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A unique set of 6 circulating microRNAs for early detection of non-small cell lung cancer.

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A unique set of 6 circulating microRNAs for early detection of non-small cell lung cancer.

Oncotarget. 2016 Jun 14;7(24):37250-37259

Authors: Halvorsen AR, Bjaanæs M, LeBlanc M, Holm AM, Bolstad N, Rubio L, Peñalver JC, Cervera J, Mojarrieta JC, López-Guerrero JA, Brustugun OT, Helland Å

Abstract
INTRODUCTION: Circulating microRNAs are promising biomarkers for diagnosis, predication and prognostication of diseases. Lung cancer is the cancer disease accountable for most cancer deaths, largely due to being diagnosed at late stages. Therefore, diagnosing lung cancer patients at an early stage is crucial for improving the outcome. The purpose of this study was to identify circulating microRNAs for detection of early stage lung cancer, capable of discriminating lung cancer patients from those with chronic obstructive pulmonary disease (COPD) and healthy volunteers.
RESULTS: We identified 7 microRNAs separating lung cancer patients from controls. By using RT-qPCR, we validated 6 microRNAs (miR-429, miR-205, miR-200b, miR-203, miR-125b and miR-34b) with a significantly higher abundance in serum from NSCLC patients. Furthermore, the 6 miRNAs were validated in a different dataset, revealing an area under the receiver operating characteristic curve of 0.89 for stage I-IV and 0.88 for stage I/II.
MATERIALS AND METHODS: We profiled the expression of 754 unique microRNAs by TaqMan Low Density Arrays, and analyzed serum from 38 patients with NSCLC, 16 patients suffering from COPD and 16 healthy volunteers from Norway, to explore their potential as diagnostic biomarkers. For validation, we analyzed serum collected from high-risk individuals enrolled in the Valencia branch of the International Early Lung Cancer Action Program screening trial (n=107) in addition to 51 lung cancer patients.
CONCLUSIONS: Considering the accessibility and stability of circulating miRNAs, these 6 microRNAs are promising biomarkers as a supplement in future screening studies.

PMID: 27191990 [PubMed - indexed for MEDLINE]

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.

lør, 01/06/2018 - 10:30
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Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.

Ann Oncol. 2016 Jul;27(7):1291-8

Authors: Chatterjee M, Turner DC, Felip E, Lena H, Cappuzzo F, Horn L, Garon EB, Hui R, Arkenau HT, Gubens MA, Hellmann MD, Dong D, Li C, Mayawala K, Freshwater T, Ahamadi M, Stone J, Lubiniecki GM, Zhang J, Im E, De Alwis DP, Kondic AG, Fløtten Ø

Abstract
BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients.
PATIENTS AND METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology.
RESULTS: Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses.
CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.
CLINICALTRIALSGOV REGISTRY: NCT01295827.

PMID: 27117531 [PubMed - indexed for MEDLINE]

Trajectory of sleep disturbances in patients undergoing lung cancer surgery: a prospective study.

tor, 12/28/2017 - 10:30
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Trajectory of sleep disturbances in patients undergoing lung cancer surgery: a prospective study.

Interact Cardiovasc Thorac Surg. 2017 Aug 01;25(2):285-291

Authors: Halle IH, Westgaard TK, Wahba A, Oksholm T, Rustøen T, Gjeilo KH

Abstract
OBJECTIVES: Patients with lung cancer report sleep difficulties to be frequent and bothersome symptoms. This study describes the trajectory of sleep from before and up to 12 months after surgery for lung cancer. Further, it investigates possible associations between sleep disturbance, demographic and clinical characteristics before surgery.
METHODS: This study is part of a longitudinal multicentre study. Sleep disturbance was measured by The General Sleep Disturbance Scale (GSDS) that investigates frequencies of sleep difficulties (21 items) and a total sum score ≥43 indicates a clinically meaningful level of sleep disturbance (score range 0-147). Linear mixed models were used to study changes in sleep from baseline to 1, 5, 9 and 12 months after surgery.
RESULTS: The percentage of patients (n = 264) reporting sleep disturbances was 60.9% at baseline, 68.5% at Month 1, 55.4% at Month 5, 51.3% at Month 9 and 49.7% at Month 12. The increase to and decrease from Month 1 was the only significant alteration in the occurrence of sleep disturbance. The patients reported most problems within the subscales sleep quantity, early awakenings and sleep quality. Factors associated with sleep disturbance were lower age, use of pain medication and psychotropic medication and higher comorbidity score.
CONCLUSIONS: Lung cancer patients sleep poorly, before as well as after surgery. There is a need to address sleeping disturbance routinely in clinical practice and screening for sleeping problems is indicated. Further studies are warranted concerning factors that contribute to sleep disturbance and how they best can be treated.

PMID: 28486702 [PubMed - indexed for MEDLINE]

Corrigendum to "Prognostic relevance of estrogen receptor α, β and aromatase expression in non-small cell lung cancer" [Steroids 113 (2016) 5-13].

ons, 12/27/2017 - 10:30
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Corrigendum to "Prognostic relevance of estrogen receptor α, β and aromatase expression in non-small cell lung cancer" [Steroids 113 (2016) 5-13].

Steroids. 2017 Dec 19;:

Authors: Skjefstad K, Grindstad T, Rakaee Khanehkenari M, Richardsen E, Donnem T, Kilvaer T, Andersen S, Bremnes RM, Busund LT, Al-Saad S

PMID: 29273210 [PubMed - as supplied by publisher]

Tumour size reduction after the first chemotherapy-course and outcomes of chemoradiotherapy in limited disease small-cell lung cancer.

søn, 12/24/2017 - 10:30
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Tumour size reduction after the first chemotherapy-course and outcomes of chemoradiotherapy in limited disease small-cell lung cancer.

Lung Cancer. 2016 Dec;102:9-14

Authors: Halvorsen TO, Herje M, Levin N, Bremnes RM, Brustugun OT, Fløtten Ø, Kaasa S, Sundstrøm S, Grønberg BH

Abstract
OBJECTIVES: Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended for limited disease small-cell lung cancer (LD SCLC). TRT should start as early as possible, often meaning with the second course due to patient referral time and the fact that TRT planning takes time. Early assessment of response to the first course of chemotherapy may be a useful way to individualise treatment. The aims of this study were to assess tumour size reduction after the first chemotherapy-course, and whether this reduction was associated with outcomes in LD SCLC.
MATERIAL AND METHODS: A randomised trial comparing twice-daily (45Gy/30 fractions) with once-daily (42Gy/15 fractions) TRT, given concurrently with four courses of cisplatin/etoposide (n=157) was the basis for this study. Tumour size was assessed on CT scans at baseline and planning scans for TRT according to RECIST 1.0.
RESULTS: CT scans were available for 135 patients (86%). Ninety-four percent had a reduction in tumour size after the first chemotherapy-course. The median reduction in sum of diameters (SOD) of measurable lesions was ÷16mm (÷84 to +10mm), corresponding to ÷18% (÷51 to +12%). Eighty-two percent had stable disease, 18% partial response. Reduction in SOD was significantly associated with complete response at first follow-up (OR: 1.05, 95% CI 1.01-1.09; p=0.013), PFS (HR: 0.97, 95% CI 0.96-0.99; p=0.001), and overall survival (HR: 0.98, 95% CI 0.96-1.00; p=0.010).
CONCLUSION: Response from the first course of chemotherapy had a significant positive association with outcomes from chemoradiotherapy, and might be used to stratify and randomise patients in future studies.

PMID: 27987595 [PubMed - indexed for MEDLINE]

The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC.

tir, 12/19/2017 - 10:30
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The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC.

J Thorac Oncol. 2017 Feb;12(2):194-207

Authors: Manegold C, Dingemans AC, Gray JE, Nakagawa K, Nicolson M, Peters S, Reck M, Wu YL, Brustugun OT, Crinò L, Felip E, Fennell D, Garrido P, Huber RM, Marabelle A, Moniuszko M, Mornex F, Novello S, Papotti M, Pérol M, Smit EF, Syrigos K, van Meerbeeck JP, van Zandwijk N, Chih-Hsin Yang J, Zhou C, Vokes E

Abstract
Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types.

PMID: 27729297 [PubMed - indexed for MEDLINE]

The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.

tir, 12/19/2017 - 10:30
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The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.

J Thorac Oncol. 2016 May;11(5):681-92

Authors: Detterbeck FC, Bolejack V, Arenberg DA, Crowley J, Donington JS, Franklin WA, Girard N, Marom EM, Mazzone PJ, Nicholson AG, Rusch VW, Tanoue LT, Travis WD, Asamura H, Rami-Porta R, IASLC Staging and Prognostic Factors Committee, Advisory Boards, Multiple Pulmonary Sites Workgroup, Participating Institutions

Abstract
INTRODUCTION: Separate tumor nodules with the same histologic appearance occur in the lungs in a small proportion of patients with primary lung cancer. This article addresses how such tumors can be classified to inform the eighth edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors, and pneumonic-type lung cancer, which are addressed in separate analyses.
METHODS: Survival of patients with separate tumor nodules in the International Association for the Study of Lung Cancer database were analyzed. This was compared with a systematic literature review.
RESULTS: Survival of clinically staged patients decreased according to the location of the separate tumor nodule relative to the index tumor (same lobe > same side > other side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However, there was also a decrease in the proportion of patients resected; among only surgically resected or among nonresected patients no survival differences were noted. There were no survival differences between patients with same-lobe nodules and those with other T3 tumors, between patients with same-side nodules and those with T4 tumors, and patients with other-side nodules and those with other M1a tumors. The data correlated with those identified in a literature review.
CONCLUSIONS: Tumors with same-lobe separate tumor nodules (with the same histologic appearance) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the seventh and eighth edition of the TNM classification of lung cancer.

PMID: 26940530 [PubMed - indexed for MEDLINE]

The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification.

tir, 12/19/2017 - 10:30
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The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification.

J Thorac Oncol. 2016 May;11(5):639-50

Authors: Detterbeck FC, Nicholson AG, Franklin WA, Marom EM, Travis WD, Girard N, Arenberg DA, Bolejack V, Donington JS, Mazzone PJ, Tanoue LT, Rusch VW, Crowley J, Asamura H, Rami-Porta R, IASLC Staging and Prognostic Factors Committee, Advisory Boards, Multiple Pulmonary Sites Workgroup, Participating Institutions

Abstract
INTRODUCTION: Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue.
METHODS: A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review.
RESULTS: Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor-T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location-with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement.
CONCLUSION: We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.

PMID: 26940528 [PubMed - indexed for MEDLINE]

The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer.

ons, 11/29/2017 - 10:30
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The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer.

J Thorac Oncol. 2016 Jun;11(6):789-800

Authors: Bremnes RM, Busund LT, Kilvær TL, Andersen S, Richardsen E, Paulsen EE, Hald S, Khanehkenari MR, Cooper WA, Kao SC, Dønnem T

Abstract
A malignant tumor is not merely an accumulation of neoplastic cells, but constitutes a microenvironment containing endothelial cells, fibroblasts, structural components, and infiltrating immune cells that impact tumor development, invasion, metastasis, and outcome. Hence, the evolution of cancers reflects intricate cellular and molecular interactions between tumor cells and constituents of the tumor microenvironment. Recent studies have shed new light on this complex interaction between tumor and host immune cells and the resulting immune response. The composition of the immune microenvironment differs across patients as well as in cancers of the same type, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, and macrophages. The type, density, location, and organization of immune cells within solid tumors define the immune contexture, which has proved to be a major determinant of tumor characteristics and patient outcome. Lung cancer consists mostly of non-small cell lung cancer (85%); it is our most deadly malignant disease, with the 5-year survival rate being merely 15%. This review focuses on the immune contexture; the tumor-suppressing roles of tumor-infiltrating lymphocytes; and the relevance of this immune contexture for cancer diagnostics, prognostication, and treatment allocation, with an emphasis on non-small cell lung cancer.

PMID: 26845192 [PubMed - indexed for MEDLINE]

The IASLC Lung Cancer Staging Project: Methodology and Validation Used in the Development of Proposals for Revision of the Stage Classification of NSCLC in the Forthcoming (Eighth) Edition of the TNM Classification of Lung Cancer.

ons, 11/08/2017 - 10:30
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The IASLC Lung Cancer Staging Project: Methodology and Validation Used in the Development of Proposals for Revision of the Stage Classification of NSCLC in the Forthcoming (Eighth) Edition of the TNM Classification of Lung Cancer.

J Thorac Oncol. 2016 Sep;11(9):1433-46

Authors: Detterbeck FC, Chansky K, Groome P, Bolejack V, Crowley J, Shemanski L, Kennedy C, Krasnik M, Peake M, Rami-Porta R, IASLC Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions

Abstract
INTRODUCTION: Stage classification provides a consistent language to describe the anatomic extent of disease and is therefore a critical tool in caring for patients. The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer developed proposals for revision of the classification of lung cancer for the eighth edition of the tumor, node, and metastasis (TNM) classification, which takes effect in 2017.
METHODS: An international database of 94,708 patients with lung cancer diagnosed in 1999-2010 was assembled. This article describes the process and statistical methods used to refine the lung cancer stage classification.
RESULTS: Extensive analysis allowed definition of tumor, node, and metastasis categories and stage groupings that demonstrated consistent discrimination overall and within multiple different patient cohorts (e.g., clinical or pathologic stage, R0 or R-any resection status, geographic region). Additional analyses provided evidence of applicability over time, across a spectrum of geographic regions, histologic types, evaluative approaches, and follow-up intervals.
CONCLUSIONS: An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness; a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.

PMID: 27448762 [PubMed - indexed for MEDLINE]

CTLA-4 expression in the non-small cell lung cancer patient tumor microenvironment: diverging prognostic impact in primary tumors and lymph node metastases.

ons, 11/08/2017 - 10:30
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CTLA-4 expression in the non-small cell lung cancer patient tumor microenvironment: diverging prognostic impact in primary tumors and lymph node metastases.

Cancer Immunol Immunother. 2017 Nov;66(11):1449-1461

Authors: Paulsen EE, Kilvaer TK, Rakaee M, Richardsen E, Hald SM, Andersen S, Busund LT, Bremnes RM, Donnem T

Abstract
The immune checkpoint receptor CTLA-4 plays a crucial part in negatively regulating T cell activation and maintaining self-tolerance. It is frequently overexpressed in a variety of malignancies, yet its prognostic impact in non-small cell lung cancer (NSCLC) remains unclear. We constructed tissue microarrays from tumor tissue samples and evaluated the immunohistochemical expression of CTLA-4 in 536 patients with primary resected stage I-IIIA NSCLC. Expression of CTLA-4 was analyzed in tumor and stromal primary tumor tissue and in locoregional metastatic lymph nodes. CTLA-4 expression in neither tumor epithelial cells (T-CTLA-4) nor stromal cells (S-CTLA-4) of primary tumors was significantly associated with disease-specific survival (DSS) in all patients. However, high S-CTLA-4 expression independently predicted significantly improved DSS in the squamous cell carcinoma subgroup (HR 0.62, 95% CI 0.41-0.93, P = 0.021). In contrast, there was an independent negative prognostic impact of T-CTLA-4 expression in metastatic lymph nodes (HR 1.65, 95% CI 1.03-2.65, P = 0.039). Our results indicate that the expression of CTLA-4 has diverging prognostic impacts in metastatic NSCLC lymph nodes versus primary tumors. The presented results highlight important differences in the tumor microenvironments of primary and metastatic NSCLC tissues, and have potential to guide treatment and clinical sampling strategies.

PMID: 28707078 [PubMed - indexed for MEDLINE]

PIK3CA mutations as prognostic factor in squamous cell lung carcinoma.

tir, 11/07/2017 - 10:30
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PIK3CA mutations as prognostic factor in squamous cell lung carcinoma.

Lung Cancer. 2017 Jan;103:52-57

Authors: McGowan M, Hoven AS, Lund-Iversen M, Solberg S, Helland Å, Hirsch FR, Brustugun OT

Abstract
OBJECTIVES: Mutation in the PIK3CA gene is reported frequent in squamous cell carcinomas of the lung, but its potential prognostic role is still obscure. We have studied the prognostic importance of PIK3CA mutations as well as the relation to other markers in a large number of early stage lung cancers of squamous carcinoma subtype.
PATIENTS AND METHODS: Tumour tissue was obtained from 308 consecutively operated lung cancer patients with squamous cell carcinoma in the period 2003-2013. DNA was isolated according to standard procedures, and mutation analysis was done with either the SnapShot method and/or using PIK3CA specific primers in the Cobas system. PD-L1-expression was analysed with immunohistochemistry After thorough follow-up (median 67.6 months), overall survival and time to relapse was calculated.
RESULTS: Tumour tissue from 102 females and 206 males were analysed. 167 (54.2%) were in stage I, 96 (31.2%) in stage II and 45 (14.6%) in stage III. PIK3CA mutation was found in 35 (11.4%) patients, most frequently in exon 20. There were no differences in sex, stage or smoking behaviour between mutated and non-mutated cases. Patients with PIK3CA mutations had a significantly longer overall survival (p=0.042) and time to relapse (p=0.030) than non-mutated cases, and the difference in time to relapse was also retained in stage I-cases (p=0.044). PD-L1-expression was less frequent among mutated cases.
CONCLUSION: Our results indicate that PIK3CA mutations may confer a survival advantage in early stage squamous cell lung cancers, but further work is needed to confirm this finding.

PMID: 28024696 [PubMed - indexed for MEDLINE]

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

ons, 11/01/2017 - 09:30

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

Carcinogenesis. 2017 Oct 20;:

Authors: Li Y, Xiao X, Han Y, Gorlova O, Qian D, Leighl N, Johansen JS, Barnett M, Chen C, Goodman G, Cox A, Taylor F, Woll P, Wichmann HE, Manz J, Muley T, Risch A, Rosenberger A, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Houlston R, Artigas MS, Grankvist K, Johansson M, Shepherd FA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Liu G, Bojesen SE, Wu X, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Bertazzi PA, Pesatori AC, Christiani DC, Caporaso N, Johansson M, McKay JD, Brennan P, Hung RJ, Amos CI

Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between SNPs and smoking status (never vs ever smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13,336 NSCLC cases. Candidate SNPs with p-value less than 0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with p-value less than 3.5x10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 NSCLC cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis p-value for these two SNPs were 1.24 with 6.96x10-7 and 1.37 with 3.49x10-7, respectively. Additionally, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and p-value of 8.12x10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

PMID: 29059373 [PubMed - as supplied by publisher]

Randomized phase III PITCAP trial and meta-analysis of induction chemotherapy followed by thoracic irradiation with or without concurrent taxane-based chemotherapy in locally advanced NSCLC.

tir, 10/24/2017 - 09:30
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Randomized phase III PITCAP trial and meta-analysis of induction chemotherapy followed by thoracic irradiation with or without concurrent taxane-based chemotherapy in locally advanced NSCLC.

Lung Cancer. 2016 Oct;100:30-37

Authors: Ardizzoni A, Tiseo M, Boni L, Di Maio M, Buffoni L, Belvedere O, Grossi F, D'Alessandro V, de Marinis F, Barbera S, Caroti C, Favaretto A, Cortinovis D, Morrica B, Tixi L, Ceschia T, Parisi S, Ricardi U, Grimaldi A, Loreggian L, Navarria P, Huber RM, Belani C, Brunsvig PF, Scagliotti GV, Scolaro T

Abstract
BACKGROUND: Chemo-radiotherapy is standard of care in the treatment of unresectable stage III NSCLC. We aimed at assessing whether the addition of concurrent taxane-chemotherapy to thoracic irradiation following chemotherapy was able to improve treatment outcome.
MATERIAL AND METHODS: In PITCAP trial, patients with unresectable stage III NSCLC were randomized to receive 2 cycles of platinum-paclitaxel followed by 60-61.2Gy thoracic irradiation (control arm) or by same radiotherapy with concomitant weekly paclitaxel (experimental arm). A literature-based meta-analysis including all studies with same design was also performed.
RESULTS: At the time of the second interim analysis, when 151 patients were randomized, accrual was terminated. With a median follow-up of 6.1 years, median survival was 13.2 vs 15.1 months, with a 3-year survival rate of 19.5 vs 21.2% in the control and experimental arm, respectively (HR: 0.97; 95% CI 0.69-1.36; p=0.845). Treatment toxicity was manageable in both arms. The meta-analysis of 5 trials (n=866) confirmed the lack of a meaningful effect on 1-year overall survival of a taxane added concurrently to radiotherapy.
CONCLUSIONS: These results do not support a meaningful survival benefit with the addition of single agent taxane given concurrently to radiotherapy after platinum-based induction in locally advanced NSCLC.

PMID: 27597278 [PubMed - indexed for MEDLINE]

Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.

tor, 10/19/2017 - 09:30
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Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial.

Lancet Oncol. 2017 Oct;18(10):1307-1316

Authors: Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, Giannone V, D'Amelio AM, Zhang P, Mookerjee B, Johnson BE

Abstract
BACKGROUND: BRAF(V600E) mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib, alone or combined with trametinib, has shown substantial antitumour activity in patients with previously treated BRAF(V600E)-mutant metastatic non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of dabrafenib plus trametinib treatment in previously untreated patients with BRAF(V600E)-mutant metastatic NSCLC.
METHODS: In this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (≥18 years of age) with previously untreated metastatic BRAF(V600E)-mutant NSCLC were enrolled into cohort C from 19 centres in eight countries within North America, Europe, and Asia. Patients received oral dabrafenib 150 mg twice per day plus oral trametinib 2 mg once per day until disease progression, unacceptable adverse events, consent withdrawal, or death. The primary endpoint was investigator-assessed overall response, defined as the percentage of patients who achieved a confirmed complete response or partial response per Response Evaluation Criteria In Solid Tumors version 1.1. The primary and safety analyses were by intention to treat in the protocol-defined population (previously untreated patients). The study is ongoing, but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634.
FINDINGS: Between April 16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated with first-line dabrafenib plus trametinib. Median follow-up was 15·9 months (IQR 7·8-22·0) at the data cutoff (April 28, 2017). The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79), with two (6%) patients achieving a complete response and 21 (58%) a partial response. All patients had one or more adverse event of any grade, and 25 (69%) had one or more grade 3 or 4 event. The most common (occurring in more than two patients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanine aminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting (three [8%]). Serious adverse events occurring in more than two patients included alanine aminotransferase increase (five [14%]), pyrexia (four [11%]), aspartate aminotransferase increase (three [8%]), and ejection fraction decrease (three [8%]). One fatal serious adverse event deemed unrelated to study treatment was reported (cardiorespiratory arrest).
INTERPRETATION: Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAF(V600E)-mutant NSCLC.
FUNDING: Novartis.

PMID: 28919011 [PubMed - indexed for MEDLINE]

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

fre, 10/13/2017 - 09:30
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Nat Genet. 2017 Jul;49(7):1126-1132

Authors: McKay JD, Hung RJ, Han Y, Zong X, Carreras-Torres R, Christiani DC, Caporaso NE, Johansson M, Xiao X, Li Y, Byun J, Dunning A, Pooley KA, Qian DC, Ji X, Liu G, Timofeeva MN, Bojesen SE, Wu X, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Shen H, Hong YC, Yuan JM, Bertazzi PA, Pesatori AC, Ye Y, Diao N, Su L, Zhang R, Brhane Y, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman CA, Wilkens LR, Fernandez-Somoano A, Fernandez-Tardon G, van der Heijden HFM, Kim JH, Dai J, Hu Z, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Doherty JA, Barnett MP, Chen C, Goodman GE, Cox A, Taylor F, Woll P, Brüske I, Wichmann HE, Manz J, Muley TR, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd FA, Tsao MS, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Koh WP, Gao YT, Houlston RS, McLaughlin J, Stevens VL, Joubert P, Lamontagne M, Nickle DC, Obeidat M, Timens W, Zhu B, Song L, Kachuri L, Artigas MS, Tobin MD, Wain LV, SpiroMeta Consortium, Rafnar T, Thorgeirsson TE, Reginsson GW, Stefansson K, Hancock DB, Bierut LJ, Spitz MR, Gaddis NC, Lutz SM, Gu F, Johnson EO, Kamal A, Pikielny C, Zhu D, Lindströem S, Jiang X, Tyndale RF, Chenevix-Trench G, Beesley J, Bossé Y, Chanock S, Brennan P, Landi MT, Amos CI

Abstract
Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

PMID: 28604730 [PubMed - indexed for MEDLINE]

Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer.

tor, 10/05/2017 - 09:30
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Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer.

Mol Carcinog. 2017 Sep;56(9):2076-2085

Authors: Samulin Erdem J, Arnoldussen YJ, Skaug V, Haugen A, Zienolddiny S

Abstract
Metastasis and cell adhesion are key aspects of cancer progression. Neurofascin (NFASC) is a member of the immunoglobulin superfamily of adhesion molecules and, while studies on NFASC are inadequate, other members have been indicated pivotal roles in cancer progression and metastasis. This study aimed at increasing the knowledge on the involvement of adhesion molecules in lung cancer progression by studying the regulation and role of NFASC in non-small cell lung cancer (NSCLC). Here, copy number variations in the NFASC gene were analyzed in tumor and non-tumorous lung tissues of 204 NSCLC patients. Frequent gene amplifications (OR = 4.50, 95%CI: 2.27-8.92, P ≤ 0.001) and increased expression of NFASC (P = 0.034) were identified in tumors of NSCLC patients. Furthermore, molecular mechanisms of NFASC in lung cancer progression were evaluated by investigating the effects of NFASC silencing on cell proliferation, viability, migration, and invasion using siRNA technology in four NSCLC cell lines. Silencing of NFASC did not affect cell proliferation or viability but rather decreased NSCLC cell migration (P ≤ 0.001) and led to morphological changes, rearrangements in the actin cytoskeleton and changes in F-actin networks in migrating NSCLC cell lines. This study is the first to report frequent copy number gain and increased expression of NFASC in NSCLC. Moreover, these data suggest that NFASC is a novel regulator of NSCLC cell motility and support a role of NFASC in the regulation of NSCLC progression.

PMID: 28418179 [PubMed - indexed for MEDLINE]

The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer.

ons, 10/04/2017 - 09:30
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The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer.

PLoS One. 2017;12(7):e0181527

Authors: Al-Saad S, Richardsen E, Kilvaer TK, Donnem T, Andersen S, Khanehkenari M, Bremnes RM, Busund LT

Abstract
INTRODUCTION: To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated.
MATERIALS AND METHODS: Stage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers.
RESULTS: In univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018).
CONCLUSION: MET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.

PMID: 28742836 [PubMed - indexed for MEDLINE]

Management of progressive pulmonary nodules found during and outside of CT lung cancer screening studies.

tir, 10/03/2017 - 09:30

Management of progressive pulmonary nodules found during and outside of CT lung cancer screening studies.

J Thorac Oncol. 2017 Sep 26;:

Authors: Meyer M, Vliegenthart R, Henzler T, Buergy D, Giordano FA, Kostrzewa M, Rathmann N, Brustugun OT, Crino L, Dingemans AC, Dusmet M, Fennell D, Grunenwald D, Huber RM, Moniuszko M, Mornex F, Papotti M, Pilz L, Senan S, Syrigos K, Pérol M, Gray JE, Schabel C, van Meerbeeck J, van Zandwijk N, Zhou CC, Manegold C, Voigt W, Roessner ED

Abstract
Although the effectiveness of screening for lung cancer remains controversial, it is a fact that the majority of lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force (USPSTF) revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography (LDCT) in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, however with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them remains the open question on how enlarging pulmonary nodules (PNs) detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches, as well as the potential therapeutic options for enlarging PNs, followed by a meeting report including consensus statements of an interdisciplinary expert panel that discussed the potential of the different therapeutic options during the Dresden 2015 Post World Congress of Lung Cancer (WCLC) - International Association for the Study of Lung Cancer (IASLC) meeting.

PMID: 28962947 [PubMed - as supplied by publisher]

Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

søn, 10/01/2017 - 09:30
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Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

Eur J Cardiothorac Surg. 2017 Jul 25;:

Authors: Bugge AS, Lund MB, Valberg M, Brustugun OT, Solberg S, Kongerud J

Abstract
OBJECTIVES: Surgical resection is the recommended treatment for patients with early-stage non-small-cell lung cancer. However, it is believed that causes other than lung cancer can lead to death following surgical resection. Investigating the risk factors for overall mortality and analysing the specific causes of death may indicate the degree of influence of other causes of death.
METHODS: We assessed individual risk factors affecting overall and cause-specific mortality in a Cox proportional hazards model in a cohort of patients with resected Stage I/II non-small-cell lung cancer ( n  = 756) from 2007 to 2015 in a tertiary university centre. The follow-up period ranged from 3 days to 9.3 years. Median survival time was 7.3 years (95% confidence interval 6.0-7.9). A few patients died of cardiovascular disease ( n  = 19) and were included in the group 'other cause'. In a competing risk model, we evaluated the risk factors for specific causes of death in patients dying of lung cancer and dying of non-lung cancer specific conditions.
RESULTS: The overall survival was 94%, 62% and 50% at 1, 5 and 7 years, respectively. At the end of the follow-up period, the risk of having died of, respectively, lung cancer or other causes was 36% and 24%. The cumulative incidence of death of lung cancer increased continuously during the study. Risk factors predicting death of all causes and death of non-small-cell lung cancer were increasing age, severely reduced lung function, Eastern Cooperative Oncology Group Performance Status ≥2, preoperative examination without positron emission tomography/computed tomography, histological tumour diagnosis other than adenocarcinoma and squamous cell carcinoma and increasing disease stage. In patients dying of other causes, age, gender, body mass index, smoking and Eastern Cooperative Oncology Group Performance Status ≥2 affected the mortality rate.
CONCLUSIONS: The probability of having died of lung cancer continued to increase beyond 5 years after the operation. Surveillance of risk factors associated with an increased mortality rate should be considered in the postoperative follow-up examination after lung cancer resection.

PMID: 28950311 [PubMed - as supplied by publisher]