after failure with platinum-based chemotherapy, received sunitinib 37.5 mg per day. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), 1-year survival rate, and safety.
Results:
Of 47 patients receiving sunitinib, one patient achieved a confirmed partial response (ORR 2.1% (95% confidence interval (CI) 0.1, 11.3)) and 11 (23.4%) had stable disease (SD) ⩾8 weeks. Five patients had SD>6 months. Median PFS was 11.9 weeks (95% CI 8.6, 14.1) and median OS was 37.1 weeks (95% CI 31.1, 69.7). The 1-year survival probability was 38.4% (95% CI 24.2, 52.5). Treatment was generally well tolerated.
Conclusions:
The safety profile and time-to-event analyses, albeit relatively low response rate of 2%, suggest single-agent sunitinib on a CDD schedule may be a potential therapeutic agent for patients with advanced, refractory NSCLC.
doi:10.1038/sj.bjc.6605346
PMCID: PMC2778527  PMID: 19826424
non-small cell lung cancer; phase II; sunitinib; tyrosine kinase inhibitor
16.  Influence of Comorbidities on the Efficacy of Radiotherapy with or without Chemotherapy in Elderly Stage III Non-small Cell Lung Cancer Patients 
Purpose
The current study was conducted in order to evaluate the clinical outcome of radical radiotherapy (RT) with or without chemotherapy for elderly patients with stage III non-small cell lung cancer (NSCLC).
Materials and Methods
Between 1990 and 2010, 125 patients, aged 70 years or more, received radical RT with or without chemotherapy for treatment of stage III NSCLC. We reviewed the patients' prognostic factors, including comorbidities. Comorbidity status was evaluated using a simplified comorbidity score (SCS). Of the patients reviewed, 82 received radical RT alone, whereas the other 43 patients underwent chemoradiotherapy (CRT). A platinum-based chemotherapy regimen was most commonly used (42/43).
Results
The two-year overall-survival (OS) and progression-free survival (PFS) rates were 32.2% and 21.8%, respectively. SCS was the independent prognostic factor for OS. In the frail elderly subgroup with a SCS of ≥10, CRT demonstrated a significant difference in PFS, but not in OS. In contrast, OS and PFS following CRT were significantly superior to RT in the fit elderly subgroup with a SCS of <10. The incidence of severe pulmonary toxicities in the frail elderly subgroup was significantly higher than that in the fit elderly subgroup.
Conclusion
Multiple comorbidities evaluated according to the SCS are related to poor OS in elderly patients with stage III NSCLC. CRT improved clinical outcome when compared to RT in the fit elderly subgroup, however, the gain from this treatment was negated in the frail elderly subgroup with multiple comorbidities. Therefore, evaluation of comorbidity is necessary in order to determine whether chemotherapy should be combined with RT in elderly patients with stage III NSCLC.
doi:10.4143/crt.2012.44.4.242
PMCID: PMC3546271  PMID: 23341788
Non-small cell lung carcinoma; Elderly; Chemoradiotherapy; Comorbidity; Radical radiotherapy
17.  Common genetic variants in cell cycle pathway are associated with survival in stage III–IV non-small-cell lung cancer 
Carcinogenesis  2011;32(12):1867-1871.
Cell cycle progression contributes to the cellular response to DNA-damaging factors, such as chemotherapy and radiation. We hypothesized that the genetic variations in cell cycle pathway genes may modulate treatment responses and affect survival in patients with advanced non-small-cell lung cancer (NSCLC). We genotyped 374 single-nucleotide polymorphisms (SNPs) from 49 cell cycle-related genes in 598 patients with stages III–IV NSCLC treated with first-line platinum-based chemotherapy with/without radiation. We analyzed the individual and combined associations of these SNPs with survival and evaluated their gene–gene interactions using survival tree analysis. In the analysis of survival in all the patients, 39 SNPs reached nominal significance (P < 0.05) and 4 SNPs were significant at P <0.01. However, none of these SNPs remained significant after correction for multiple comparisons at a false discovery rate of 10%. In stratified analysis by treatment modality, after adjusting for multiple comparisons, nine SNPs in chemotherapy alone and one SNP in chemoradiation remained significant. The most significant SNP in chemotherapy group was CCNB2:rs1486878 [hazard ratio (HR) = 1.69, 95% confidence interval (CI), 1.25–2.30, P = 0.001]. TP73: rs3765701 was the only significant SNP in chemoradiation group (HR = 1.87; 95% CI = 1.35–2.59, P = 1.8 × 10−4). In cumulative analysis, we found a significant gene-dosage effect in patients receiving chemotherapy alone. Survival tree analysis demonstrated potential higher order gene–gene and gene–treatment interactions, which could be used to predict survival status based on distinct genetic signatures. These results suggest that genetic variations in cell cycle pathway genes may affect the survival of patients with stages III–IV NSCLC individually and jointly.
doi:10.1093/carcin/bgr217
PMCID: PMC3220611  PMID: 21965272
18.  Response to First-Line Chemotherapy in Patients with Non-Small Cell Lung Cancer According to RRM1 Expression 
PLoS ONE  2014;9(3):e92320.
Background
The response to cytotoxic chemotherapy varies greatly in patients with advanced non-small cell lung cancer (NSCLC), and molecular markers may be useful in determining a preferable therapeutic approach for individual patients. This retrospective study was performed to evaluate the predictive value of ribonucleotide reductase regulatory subunit M1 (RRM1) on the therapeutic efficacy of platinum-based chemotherapy in patients with NSCLC.
Methods
Patients with advanced NSCLC who received platinum doublet chemotherapy (n = 229) were included in this retrospective study, and their clinical outcomes were analyzed according to RRM1 expression.
Results
In patients receiving gemcitabine-based therapy, the disease control rate (DCR) and progression-free survival (PFS) of patients with RRM1-negative tumors were significantly higher than in patients with RRMI-positive tumors (P = 0.041 and P = 0.01, respectively), and multivariate analysis showed that RRM1 expression was an independent prognostic factor (P = 0.013). No similar differences were found in patients receiving docetaxel- or vinorelbine-based therapy. In RRM1-positive patients, the DCRs for docetaxel and vinorelbine were higher than for gemcitabine (P = 0.047 and P = 0.047, respectively), and docetaxel and vinorelbine showed a longer PFS than gemcitabine-based chemotherapy (P = 0.012 and P = 0.007). No similar differences were found among patients with RRM1-negative tumors.
Conclusions
Negative RRM1 expression in advanced NSCLC is associated with a higher response rate to gemcitabine-based chemotherapy. In patients with RRM1-positive tumors, docetaxel and vinorelbine showed a higher therapeutic efficacy than gemcitabine-based therapy. Additional prospective studies are needed to investigate the predictive meaning of RRM1 in the response to chemotherapy.
doi:10.1371/journal.pone.0092320
PMCID: PMC3960222  PMID: 24647522
19.  Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2012;30(27):3345-3352.
Purpose
Platinum resistance is a major limitation in the treatment of advanced non–small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC.
Patients and Methods
We measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post- versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis.
Results
Tissue platinum concentration correlated significantly with percent reduction in tumor size (P < .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P = .034), progression-free survival (P = .018), and overall survival (P = .005) in the multicovariate Cox model analysis after adjusting for number of cycles.
Conclusion
This clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted.
doi:10.1200/JCO.2011.40.8120
PMCID: PMC3438232  PMID: 22891266
20.  Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma 
Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death in both men and women in the United States. Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease. Improvements in overall survival and quality of life have been modest. Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many NSCLC patients. In this review, we present a summary of many of the currently investigated biologic targets in NSCLC, discuss their current clinical trial status, and also discuss the potential for development of other targeted agents.
doi:10.5306/wjco.v4.i2.29
PMCID: PMC3659261  PMID: 23696960
Non-small cell lung cancer; Molecular targeted therapy; Vascular endothelial growth factor; Epidermal growth factor receptor; Tyrosine kinase inhibitors; BRAF; Anaplastic lymphoma kinase
21.  A retrospective study: platinum-based induction chemotherapy combined with gemcitabine or paclitaxel for stage IIB-IIIA central non-small-cell lung cancer 
Background
Several encouraging phase III clinical trials have evaluated platinum-based induction chemotherapy against stage IIB-IIIA non-small-cell lung cancer (NSCLC). Chemotherapy efficacy was assessed using common regimens in this retrospective analysis.
Methods
From 2007 to 2011, the clinical records of stage IIB-IIIA NSCLC patients undergoing surgery after neoadjuvant chemotherapy were reviewed. Gathered data were tested for significance and variables impacting survival were assessed by univariate and Cox regression analyses.
Results
Overall, 84% of patients were male and 93% had central disease. Platinum-based chemotherapy protocols with gemcitabine or paclitaxel gave an overall response rate of 55% (45/82) and 6.1% pathological complete response (5/82). Clinical response was unassociated with regimen or histology, while more pneumonectomies were performed in the stable compared to partial response disease group (P =0.040). Postoperative mortality was 1.2% (1/82), and complications, unassociated with regimen or histology, were atelectasis (26.8%) and supraventricular arrhythmias (13.4%). Right-sided procedures appeared to increase the incidence of bronchopleural fistula (P =0.073). The median disease-free survival time was 18 months and median overall survival time was not reached. Disease-free survival rates at one, two, and three years were 54%, 47%, and 33%, while the overall survival rate was 73%, 69%, and 59%, respectively. Disease-free survival predictors were radiographic response and mediastinal lymphadenopathy before chemotherapy (P =0.012 and 0.002, respectively).
Conclusions
Two cycles of platinum-based chemotherapy with gemcitabine or paclitaxel is efficacious for patients with stage IIB-IIIA central disease. Patients achieving clinical response had improved disease-free survival times, while those with mediastinal lymphadenopathy had a higher postoperative recurrence risk.
doi:10.1186/1477-7819-11-76
PMCID: PMC3621287  PMID: 23517534
Non-small-cell lung cancer; Induction chemotherapy; Central disease; Resection; Squamous
22.  Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy 
Background
Recent studies have shown that human copper transporter 1 (hCtr1), the major copper influx transporter, is involved in the transport of platinum-based antitumor agents. We investigated the predictive and prognostic values of hCtr1, and cooper efflux transporters ATP7A and ATP7B, in patients with locally advanced non-small cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy.
Methods
From 2004 to 2009, we identified 54 consecutive stage III NSCLC patients who underwent first-line platinum-based doublet chemotherapy. Immunohistochemical studies of hCtr1, ATP7A and ATP7B on the paraffin-embedded pre-treatment tumor samples were performed and correlated with chemotherapy response and survival.
Results
Overexpression of hCtr1, ATP7A and ATP7B were observed in 68%, 48% and 74% of the participants, respectively. hCtr1 overexpression was associated with better chemotherapy responses (P < 0.01); whereas ATP7A and ATP7B were not. Patients with hCtr1 overexpressing tumors had better progression-free survival (PFS) and overall survival (OS) (P = 0.01 and 0.047, respectively). In multivariate analyses for chemotherapy response and PFS, only hCtr1 overexpression emerged as a favorable independent predictive and prognostic factor (all P < 0.01).
Conclusion
This is the first report to state that hCtr1 is not only an independent predictor of platinum-based chemotherapy response but also a prognostic factor in stage III NSCLC.
doi:10.1016/j.lungcan.2011.06.011
PMCID: PMC3319119  PMID: 21788094
Human copper transporter 1; Cisplatin; ATP7A; ATP7B; Non-small cell lung cancer; Prognosis
23.  Differential efficacy of docetaxel according to non-small cell lung cancer histology and the therapeutic effect of epidermal growth factor receptor tyrosine kinase inhibitors 
Oncology Letters  2011;2(6):1059-1064.
The active mutation of epidermal growth factor receptor (EGFR) and clinical characteristics are significant biomarkers for chemotherapy selection in non-small cell lung cancer (NSCLC). Although docetaxel is a key agent in second-line therapy for NSCLC, predictive biomarkers for assessing its efficacy have yet to be determined. To assess the clinical efficacy of docetaxel in second-line therapy for NSCLC according to NSCLC histology and the therapeutic effect of EGFR-tyrosine kinase inhibitors (EGFR-TKIs), we retrospectively reviewed 454 NSCLC patients treated with docetaxel between April 2002 and April 2009. In total, 239 patients with advanced NSCLC treated with docetaxel as second-line therapy following failure of platinum-based chemotherapy were analyzed in this study. A total of 59 (25%) patients had squamous cell carcinoma. The overall response rate and median progression-free survival time in the squamous cell group were significantly inferior to those in the non-squamous cell group (p=0.031 and p=0.005, respectively). Following the failure of docetaxel, 91 non-squamous patients were treated with EGFR-TKIs. The patients that achieved clinical benefit from EGFR-TKIs (n=32) demonstrated a significantly better response rate and longer progression-free survival compared to the other group (p<0.001 and p=0.027, respectively). In the univariate and multivariate analysis, the favorable therapeutic effect of EGFR-TKIs had an independent effect on progression- free survival (HR 1.484, p=0.0464). In conclusion, this retrospective study suggests that non-squamous histology and favorable therapeutic effect from EGFR-TKIs are useful markers for predicting the efficacy of docetaxel in second-line therapy for NSCLC.
doi:10.3892/ol.2011.400
PMCID: PMC3406568  PMID: 22848267
non-small cell lung cancer; docetaxel; second-line therapy; EGFR-TKI; predictive biomarker; histology
24.  Looking Beyond Surveillance, Epidemiology, and End Results 
Introduction
Chemotherapy prolongs survival without substantially impairing quality of life for medically fit patients with advanced non-small cell lung cancer (NSCLC), but population-based studies have shown that only 20 to 30% of these patients receive chemotherapy. These earlier studies have relied on Medicare-linked Surveillance, Epidemiology, and End Results (SEER) data, thus excluding the 30 to 35% of lung cancer patients younger than 65 years. Therefore, we determined the use of chemotherapy in a contemporary, diverse NSCLC population encompassing all patient ages.
Methods
We performed a retrospective analysis of patients diagnosed with stage IV NSCLC from 2000 to 2007 at the University of Texas Southwestern Medical Center. Demographic, treatment, and outcome data were obtained from hospital tumor registries. The association between these variables was assessed using univariate analysis and multivariate logistic regression.
Results
In all, 718 patients met criteria for analysis. Mean age was 60 years, 58% were men, and 45% were white. Three hundred fifty-three patients (49%) received chemotherapy. In univariate analysis, receipt of chemotherapy was associated with age (53% of patients younger than 65 years versus 41% of patients aged 65 years and older; p = 0.003) and insurance type (p < 0.001). In a multivariate model, age and insurance type remained associated with receipt of chemotherapy. For individuals receiving chemotherapy, median survival was 9.2 months, compared with 2.3 months for untreated patients (p < 0.001).
Conclusions
In a contemporary population representing the full age range of patients with advanced NSCLC, chemotherapy was administered to approximately half of all patients—more than twice the rate reported in some earlier studies. Patient age and insurance type are associated with receipt of chemotherapy.
doi:10.1097/JTO.0b013e3181e9a00f
PMCID: PMC3466589  PMID: 20631635
Non small-cell lung cancer; Chemotherapy; Metastatic; Practice patterns; Insurance
25.  Effect of Polymorphisms in XPD on Clinical Outcomes of Platinum-Based Chemotherapy for Chinese Non-Small Cell Lung Cancer Patients 
PLoS ONE  2012;7(3):e33200.
Purpose
Xeroderma pigmentosum group D (XPD) codes for a DNA helicase involved in nucleotide excision repair that removes platinum-induced DNA damage. Genetic polymorphisms of XPD may affect DNA repair capacity and lead to individual differences in the outcome of patients after chemotherapy. This study aims to identify whether XPD polymorphisms affect clinical efficacy among advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.
Experimental Design
353 stage III-IV NSCLC patients receiving platinum-based chemotherapy as the first-line treatment were enrolled in this study. Four potentially functional XPD polymorphisms (Arg156Arg, Asp312Asn, Asp711Asp and Lys751Gln) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR-based sequencing.
Results
Variant genotypes of XPD Asp312Asn, Asp711Asp and Lys751Gln were significantly associated with poorer NSCLC survival (P = 0.006, 0.006, 0.014, respectively, by log-rank test). The most common haplotype GCA (in order of Asp312Asn, Asp711Asp and Lys751Gln) also exhibited significant risk effect on NSCLC survival (log-rank P = 0.001). This effect was more predominant for patients with stage IIIB disease (P = 2.21×10−4, log-rank test). Increased risks for variant haplotypes of XPD were also observed among patients with performance status of 0–1 and patients with adenocarcinoma. However, no significant associations were found between these polymorphisms, chemotherapy response and PFS.
Conclusions
Our study provides evidence for the predictive role of XPD Asp312Asn, Asp711Asp and Lys751Gln polymorphisms/haplotype on NSCLC prognosis in inoperable advanced NSCLC patients treated with platinum-based chemotherapy.
doi:10.1371/journal.pone.0033200
PMCID: PMC3315552  PMID: 22479369

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