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1.  Immunotherapy in the treatment of non-small cell lung cancer 
Advances in the understanding of the role of the immune system in tumor immunosurveillance have resulted in the recognition that tumors can evade immune destruction via the dysregulation of co-inhibitory or checkpoint signals. This has led to the development of a generation immunotherapeutic agents targeting the immune checkpoint pathway. Recent early phase studies of immune checkpoint modulators, such as CTLA-4, PD-1 and PD-L1 inhibitors in NSCLC have reported promising results with prolonged clinical responses and tolerable toxicity. This article provides an overview of co-stimulatory and inhibitory molecules that regulate the immune response to tumors, recent therapies that have been developed to exploit these interactions and the role of predictive biomarkers in treatment selection.
doi:10.1016/j.lungcan.2014.05.005
PMCID: PMC4332778  PMID: 24880938
Immunotherapy; Non-small cell lung cancer; PD-L1; CTLA-4; Ipilimumab; Nivolumab
2.  Patient willingness and barriers to receiving a CT scan for lung cancer screening 
CT scans are becoming a more common method for detecting lung cancers at an earlier, potentially more curable, stage of disease. There is currently little data on attitudes and beliefs about screening for lung cancer. This paper presents the results of a 2011 survey of adult current and former smokers that queried about past use of CT scanning and reasons for having or not having the screening done. A random-digit dialed telephone survey was administered to a representative sample of 1,290 US adults. Logistic regression analyses were used to examine the correlates of having the test while controlling for the covariates. A total of 13.4% (n=45) of the sample had ever had a CT scan to detect lung cancer. Of current smokers, 14.6% had received a CT scan, as compared with 12.7% of former smokers. The oldest age group (55+) was significantly more likely to have received a CT scan than the younger age groups. 78.5% of current smokers and 81.4% of former smokers indicated willingness to get the test if advised to do so by their doctor. Among those who said they were not willing to get screened, lack of insurance coverage was cited by 33% of current smokers and 25% of former smokers. Additionally, 33% of current smokers were afraid to find out whether they had cancer. The main barrier to CT scanning for lung cancer is likely to be insurance coverage for the test, which would be a burden for those on limited and fixed incomes. Next steps should include further research into the effect of increased public education about the availability, risks, benefits and barriers to lung cancer screening.
doi:10.1016/j.lungcan.2014.03.003
PMCID: PMC4327769  PMID: 24674155
lung cancer; barriers to screening
3.  Cediranib in patients with malignant mesothelioma: A phase II trial of the University of Chicago Phase II Consortium 
Introduction
Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors -1, -2, and -3.
Methods
We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily.
Results
Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR + SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥ grade 3 hypertension (8.5 vs. 4.1 months, p=0.024).
Conclusion
This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated.
doi:10.1016/j.lungcan.2012.06.011
PMCID: PMC4319647  PMID: 22831987
Mesothelioma; cediranib; vascular endothelial growth factor; hypertension
4.  SNPs in PTGS2 and LTA Predict Pain and Quality of Life in Long Term Lung Cancer Survivors 
PURPOSE
Lung cancer survivors report the lowest quality of life relative to other cancer survivors. Pain is one of the most devastating, persistent, and incapacitating symptoms for lung cancer survivors. Prevalence rates vary with 80–100% of survivors experiencing cancer pain and healthcare costs are five times higher in cancer survivors with uncontrolled pain. Cancer pain often has a considerable impact on quality of life among cancer patients and cancer survivors. Therefore, early identification, and treatment is important. Although recent studies have suggested a relationship between single nucleotide polymorphisms (SNPs) in several cytokine and inflammation genes with cancer prognosis, associations with cancer pain are not clear. Therefore, the primary aim of this study was to identify SNPs related to pain in long term lung cancer survivors.
PATIENTS AND METHODS
Participants were enrolled in the Mayo Clinic Lung Cancer Cohort upon diagnosis of their lung cancer. 1149 Caucasian lung cancer survivors, (440 surviving < 3 years; 354 surviving 3–5 years; and 355 surviving> 5 years) completed study questionnaires and had genetic samples available. Ten SNPS from PTGS2 and LTA genes were selected based on the serum literature. Outcomes included pain, and quality of life as measured by the SF-8.
RESULTS
Of the 10 SNPs evaluated in LTA and PTGS2 genes, 3 were associated with pain severity (rs5277; rs1799964), social function (rs5277) and mental health (rs5275). These results suggested both specificity and consistency of these inflammatory gene SNPs in predicting pain severity in long term lung cancer survivors.
CONCLUSION
These results provide support for genetic predisposition to pain severity and may aid in identification of lung cancer survivors at high risk for morbidity and poor QOL.
doi:10.1016/j.lungcan.2012.02.017
PMCID: PMC4314090  PMID: 22464751
genetics; SNPs; pain; quality of life; lung cancer; cytokines; LTA; PTGS2
5.  [No title available] 
PMCID: PMC3922123  PMID: 24355259
6.  [No title available] 
PMCID: PMC4293119  PMID: 25218177
7.  Challenges Scoring Radiation Pneumonitis in Patients Irradiated For Lung Cancer 
Background and Purpose
To quantify uncertainties in scoring radiation pneumonitis.
Materials and Methods
Records of 434 patients irradiated for lung cancer from 2000–2010 were retrospectively reviewed; IRB-approved study. From these, 121 received ≥60 Gy for non-small cell lung cancer (NSCLC) with ≥6 months follow-up. Patients where the physicians were uncertain of the diagnosis due to confounding factors were deemed “hard to score”. Subgroups were defined based on lung dosimetric parameters, and frequencies in different subgroups were compared via Fisher’s exact test.
Results
21/121 of patients were considered to have pneumonitis; median follow 17 months. Of these, 10/21 were “hard to score”; reasons including acute COPD exacerbation, infection, and tumor progression. “Hard to score” pneumonitis was slightly more common in patients with a COPD history (15%) vs. without COPD (4%) (p=0.05); and with a pre-RT FEV1 < 1.7L (16%) vs. ≥ 1.7L (4%) (p=0.09). Rates of “unambiguous” pneumonitis trended to be non-significantly slightly higher in patients higher mean lung doses, V5, and V30.
Conclusion
Radiation pneumonitis occurred in 17% of patients undergoing RT for NSCLC; with diagnostic uncertainty in 48% of these. Poor pre-RT pulmonary function increases the rate of “hard to score” pneumonitis. Dosimetric parameters are slightly better related to “unambiguous” than “hard to score” pneumonitis, as expected.
doi:10.1016/j.lungcan.2011.11.025
PMCID: PMC4287383  PMID: 22230037
Lung cancer; Non-small cell carcinoma; Radiation therapy; Pneumonitis; Toxicity scoring; Dosimetric parameters
8.  Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer 
Introduction
The multitargeted tyrosine kinase inhibitor (TKI) crizotinib is active against ALK translocated non-small-cell lung cancer (NSCLC); however acquired resistance invariably develops over time. ALK mutations have previously been implicated in only a third of resistant tumors. We sought to evaluate alternative mechanisms of resistance and preclinical strategies to overcome these in a cell line driven by EML4-ALK.
Methods
We selected the NSCLC cell line NCI-H3122 (H3122: EML4-ALK E13;A20) and derived resistant variants that were able to grow in the presence of 1μM crizotinib. These were analyzed for ALK mutations, sensitivity to crizotinib in combination to other TKIs, and for activation of alternative tyrosine kinases.
Results
All H3122 crizotinib resistant (CR) clones lacked amplification or mutations in the kinase domain of ALK. To evaluate if possible alternative kinases functioned as “bypass” tracks for downstream signaling activation in these resistance cells, we performed of phosho-receptor tyrosine kinase array that demonstrated that CR clones had higher phospho-EGFR signals than H3122 cells before and after exposure to crizotinib. A functional approach of dual ALK TKI (with crizotinib) with combinatory TKI inhibition was used as a secondary screen for possible targets. Crizotinib + erlotinib (reversible EGFR TKI) and crizotinib + afatinib (irreversible EGFR/ERBB2 TKI) were able to inhibit the growth of H3122 CR clones, confirming EGFR activation as a mechanism of resistance. The removal of crizotinib from the culture media re-sensitized CR cells to crizotinib.
Conclusions
We identified activation of EGFR as a mechanism of resistance to crizotinib in preclinical models of ALK translocated NSCLC. If EGFR activation is confirmed as a predominant mechanism of ALK TKI-induced resistance in patient-derived tumors, the use of ALK plus EGFR TKIs could be explored for this important cohort of NSCLCs.
doi:10.1016/j.lungcan.2013.09.019
PMCID: PMC3947244  PMID: 24199682
lung cancer; non-small-cell lung cancer; tyrosine kinase; kinase inhibitor; epidermal growth factor receptor; EGFR; EGF; anaplastic lymphoma kinase; ALK; crizotinib; erlotinib; afatinib
9.  A pilot test of a combined tobacco dependence treatment and lung cancer screening program 
Lung cancer screening with computed tomography has demonstrated a significant reduction in mortality. While these findings are important for the lung cancer research field, the most important risk factor for lung cancer, i.e. smoking, should not be ignored. We performed a pilot study to examine the feasibility of delivering a program that included both tobacco dependence treatment and lung cancer screening. The objectives of this study were to: (1) estimate the proportion of smokers who complied with a 12-week treatment protocol that included both tobacco dependence treatment and lung cancer screening, (2) obtain preliminary estimates of abstinence and quit attempts at 4 and 6 months, and (3) obtain preliminary estimates of the cognitive social health information processing (C-SHIP) constructs and how they change following the intervention. In this randomized pilot study, 18 volunteers completed a 12-week protocol: half received the tobacco dependence treatment program before a CT scan (BCT) and the other received the CT scan first, followed by the treatment program (ACT). The treatment protocol included both nurse-delivered telephone counseling and either nicotine replacement therapy or varenicline. Only one person did not complete all follow-up evaluations. At 4 months post enrollment, the carbon monoxide confirmed quit rates were 33.3% in the BCT arm and 22.2% in the ACT arm (27.8% overall), and all but one had made a 24-h attempt to quit. At 6 months the confirmed abstinence decreased to 22.1% in the BCT arm and 11.1% in the ACT arm (16.7% overall), and 72.2% of participants had made a 24-h quit attempt. These preliminary results suggest that it might be better to deliver treatment before the screening test. Future randomized trials with a larger sample size are needed to confirm these findings.
doi:10.1016/j.lungcan.2011.10.011
PMCID: PMC4272196  PMID: 22088938
Lung cancer screening; Smoking cessation; Nicotine replacement therapy; Varenicline; Epidemiology; Public health
10.  Does Histology Predict Survival of Advanced Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy? An Analysis of the Eastern Cooperative Oncology Group Study E1594 
Introduction
We conducted this analysis to determine whether survival of advanced NSCLC patients treated with platin-based chemotherapy doublets involving paclitaxel, docetaxel or gemcitabine was dependent on histological subtypes and treatment regimen.
Methods
We retrospectively analyzed data from E1594, a front-line phase III study in which advanced NSCLC patients were randomized to receive one of four regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, and carboplatin-paclitaxel. Patients were classified into four histology groups: squamous cell (SCC), adeno- (AC), large cell (LCC) and others including not otherwise specified (O/NOS) carcinoma. Logrank test was performed to compare overall survival (OS) and progression free survival (PFS) distributions according to histology as well as treatment.
Results
Of 1,139 patients including 716 men and 423 women, AC was the most common subtype (56.8%), followed by SCC (19.7%), O/NOS (17.0%) and LCC (6.5%). Men were more likely to have SCC and women were more likely to have AC (p=0.002). Among the four histology groups, there was no imbalance in regard to race, performance status, weight loss, brain metastasis or treatment. In each histology group, we found no significant difference in OS and PFS between the four chemotherapy regimens. Conversely, in each treatment arm, the survival outcome was similar between the four histology subtypes.
Conclusions
Our analysis suggests that histology does not predict survival benefit in advanced NSCLC patients treated with first-line platin-based doublets involving paclitaxel, docetaxel or gemcitabine.
doi:10.1016/j.lungcan.2013.03.018
PMCID: PMC4264629  PMID: 23611404
NSCLC; Histology; Prognostic; Survival; First-line Chemotherapy
11.  Development of ferret as a human lung cancer model by injecting 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) 
Objective
Development of new animal lung cancer models that are relevant to human lung carcinogenesis is important for lung cancer research. Previously we have shown the induction of lung tumor in ferrets (Mustela putorius furo) exposed to both tobacco smoke and a tobacco carcinogen (4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK). In the present study, we investigated whether NNK treatment alone induces both preneoplastic and neoplastic lesions in the lungs of ferrets.
Methods
We exposed ferrets to NNK by i.p. injection of NNK (50 mg/kg BW) once a month for four consecutive months and then followed up for 24, 26 and 32 weeks. The incidences of pulmonary preneoplastic and neoplastic lesions were assessed by histopathological examination. The expressions of α7 nicotinic acetylcholine receptor (α7 nAChR, which has been shown to promote lung carcinogenesis) and its related molecular biomarkers in lungs were examined by immunohistochemistry and/or Western blotting analysis.
Results
Ferrets exposed to NNK alone developed both preneoplastic lesions (squamous metaplasia, dysplasia and atypical adenomatous hyperplasia) and tumors (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma), which are commonly seen in humans. The incidence of tumor induced by NNK was time-dependent in the ferrets (16.7%, 40.0% and 66.7% for 24, 26 and 32 weeks, respectively). α7 nAChR is highly expressed in the ferret bronchial/bronchiolar epithelial cells, and alveolar macrophages in ferrets exposed to NNK, and in both squamous cell carcinoma and adenocarcinoma of the ferrets. In addition, we observed the tendency for an increase in phospho-ERK and cyclin D1 protein levels (p = 0.081 and 0.080, respectively) in the lungs of ferrets exposed to NNK.
Conclusion
The development of both preneoplastic and neoplastic lesions in ferret lungs by injecting NNK alone provides a simple and highly relevant non-rodent model for studying biomarkers/molecular targets for the prevention, detection and treatment of lung carcinogenesis in humans.
PMCID: PMC4097109  PMID: 24396883
ferret; tobacco carcinogen; NNK; lung cancer; α7 nicotinic acetylcholine receptor
12.  Predictors of pulmonary toxicity in limited stage small cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904 
Introduction
Standard therapy for limited stage small cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy followed by prophylactic cranial radiotherapy. Predictors of post chemoradiotherapy pulmonary toxicity in limited stage (LS) small cell lung cancer (SCLC) patients are not well defined. Current guidelines are derived from non-small cell lung cancer regimens, and do not account for the unique biology of this disease. Therefore, we analyzed patients on three consecutive CALGB LS-SCLC trials treated with concurrent chemotherapy and daily high dose radiotherapy (70 Gy) to determine patient and treatment related factors predicting for post-treatment pulmonary toxicity.
Methods
Patients treated on CALGB protocols 39808, 30002, 30206 investigating two cycles of chemotherapy followed by concurrent chemotherapy and 70 Gy daily thoracic radiation therapy were pooled. Patient, tumor, and treatment related factors were evaluated to determine predictors of grade 3–5 pulmonary toxicities after concurrent chemoradiotherapy.
Results
100 patients were included. No patient experienced grade 4–5 post-treatment pulmonary toxicity. Patients who experienced post-treatment pulmonary toxicity were more likely to be older (median age 69 vs 60, p=0.09) and have smaller total lung volumes (2565 cc vs 3530 cc, p=0.05).). Furthermore, exposure of larger volumes of lung to lower (median V5=70%, p=0.09, median V10=63%, p=0.07), intermediate (median V20=50, p=0.04) and high (median V60=25%, p=0.01) doses of radiation were all associated with post-treatment grade 3 pulmonary toxicity, as was a larger mean lung radiation dose (median 31 Gy) p=0.019.
Conclusion
Post-treatment pulmonary toxicity following the completion of 2 cycles of chemotherapy followed by concurrent chemotherapy and high dose daily radiation therapy was uncommon. Care should be taken to minimize mean lung radiation exposure, as well as volumes of low, intermediate and high doses of radiation.
PMCID: PMC4098705  PMID: 24396884
limited stage; small cell lung cancer; high dose chemoradiotherapy; toxicity predictors; pneumonitis; lung toxicity radiation
13.  Intensity Modulated Radiotherapy for Stage III Non-Small Cell Lung Cancer in the United States: Predictors of Use and Association with Toxicities 
Lung cancer (Amsterdam, Netherlands)  2013;82(2):10.1016/j.lungcan.2013.08.015.
Summary
Background
Intensity modulated radiotherapy for stage III lung cancer has become commonplace in the United States in the absence of randomized controlled trials. We used a large, population-based database to determine which factors led to increased utilization of IMRT and to evaluate associations of IMRT with toxicities.
Methods
The Surveillance, Epidemiology, and End Results (SEER)-Medicare records identified 3,986 individuals aged 66 years or older diagnosed with stage III lung cancer between 2001 and 2007 and treated with IMRT or 3D conformal radiotherapy. Predictors of IMRT use were determined using logistic regression. Associations of IMRT use with diagnosis codes for radiation-related toxicities were evaluated with multivariate proportional hazards regression and propensity-score matching.
Results
Among the 3,986 patients studied, the median age was 75 years, 54.1% were male, and 62% had IIIA disease. Two hundred fifty seven (6.5%) patients received IMRT, with use increasing from from 0.5% in 2001 to 14.7% in 2007 (P<0.001). Key predictors of IMRT delivery included increasing year of diagnosis and treatment in a freestanding center (odds ratio, 2.10; 95% confidence interval [CI], 1.59–2.77, P<0.001); tumor size, stage, and number of radiotherapy fractions delivered were not associated with IMRT use. IMRT use was not associated with a higher burden of lung or esophagus toxicities when compared to 3DCRT.
Conclusion
These findings suggest that practice environment strongly influenced adoption of IMRT for lung cancer. Patient and tumor factors were not significant predictors of IMRT use. Esophagus and lung toxicity rates were similar between IMRT and 3DCRT.
doi:10.1016/j.lungcan.2013.08.015
PMCID: PMC3839043  PMID: 24018022
non-small cell lung cancer; technology utilization; IMRT; radiation technique; comparative effectiveness
14.  Diagnostic evaluation following a positive lung screening chest radiograph in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cancer Screening Trial 
Lung cancer (Amsterdam, Netherlands)  2013;82(2):10.1016/j.lungcan.2013.07.017.
Lung cancer is the major cause of cancer mortality. One of the aims of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was to determine if annual screening chest radiographs reduce lung cancer mortality. We enrolled 154,900 individuals, aged 55–74 years; 77,445 were randomized to the intervention arm and received an annual chest radiograph for 3 or 4 years. Participants with a positive screen underwent diagnostic evaluation under guidance of their primary physician. Methods of diagnosis or exclusion of cancer, interval from screen to diagnosis, and factors predicting diagnostic testing were evaluated. One or more positive screens occurred in 17% of participants. Positive screens resulted in biopsy in 3%, with 54% positive for cancer. Biopsy likelihood was associated with a mass, smoking, age, and family history of lung cancer. Diagnostic testing stopped after a chest radiograph or computed tomography/magnetic resonance imaging in over half. After a second or subsequent positive screen, evaluation stopped after comparison to prior radiographs in over half. Of 308 screen-detected cancers, the diagnosis was established by thoracotomy/thoracoscopy in 47.7%, needle biopsy in 27.6%, bronchoscopy in 20.1% and mediastinoscopy in 2.9%. Eighty-four percent of screen-detected lung cancers were diagnosed within 6 months. Diagnostic evaluations following a positive screen were conducted in a timely fashion. Lung cancer was diagnosed by tissue biopsy or cytology in all cases. Lung cancer was excluded during evaluation of positive screening examinations by clinical or radiographic evaluation in all but 1.4% who required a tissue biopsy.
doi:10.1016/j.lungcan.2013.07.017
PMCID: PMC3818308  PMID: 23993734
Lung Neoplasms/mortality; Radiography/screening/methods; Risk factors
15.  Effectiveness of Radiation Therapy Alone for Elderly Patients with Unresected Stage III Non-Small Cell Lung Cancer 
Lung cancer (Amsterdam, Netherlands)  2013;82(2):10.1016/j.lungcan.2013.06.011.
Purpose
Chemoradiotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Elderly patients, who are often considered unfit for combined chemoradiotherapy, frequently receive radiation therapy (RT) alone. Using population-based data, we evaluated the effectiveness and tolerability of lone RT in unresected elderly stage III NSCLC patients.
Methods and Materials
Using the Surveillance, Epidemiology and End Results (SEER) registry linked to Medicare records we identified 10,376 cases of unresected stage III NSCLC that were not treated with chemotherapy, diagnosed between 1992 and 2007. We used logistic regression to determine propensity scores for RT treatment using patients’ pre-treatment characteristics. We then compared survival of patients who underwent lone RT vs. no treatment using a Cox regression model adjusting for propensity scores. The adjusted odds for toxicity among patients treated with and without RT were also estimated.
Results
Overall, 6,468 (62%) patients received lone RT. Adjusted analyses showed that RT was associated with improved overall survival in unresected stage III NCSLC (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.74–0.79) after controlling for propensity scores. RT treated patients had an increased adjusted risk of hospitalization for pneumonitis (odds ratio [OR]: 89, 95% CI: 12–636), and esophagitis (OR: 8, 95% CI: 3–21).
Conclusions
These data suggest that use of RT alone may improve the outcomes of elderly patients with unresected stage III NSCLC. Severe toxicity, however, was considerably higher in the RT treated group. The potential risks and benefits of RT should be carefully discussed with eligible elderly NSCLC patients.
doi:10.1016/j.lungcan.2013.06.011
PMCID: PMC3845375  PMID: 24011407
Non-small cell lung cancer; Radiotherapy; Lone Radiotherapy; Elderly; Outcomes; Toxicity; Unresectable lung cancer
16.  Smoking status and self-reported race affect the frequency of clinically-relevant oncogenic alterations in non-small-cell lung cancers at a United States-based academic medical practice 
Introduction
The identification of somatic genomic aberrations in non-small-cell lung cancer (NSCLC) is part of evidence-based practice guidelines for care of patients with NSCLC. We sought to establish the frequency and correlates of these changes in routine patient-tumor sample pairs.
Methods
Clinicopathologic data and tumor genotype were retrospectively compiled and analyzed from an overall cohort of 381 patient-tumor samples.
Results
Of these patients, 75.9% self-reported White race, 13.1% Asian, 6.5% Black, 27.8% were never-smokers, 54.9% former-smokers and 17.3% current-smokers. The frequency of EGFR mutations was 23.9%(86/359), KRAS mutations 34.2%(71/207) and ALK FISH positivity 9.1%(23/252) in tumor samples, and almost all had mutually exclusive results for these oncogenes. In tumors from White, Black and Asian patients, the frequencies of EGFR mutations were 18.4%, 18.2% and 62%, respectively; of ALK FISH positivity 7.81%, 0% and 14.8%, respectively; and of KRAS mutations 41.6%, 20% and 0%. These patterns changed significant with increasing pack-year history of smoking. In White patients, the frequencies of EGFR mutations and ALK FISH positivity decreased with increasing pack-year cohorts; while the frequencies of KRAS mutations increased. Interestingly, in Asian patients the frequencies of EGFR mutations were similar in never smokers and in the cohorts with less then 45pack-year histories of smoking and only decreased in the 45pack-year plus cohort.
Conclusions
The frequencies of somatic EGFR, KRAS, and ALK gene abnormalities using routine lung cancer tissue samples from our United States-based academic medical practice reflect the diverse ethnicity (with a higher frequency of EGFR mutations in Asian patients) and smoking patterns (with an inverse correlation between EGFR mutation and ALK rearrangement) of our tested population. These results may help other medical practices appreciate the expected results from introduction of routine tumor genotyping techniques into their day-to-day care of NSCLC.
doi:10.1016/j.lungcan.2013.07.013
PMCID: PMC3800098  PMID: 23932486
lung cancer; non-small-cell lung cancer; never smokers; epidermal growth factor receptor; EGFR; anaplastic lymphoma kinase; ALK; KRAS; tumor genotype; ethnicipty; Asian; White; Black
17.  Cross-validation analysis of the prognostic significance of mucin expression in patients with resected non-small cell lung cancer treated with adjuvant chemotherapy: results from IALT, JBR.10 and ANITA 
INTRODUCTION
CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR)=1.9, p=0.002) and overall survival (OS; HR=1.9, p=0.004).
METHODS
To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy.
RESULTS
The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15% respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p<0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR=1.2 [1.0–1.5], p=0.06) but not significantly so for OS (HR=1.1 [0.9–1.4], p=0.25). Prognostic value did not vary according to histology: HR=1.3 [1.0–1.6] in adenocarcinoma vs. 1.6 [1.2–2.2] for DFS in other histology (interaction p=0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p=0.27; OS p=0.49).
CONCLUSIONS
Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy.
doi:10.1016/j.lungcan.2013.06.015
PMCID: PMC3804220  PMID: 23920379
Non-small cell lung cancer; prognostic factors; mucin; predictive factors; adenocarcinoma
18.  Support Service Use and Interest in Support Services among Lung Cancer Patients 
Lung cancer (Amsterdam, Netherlands)  2013;82(1):10.1016/j.lungcan.2013.06.020.
Summary
Objectives
This study examined support service use and interest in support services among lung cancer patients (N = 165) at two comprehensive medical centers in the midwestern United States.
Materials and Methods
Patients completed an assessment of support service use (i.e., receipt of mental health services, complementary and alternative medicine [CAM], and help from a spiritual leader), interest in support services, and physical and psychological symptoms.
Results
Only 40% of patients with significant anxiety and depressive symptoms and 28% of the entire sample reported current mental health service use. However, nearly half (47%) of all patients were receiving support from a spiritual leader. Having late-stage lung cancer and a religious affiliation predicted receipt of spiritual support. Few patients who were not receiving mental health services or spiritual support were interested in these services (range = 4% to 18%). Conversely, although interest in CAM was expressed by a substantial minority of patients (27%) who were not using these services, rates of CAM use were relatively low (22%).
Conclusion
Findings suggest that distressed lung cancer patients underuse mental health services, but many patients receive help from spiritual leaders. Given the lack of interest in mental health services among patients who are not receiving them, efforts are needed to enhance palatability of services and identify and reduce barriers to evidence-based service use.
doi:10.1016/j.lungcan.2013.06.020
PMCID: PMC3814017  PMID: 23932457
lung neoplasms; mental health services; complementary therapies; spiritual therapies; religion; psychological distress
19.  Frequency of EGFR and KRAS Mutations in Patients with Non Small Cell Lung Cancer by Racial Background: Do Disparities exist? 
Introduction
Mutations in EGFR and KRAS can impact treatment decisions for patients with NSCLC. The incidence of these mutations varies, and it is unclear whether there is a decreased frequency among African Americans (AfAs).
Methods
We performed a retrospective chart review of 513 NSCLC patients undergoing EGFR and KRAS mutational analysis at the Hospital of the University of Pennsylvania between May 2008 and November 2011. Clinical and pathologic data were abstracted from the patients’ electronic medical record.
Results
Of 497 patients with informative EGFR mutation analyses, the frequency of EGFR mutation was 13.9%. The frequency of EGFR mutations was associated with race (p<0.001) and was lower in AfA patients compared to Caucasian (C) patients but did not reach statistical significance (4.8% vs 13.7%, p=0.06). Mean Charlson Comorbidity Index and number of cigarette pack years were significantly lower in patients with EGFR mutations (p=0.01 and p<0.001, respectively). Multivariable logistic regression analysis showed a significant association between race and EGFR mutation (p=0.01), even after adjusting for smoking status (p<0.001) and gender (p=0.03). KRAS mutation (study frequency 28.1%) was not associated with race (p=0.08; p=0.51 for Afa vs C patients), but was more common among smokers (p<0.001) and females (p=0.01).
Conclusions
Based on multivariable analysis, even after adjusting for smoking status and gender, we found that race was statistically significantly associated with EGFR mutation, but not KRAS mutational status. To our knowledge, this is the largest single institution series to date evaluating racial differences in EGFR and KRAS mutational status among patients with NSCLC.
doi:10.1016/j.lungcan.2013.05.011
PMCID: PMC3749295  PMID: 23806795
EGFR; KRAS; Racial Disparity; NSCLC
20.  History of lung disease and risk of lung cancer in a population with high household fuel combustion exposures in rural China 
Lung cancer (Amsterdam, Netherlands)  2013;81(3):10.1016/j.lungcan.2013.06.019.
History of chronic lung diseases and household coal use for heating and cooking are established risk factors of lung cancer; however, few studies have been able to explore these risk factors simultaneously. Xuanwei, China, has some of the highest rates of lung cancer in China and most residents experience substantial in-home coal smoke exposures. Using a population-based case-control study of 498 lung cancer cases and 498 age-matched controls, we evaluated the risk of lung cancer in relation to coal smoke exposure and history of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), chronic bronchitis, and emphysema. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression adjusting for potential confounders. We observed an increased risk of lung cancer with history of any chronic lung disease among males (OR=14.2; 95%CI =4.3 to 46.9), females (OR=2.6; 95%CI =1.1 to 6.3), smokers (OR=12.7; 95%CI =3.5 to 45.8), and nonsmokers (OR=2.6; 95%CI =1.1 to 6.4). Specifically, TB (OR=83.7; 95%CI =11.0 to 634.7), COPD (OR=3.2; 95%CI =1.7 to 6.0), and emphysema and chronic bronchitis (OR=3.3; 95%CI =1.7 to 6.4) were associated with increased risks. These findings suggest that history of chronic lung diseases may also increase risk of lung cancer in populations with indoor coal smoke exposures.
doi:10.1016/j.lungcan.2013.06.019
PMCID: PMC3845667  PMID: 23891511
Chronic lung disease; lung cancer; never smoking; Xuanwei; China
21.  Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence 
Radiotherapy is routinely used for the treatment of lung cancer. However, the mechanisms underlying ionizing radiation (IR)-induced senescence and its role in lung cancer treatment are poorly understood. Here, we show that IR suppresses the proliferation of human non-small cell lung cancer (NSCLC) cells via an apoptosis-independent mechanism. Further investigations reveal that the anticancer effect of irradiation correlates well with IR-induced premature senescence, as evidenced by increased senescence-associated β-glactosidase (SA-β-gal) staining, decreased BrdU incorporation and elevated expression of p16INK4a (p16) in irradiated NSCLC cells. Mechanistic studies indicate that the induction of senescence is associated with activation of the p53-p21 pathway, and that inhibition of p53 transcriptional activity by PFT-α attenuates IR-induced tumor cell killing and senescence. Gain-of-function assays demonstrate that restoration of p53 expression sensitizes H1299 cells to irradiation, whereas knockdown of p53 expression by siRNA inhibits IR-induced senescence in H460 cells. Furthermore, treatment with Nutlin-3a, a small molecule inhibitor of MDM2, enhances IR-induced tumor cell killing and senescence by stabilizing the activation of the p53-p21 signaling pathway. Taken together, these findings demonstrate for the first time that pharmacological activation of p53 by Nutlin-3a can sensitize lung cancer cells to radiation therapy via promoting IR-induced premature senescence.
doi:10.1016/j.lungcan.2013.04.017
PMCID: PMC3739976  PMID: 23683497
Non-small cell lung cancer; Radiotherapy; Senescence; p53; Nutilin-3a; siRNA
22.  NUCLEAR EGFR PROTEIN EXPRESSION PREDICTS POOR SURVIVAL IN EARLY STAGE NON-SMALL CELL LUNG CANCER 
Introduction
Nuclear EGFR (nEGFR) has been identified in various human tumor tissues, including cancers of the breast, ovary, oropharynx, and esophagus, and has predicted poor patient outcomes. We sought to determine if protein expression of nEGFR is prognostic in early stage non-small cell lung cancer (NSCLC).
Methods
Resected stage I and II NSCLC specimens were evaluated for nEGFR protein expression using immunohistochemistry (IHC). Cases with at least one replicate core containing ≥5% of tumor cells demonstrating strong dot-like nucleolar EGFR expression were scored as nEGFR positive.
Results
Twenty-three (26.1% of the population) of 88 resected specimens stained positively for nEGFR. Nuclear EGFR protein expression was associated with higher disease stage (45.5% of stage II vs. 14.5% of stage I; p=0.023), histology (41.7% in squamous cell carcinoma vs. 17.1% in adenocarcinoma; p=0.028), shorter progression-free survival (PFS) (median PFS 8.7 months [95% CI 5.1–10.7 mo] for nEGFR positive vs. 14.5 months [95% CI 9.5–17.4 mo] for nEGFR negative; hazard ratio (HR) of 1.89 [95% CI 1.15–3.10]; p=0.011), and shorter overall survival (OS) (median OS 14.1 months [95% CI 10.3–22.7 mo] for nEGFR positive vs. 23.4 months [95% CI 20.1–29.4 mo] for nEGFR negative; HR of 1.83 [95% CI 1.12–2.99]; p=0.014).
Conclusions
Expression of nEGFR protein was associated with higher stage and squamous cell histology, and predicted shorter PFS and OS, in this patient cohort. Nuclear EGFR serves as a useful independent prognostic variable and as a potential therapeutic target in NSCLC.
doi:10.1016/j.lungcan.2013.03.020
PMCID: PMC3679338  PMID: 23628526
non-small cell lung cancer; nuclear; epidermal growth factor receptor; prognosis; biomarker; survival analysis
23.  CHK1 levels correlate with sensitization to pemetrexed by CHK1 inhibitors in non-small cell lung cancer cells 
Objective
Overexpression of checkpoint kinase 1 (CHK1) is associated with poorer patient outcome and therapeutic resistance in multiple tumor models. Inhibition of CHK1 has been proposed as a strategy to increase the effectiveness of chemotherapeutic agents, especially in p53-deficient tumors. In this study, we evaluated the effects of a novel CHK1 inhibitor, MK-8776, in combination with pemetrexed (PMX) on cell proliferation and survival in a panel of p53 mutant non-small cell lung cancer (NSCLC) cell lines.
Methods
We examined CHK1 expression in 442 resected lung adenocarcinoma specimens using Affymetrix U133A gene expression arrays. We correlated CHK1 mRNA expression with patient survival, tumor differentiation and genomic complexity. We evaluated CHK1 levels in NSCLC cell lines and identified four p53 mutant cell lines with variable CHK1 expression (H1993, H23, H1437 and H1299) based on publicly available gene expression data. We confirmed differential CHK1 mRNA and CHK1 protein levels by qRT-PCR, ELISA, Western Blot analysis (WB) and immunohistochemistry. We examined cell line sensitization to PMX in response to CHK1 inhibition with MK-8776 using WST-1 and clonogenic survival assays.
Results
We found that elevated CHK1 expression in primary lung adenocarcinomas correlates with poor tumor differentiation and significantly worse patient survival. Tumors with elevated CHK1 mRNA levels have a higher number of gene mutations and DNA copy number gain or amplifications. CHK1 inhibition by MK-8776 enhances sensitivity of NSCLC cell lines to PMX. CHK1 mRNA and protein expression are variable among NSCLC cell lines, and cells expressing higher levels of CHK1 protein are more sensitive to the CHK1 inhibition by MK-8776 as compared to low CHK1 expressing cells.
Conclusions
These findings suggest that CHK1 levels may not only serve as a biomarker of poor prognosis in surgically-resected lung adenocarcinomas, but could also be a predictive marker for CHK1 inhibitor sensitivity, pending in vivo and clinical confirmation.
doi:10.1016/j.lungcan.2013.09.010
PMCID: PMC4073640  PMID: 24113549
CHK1; Lung; Chemosensitivity; NSCLC; Patient survival; Genomic complexity
24.  Impact of renal function on treatment options and outcomes in advanced non-small cell lung cancer 
Introduction
Certain chemotherapeutic agents commonly used for advanced non-small cell lung cancer (NSCLC) require minimum threshold renal function for administration. To determine how such requirements affect treatment options, we evaluated renal function patterns in this population.
Methods
We performed a single-center retrospective analysis of patients treated for stage IV NSCLC from 2000 to 2007. Associations between patient characteristics, calculated creatinine clearance (CrCl), and clinical outcomes were determined using univariate and multivariate analyses, Cox proportional hazard models, and mixed model analysis.
Results
298 patients (3,930 Cr measurements) were included in the analysis. Patients had a median of 5 (interquartile range [IQR] 4-18) Cr measurements. Median baseline CrCl was 96 mL/min (IQR 74-123 mL/min); median nadir CrCl was 78 mL/min (IQR 56-100 mL/min). Renal function was associated with age (P<0.001), race (P=0.009), and gender (P=0.001). 23% of patients had a recorded CrCl < 60 mL/min (threshold for cisplatin), with median onset 83 days after diagnosis and median time to recover to ≥ 60 mL/min of 27 (IQR 3-85) days; 11% of patients had a recorded CrCl < 45 mL/min (threshold for pemetrexed), with median onset 122 days after diagnosis and median recovery time of 36 (IQR 3-73) days. For both thresholds, approximately 35% of patients had no documented recovery.
Conclusions
In this cohort of patients treated for stage IV NSCLC, renal function falls below commonly used thresholds for cisplatin and for pemetrexed in fewer than a quarter of patients. However, these declines may preclude administration of these drugs for prolonged periods.
doi:10.1016/j.lungcan.2013.02.011
PMCID: PMC3646907  PMID: 23499397
Non-small cell lung cancer; chemotherapy; cisplatin; pemetrexed; renal function; creatinine clearance
25.  The addition of amifostine to carboplatin and paclitaxel based chemoradiation in locally advanced non-small cell lung cancer: long-term follow-up of Radiation Therapy Oncology Group (RTOG) randomized trial 9801 
INTRODUCTION
We report the long-term results of RTOG 9801, a randomized trial investigating the ability of amifostine, a radioprotector, to reduce chemoradiation-induced esophagitis.
METHODS
Patients with stage II and IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m2 intravenously (IV) and carboplatin area under the curve (AUC) 6 both days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m2) and carboplatin (AUC 2), with hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy BID). Patients were randomly assigned to amifostine (AM) 500 mg IV four times per week or no-AM during chemoradiotherapy. Stratification factors included age (< 70 v ≥ 70 years), stage and performance status.
RESULTS
243 patients (pts) were enrolled; 120 received AM, 123 received no-AM. Two pts on each arm were found ineligible. Overall, 85% of patients were ≤70 years; 75% had a KPS ≥90. 34% had squamous histology. With median follow-up of 96.3 months (for patients still alive), overall survival was identical (Hazard ratio 1.03 (0.79–1.34), NS): five-year survival 17% in both arms. The incidence of late grade 3–5 toxicities was 16% in the AM arm and 19% in the control arm (Hazard ratio 1.24 (0.66–2.32), NS). There was no significant difference between the arms regarding overall survival, disease-free survival or long-term toxicity.
CONCLUSION
The chemoradiation regimen of carboplatin and paclitaxel produced long-term results in the multi-institutional setting comparable to other regimens. Amifostine did not appear to compromise survival. Better data is required regarding the comparative long-term toxicity of different chemoradiation regimens. NCT00003313.
doi:10.1016/j.lungcan.2013.02.008
PMCID: PMC3646966  PMID: 23477890
NSCLC; non-small cell lung cancer; chemoradiation; carboplatin; paclitaxel; amifostine

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