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Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study.

15 min 18 sek siden
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Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study.

Ann Oncol. 2018 Apr 14;:

Authors: Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, Dziadziuszko R, Griesinger F, Kotb A, Zeaiter A, Cardona A, Balas B, Johannsdottir HK, Das-Gupta A, Wolf J

Abstract
Background: This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib.
Patients and methods: ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2:1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary endpoint was investigator-assessed progression-free survival (PFS).
Results: Altogether, 107 patients were randomized (alectinib, n=72; chemotherapy, n=35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months (95% confidence interval [CI]: 6.9-12.2) with alectinib and 1.4 months (95% CI: 1.3-1.6) with chemotherapy (hazard ratio 0.15 [95% CI: 0.08-0.29]; P<0.001). Independent Review Committee-assessed PFS was also significantly longer with alectinib (HR 0.32 [95% CI: 0.17-0.59]; median PFS was 7.1 months [95% CI: 6.3-10.8] with alectinib and 1.6 months [95% CI: 1.3-4.1] with chemotherapy). In patients with measurable baseline central nervous system (CNS) disease (alectinib, n=24; chemotherapy, n=16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P<0.001). Grade ≥3 adverse events (AEs) were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 versus 6.0 weeks).
Conclusion: Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile.
Trial registration: ClinicalTrials.gov NCT02604342; Roche study MO29750.

PMID: 29668860 [PubMed - as supplied by publisher]

A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer.

tor, 04/19/2018 - 09:30

A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer.

Mol Oncol. 2018 Apr 15;:

Authors: Shen S, Zhang R, Guo Y, Loehrer E, Wei Y, Zhu Y, Yuan Q, Moran S, Fleischer T, Bjaanaes MM, Karlsson A, Planck M, Staaf J, Helland Å, Esteller M, Su L, Chen F, Christiani DC

Abstract
B-cell translocation gene 2 (BTG2) is a tumor suppressor protein and is known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early-stage non-small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1,230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3,038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumor tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51 to 2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression positively correlated with survival in each cohort (HR range, 0.28 to 0.68), which we confirmed with meta-analysis (HR = 0.61, 95%CI: 0.54-0.68). The three CpG probes all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early-stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.

PMID: 29656435 [PubMed - as supplied by publisher]

Expression of Estrogen Receptor-α and Survival in Advanced-stage Non-small Cell Lung Cancer.

man, 04/16/2018 - 11:30
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Expression of Estrogen Receptor-α and Survival in Advanced-stage Non-small Cell Lung Cancer.

Anticancer Res. 2018 04;38(4):2261-2269

Authors: Lund-Iversen M, Scott H, Strøm EH, Theiss N, Brustugun OT, Grønberg BH

Abstract
BACKGROUND/AIM: The favorable prognosis of women with non-small-cell lung cancer (NSCLC) compared to men might be explained by sex hormone-related mechanisms. We investigated whether this observation could be explained by the expression of estrogen receptor-alpha (ER-α) in tumor tissue.
MATERIALS AND METHODS: Archived, formalin fixed, paraffin embedded tumor tissue samples were retrospectively analyzed for nuclear expression of ER-α with immunohistochemistry.
RESULTS: Biopsies from 222 patients were analyzed. Twenty-three percent were ER-α positive. Fifty-four percent of the patients were men and 46% of the tumors were adenocarcinomas. One hundred-nine (49%) patients received pemetrexed and carboplatin and 113 (51%) received gemcitabine and carboplatin. Females with ER-α positive tumors who received PC had a substantial survival benefit over all other groups (20 vs. 4.6 months; p=0.003).
CONCLUSION: ER-α is an independent prognostic factor in advanced NSCLC and might also be a predictive factor for response to pemetrexed/carboplatin in women.

PMID: 29599348 [PubMed - indexed for MEDLINE]

Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC.

fre, 04/13/2018 - 08:30
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Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC.

Clin Epigenetics. 2018;10:41

Authors: Wei Y, Liang J, Zhang R, Guo Y, Shen S, Su L, Lin X, Moran S, Helland Å, Bjaanæs MM, Karlsson A, Planck M, Esteller M, Fleischer T, Staaf J, Zhao Y, Chen F, Christiani DC

Abstract
Background: KDM lysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations in KDM genes and their roles in lung cancer survival.
Methods: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites in KDM genes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation.
Results: DNA methylation at sites cg11637544 in KDM2A and cg26662347 in KDM1A were in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16-1.50, P = 1.1 × 10-4; HRcg26662347 = 1.88, 95%CI, 1.37-2.60, P = 3.7 × 10-3), and correlated with corresponding gene expression (cg11637544 for KDM2A, P = 1.3 × 10-10; cg26662347 for KDM1A P = 1.5 × 10-5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance.
Conclusions: These findings highlight the association between somatic DNA methylation in KDM genes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.

PMID: 29619118 [PubMed - in process]

Implementation of lung cancer CT screening in the Nordic countries.

fre, 04/06/2018 - 14:00
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Implementation of lung cancer CT screening in the Nordic countries.

Acta Oncol. 2017 Oct;56(10):1249-1257

Authors: Pedersen JH, Sørensen JB, Saghir Z, Fløtten Ø, Brustugun OT, Ashraf H, Strand TE, Friesland S, Koyi H, Ek L, Nyrén S, Bergman P, Jekunen A, Nieminen EM, Gudbjartsson T

Abstract
INTRODUCTION: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries.
MATERIALS AND METHODS: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening.
RESULTS AND DISCUSSION: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program.

PMID: 28571524 [PubMed - indexed for MEDLINE]

Assessment of pulmonary 18F-FDG-PET uptake and cytokine profiles in non-small cell lung cancer patients treated with radiotherapy and erlotinib.

lør, 03/31/2018 - 09:30
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Assessment of pulmonary 18F-FDG-PET uptake and cytokine profiles in non-small cell lung cancer patients treated with radiotherapy and erlotinib.

Clin Transl Radiat Oncol. 2017 Jun;4:57-63

Authors: Abravan A, Eide HA, Knudtsen IS, Løndalen AM, Helland Å, Malinen E

Abstract
Purpose: To investigate effects of radiotherapy (RT) and erlotinib on pulmonary glucose uptake using 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography (PET) during and after treatment of non-small cell lung cancer (NSCLC) and to identify associations between serum cytokine levels and lung glucose uptake.
Material and methods: Twenty-seven patients with advanced NSCLC, receiving RT alone or concomitant RT and erlotinib therapy, were examined by 18F-FDG PET before, during, and after treatment. A total of 57 18F-FDG PET scans were analyzed. Pulmonary 18F-FDG uptake and radiotherapy dose mapping were used to acquire dose-response curves for each patient, where subsequent linear regression gave a glucose uptake level in the un-irradiated parts of the lungs (SUV0) and a response slope (ΔSUV). Serum cytokine levels at corresponding time points were assessed using a multiplex bioassay. Correlations between the most robust cytokines and lung 18F-FDG dose response parameters were further investigated.
Results: From the dose response analysis, SUV0 at post-therapy was significantly higher (P < 0.001) than at mid- and pre-therapy (45% and 58%, respectively) for the group receiving RT + erlotinib. Also, SUV0 at post-therapy was higher for patients receiving RT + erlotinib compared to RT alone (42%; P < 0.001). No differences in ΔSUV were seen with treatments or time. SUV0 was positively associated (r = 0.47, P = 0.01) with serum levels of the chemokine C-C motif ligand 21 (CCL21) for patients receiving RT + erlotinib.
Conclusions: Concomitant RT and erlotinib causes an elevation in pulmonary 18F-FDG uptake post treatment compared to RT alone. Pulmonary glucose uptake is associated with an upregulation of a chemokine (CCL21) involved in inflammatory reactions.

PMID: 29594209 [PubMed]

Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer.

fre, 03/30/2018 - 09:30

Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer.

Sci Rep. 2018 Mar 22;8(1):5059

Authors: Kiselev Y, Andersen S, Johannessen C, Fjukstad B, Standahl Olsen K, Stenvold H, Al-Saad S, Donnem T, Richardsen E, Bremnes RM, Rasmussen Busund LT

Abstract
Lung cancer is the leading cause of cancer deaths. Novel predictive biomarkers are needed to improve treatment selection and more accurate prognostication. PAX6 is a transcription factor with a proposed tumour suppressor function. Immunohistochemical staining was performed on tissue microarrays from 335 non-small cell lung cancer (NSCLC) patients for PAX6. Multivariate analyses of clinico-pathological variables and disease-specific survival (DSS) was carried out, and phenotypic changes of two NSCLC cell lines with knockdown of PAX6 were characterized. While PAX6 expression was only associated with a trend of better disease-specific survival (DSS) (p = 0.10), the pN+ subgroup (N = 103) showed significant correlation between high PAX6 expression and longer DSS (p = 0.022). Median survival for pN + patients with high PAX6 expression was 127.4 months, versus 22.9 months for patients with low PAX6 expression. In NCI-H661 cells, knockdown of PAX6 strongly activated serum-stimulated migration. In NCI-H460 cells, PAX6 knockdown activated anchorage-independent growth. We did not observe any significant effect of PAX6 on proliferation in either of cell lines. Our findings strongly support the proposition of PAX6 as a valid and positive prognostic marker in NSCLC in node-positive patients. There is a need for further studies, which should provide mechanistical explanation for the role of PAX6 in NSCLC.

PMID: 29568088 [PubMed - in process]

The IASLC Lung Cancer Staging Project: External Validation of the Revision of the TNM Stage Groupings in the Eighth Edition of the TNM Classification of Lung Cancer.

lør, 03/24/2018 - 08:30
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The IASLC Lung Cancer Staging Project: External Validation of the Revision of the TNM Stage Groupings in the Eighth Edition of the TNM Classification of Lung Cancer.

J Thorac Oncol. 2017 Jul;12(7):1109-1121

Authors: Chansky K, Detterbeck FC, Nicholson AG, Rusch VW, Vallières E, Groome P, Kennedy C, Krasnik M, Peake M, Shemanski L, Bolejack V, Crowley JJ, Asamura H, Rami-Porta R, IASLC Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions

Abstract
INTRODUCTION: Revisions to the TNM stage classifications for lung cancer, informed by the international database (N = 94,708) of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee, need external validation. The objective was to externally validate the revisions by using the National Cancer Data Base (NCDB) of the American College of Surgeons.
METHODS: Cases presenting from 2000 through 2012 were drawn from the NCDB and reclassified according to the eighth edition stage classification. Clinically and pathologically staged subsets of NSCLC were analyzed separately. The T, N, and overall TNM classifications were evaluated according to clinical, pathologic, and "best" stage (N = 780,294). Multivariate analyses were carried out to adjust for various confounding factors. A combined analysis of the NSCLC cases from both databases was performed to explore differences in overall survival prognosis between the two databases.
RESULTS: The databases differed in terms of key factors related to data source. Survival was greater in the IASLC database for all stage categories. However, the eighth edition TNM stage classification system demonstrated consistent ability to discriminate TNM categories and stage groups for clinical and pathologic stage.
CONCLUSIONS: The IASLC revisions made for the eighth edition of lung cancer staging are validated by this analysis of the NCDB database by the ordering, statistical differences, and homogeneity within stage groups and by the consistency within analyses of specific cohorts.

PMID: 28461257 [PubMed - indexed for MEDLINE]

Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer.

ons, 03/21/2018 - 09:00
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Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer.

PLoS One. 2018;13(2):e0192157

Authors: Kilvaer TK, Rakaee M, Hellevik T, Østman A, Strell C, Bremnes RM, Busund LT, Dønnem T, Martinez-Zubiaurre I

Abstract
OBJECTIVES: Selective targeting of cancer-associated fibroblasts (CAFs) has been proposed to synergize with immune-checkpoint inhibitors. While the roles of CAFs in cancer development are well described, their immune-regulatory properties remain incompletely understood. This study investigates correlations between CAF and immune-markers in tumor stroma from non-small cell lung cancer (NSCLC) patients, and examines whether a combination of CAF and immune cell scores impact patient prognosis.
METHODS: Tumor specimens from 536 primary operable stage I-III NSCLC patients were organized in tissue microarrays. Expression of protein-markers was evaluated by immunohistochemistry.
RESULTS: Fibroblast and stromal markers PDGFRα, PDGFRβ, FAP-1 and vimentin showed weak correlations while αSMA, and Masson's trichrome did not correlate with any of the investigated markers. Hierarchical clustering indicated the existence of different CAF-subsets. No relevant correlations were found between any CAF-marker and the immune-markers CD3, CD4, CD8, CD20, CD68, CD1a, CD56, FoxP3 and CD45RO. High density of fibroblast-activation protein positive mesenchymal cells (CAFFAP) was associated with better prognosis in tumors with high infiltration of CD8 and CD3 T-lymphocytes.
CONCLUSIONS: The presented data suggest that CAFs, irrespective of identity, have low influence on the degree of tumor infiltration by inflammatory- and/or immune-cells. However, CAFFAP may exert immuno-adjuvant roles in NSCLC, and targeting CAFs should be cautiously considered.

PMID: 29415055 [PubMed - indexed for MEDLINE]

A new method to assess pulmonary changes using 18F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy.

tir, 03/20/2018 - 15:00
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A new method to assess pulmonary changes using 18F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy.

Acta Oncol. 2017 Nov;56(11):1597-1603

Authors: Abravan A, Knudtsen IS, Eide HA, Løndalen AM, Helland Å, van Luijk P, Malinen E

Abstract
BACKGROUND: 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) may be used for assessing radiation induced alterations in the lung. However, there is a need to further develop methodologies to improve quantification. Using computed tomography (CT), a local structure method has been shown to be superior to conventional CT-based analysis. Here, we investigate whether the local structure method based on 18F-FDG-PET improves radiotherapy (RT) dose-response quantification for lung cancer patients.
MATERIAL AND METHODS: Sixteen patients with lung cancer undergoing fractionated RT were examined by 18F-FDG-PET/CT at three sessions (pre, mid, post) and the lung was delineated in the planning CT images. The RT dose matrix was co-registered with the PET images. For each PET image series, mean (μ) and standard deviation (σ) maps were calculated based on cubes in the lung (3 × 3 × 3 voxels), where the spread in pre-therapy μ and σ was characterized by a covariance ellipse in a sub-volume of 3 × 3 × 3 cubes. Mahalanobis distance was used to measure the distance of individual cube values to the origin of the ellipse and to further form local structure 'S' maps. The structural difference maps (ΔS) and mean difference maps (Δμ) were calculated by subtracting pre-therapy maps from maps at mid- and post-therapy. Corresponding maps based on CT images were also generated.
RESULTS: ΔS identified new areas of interest in the lung compared to conventional Δμ maps. ΔS for PET and CT gave a significantly elevated lung signal compared to a control group during and post-RT (p < .05). Dose-response analyses by linear regression showed that ΔS between pre- and post-therapy for 18F-FDG-PET was the only parameter significantly associated with local lung dose (p = .04).
CONCLUSIONS: The new method using local structures on 18F-FDG-PET provides a clearer uptake dose-response compared to conventional analysis and CT-based approaches and may be valuable in future studies addressing lung toxicity.

PMID: 28849707 [PubMed - indexed for MEDLINE]

Prognostic effect of intratumoral neutrophils across histological subtypes of non-small cell lung cancer.

lør, 03/03/2018 - 10:30
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Prognostic effect of intratumoral neutrophils across histological subtypes of non-small cell lung cancer.

Oncotarget. 2016 11 01;7(44):72184-72196

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

Abstract
Recent data indicate that tumor-associated neutrophils (TANs) serve a dual role in tumor progression and regression. CD66b is a neutrophil marker and has been associated with patient outcome in various cancers. However, its clinical impact in non-small cell lung cancer (NSCLC) remains controversial. 536 NSCLC patients, of which 172 harbored lymph node metastases, were included in this study. Tissue microarrays were constructed and multiplexed immunohistochemistry of CD66b, CD34 and pan-keratin was performed to evaluate the localization and quantity of CD66b+ TANs. High intratumoral CD66b+ TANs density in squamous cell carcinoma (SCC) subgroup was an independent positive prognosticator for disease-specific survival (P = 0.038). In contrast, high intratumoral TANs density was an independent negative prognostic factor in the adenocarcinoma (ADC) subgroup (P= 0.032). Likewise, in ADC patients with lymph node metastases, high level of intratumoral TANs was associated with poor prognosis (P = 0.003). Stromal CD66b+ TANs were not associated with outcome of NSCLC patients. In conclusion, CD66b+ TANs show diverging prognostic effect in NSCLC patients according to histological subgroups. The presence of CD66b+ TANs could prove pivotal for development of an immunoscore in ADC NSCLC patients.

PMID: 27708229 [PubMed - indexed for MEDLINE]

Survival in Limited Disease Small Cell Lung Cancer According to N3 Lymph Node Involvement.

lør, 02/24/2018 - 11:30
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Survival in Limited Disease Small Cell Lung Cancer According to N3 Lymph Node Involvement.

Anticancer Res. 2018 02;38(2):871-876

Authors: Valan CD, Slagsvold JE, Halvorsen TO, Herje M, Bremnes RM, Brunsvig PF, Brustugun OT, Fløtten Ø, Levin N, Sundstrøm SH, Grønberg BH

Abstract
BACKGROUND/AIM: There are several definitions of limited disease (LD) in small cell lung cancer (SCLC), differing with respect to N3 disease accepted. We analyzed patients from a randomized trial comparing two schedules of thoracic radiotherapy (TRT) in LD SCLC to investigate whether there were survival differences between N3 subcategories (n=144).
PATIENTS AND METHODS: Patients with a baseline CT scan available were analysed. Patients received four courses of cisplatin/etoposide and TRT of 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily).
RESULTS: Median overall survival (OS) was 23.3 months in the whole cohort. N3-patients (n=37) had shorter survival than those with N0-2 (16.7 vs. 33.0 months; p<0.001). There were no significant OS-differences between the N3 subcategories, but patients with metastases to two or more N3 regions had shorter survival than other N3 patients (13.4 vs. 19.9 months; p=0.011).
CONCLUSION: There were no survival differences between the N3 subcategories, suggesting that all N3 disease should be considered as LD.

PMID: 29374714 [PubMed - indexed for MEDLINE]

LAG-3 in Non-Small-cell Lung Cancer: Expression in Primary Tumors and Metastatic Lymph Nodes Is Associated With Improved Survival.

tor, 02/08/2018 - 10:30
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LAG-3 in Non-Small-cell Lung Cancer: Expression in Primary Tumors and Metastatic Lymph Nodes Is Associated With Improved Survival.

Clin Lung Cancer. 2017 Dec 11;:

Authors: Hald SM, Rakaee M, Martinez I, Richardsen E, Al-Saad S, Paulsen EE, Blix ES, Kilvaer T, Andersen S, Busund LT, Bremnes RM, Donnem T

Abstract
BACKGROUND: Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor and a putative therapeutic target in non-small-cell lung cancer (NSCLC). We explored the prognostic effect of LAG-3+ tumor-infiltrating lymphocytes (TILs) in primary tumors and metastatic lymph nodes in NSCLC and its potential for inclusion in an immunoscore, supplementing the TNM classification.
MATERIALS AND METHODS: Primary tumor tissue from 553 stage I-IIIB NSCLC patients and 143 corresponding metastatic lymph nodes were collected. The expression of LAG-3 was evaluated by immunohistochemistry on tissue microarrays.
RESULTS: On univariate analysis, LAG-3+ TILs in the intraepithelial and stromal compartments of primary tumors and in the intraepithelial and extraepithelial compartments of metastatic lymph nodes were associated with improved disease-specific survival (DSS). On multivariate analysis, stromal LAG-3+ TILs were a significant independent predictor of improved DSS (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.43-0.82; P = .002). Stromal LAG-3+ TILs did not have prognostic impact across all pathologic stages. In the metastatic lymph nodes, intraepithelial (HR, 0.61; 95% CI, 0.38-0.99; P = .049) and extraepithelial (HR, 0.54; 95% CI, 0.29-0.70; P < .001) LAG-3+ TILs were independently associated with favorable DSS.
CONCLUSION: LAG-3+ TILs are an independent positive prognostic factor in stage I-IIIB NSCLC. LAG-3 in metastatic lymph nodes is a candidate marker for an immunoscore in NSCLC.

PMID: 29396238 [PubMed - as supplied by publisher]

Analysis of the immune microenvironment in resected non-small cell lung cancer: the prognostic value of different T lymphocyte markers.

tir, 02/06/2018 - 10:30
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Analysis of the immune microenvironment in resected non-small cell lung cancer: the prognostic value of different T lymphocyte markers.

Oncotarget. 2016 08 16;7(33):52849-52861

Authors: Usó M, Jantus-Lewintre E, Bremnes RM, Calabuig S, Blasco A, Pastor E, Borreda I, Molina-Pinelo S, Paz-Ares L, Guijarro R, Martorell M, Forteza J, Camps C, Sirera R

Abstract
The prognosis of non-small cell lung cancer (NSCLC) remains poor and heterogeneous and new biomarkers are needed. As the immune system plays a pivotal role in cancer, the study of immune-related markers may provide valuable prognostic information of NSCLC. In 122 formalin-fixed, paraffin-embedded tumor tissue samples from early-stage NSCLC, tumor and tumor-near stromal areas were microdissected and gene expression levels of conventional and regulatory T cell markers were assessed by quantitative polymerase chain reaction. Also, the presence of infiltrating CD4+, CD8+, and FOXP3+ cells in tumor samples was assessed by immunohistochemistry. The relative proportion of conventional and regulatory T cells present in the tumor environment was assessed and found to be key to understand the importance that the immune system analysis has in the prognostics of NSCLC patients. The presence of CD8+ cells in the tumor compartment was associated with better outcome, whereas the presence of FOXP3+ cells was associated with worse overall survival. The negative prognostic value of combined biomarkers, indicating high levels of FOXP3 in the stroma and low levels of CD4 or CD8 in tumors, was observed at mRNA level and was validated by immunohistochemistry.In conclusion, the proportion of T helper and cytotoxic cells vs. regulatory T cells in different locations of the tumor microenvironment have opposite prognostic impacts in resected NSCLC.

PMID: 27463005 [PubMed - indexed for MEDLINE]

Skeletal muscle radiodensity is prognostic for survival in patients with advanced non-small cell lung cancer.

man, 01/29/2018 - 10:30
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Skeletal muscle radiodensity is prognostic for survival in patients with advanced non-small cell lung cancer.

Clin Nutr. 2016 Dec;35(6):1386-1393

Authors: Sjøblom B, Grønberg BH, Wentzel-Larsen T, Baracos VE, Hjermstad MJ, Aass N, Bremnes RM, Fløtten Ø, Bye A, Jordhøy M

Abstract
BACKGROUND & AIMS: Recent research indicates that severe muscular depletion (sarcopenia) is frequent in cancer patients and linked to cachexia and poor survival. Our aim was to investigate if measures of skeletal muscle hold prognostic information in advanced non-small cell lung cancer (NSCLC).
METHODS: We included NSCLC patients with disease stage IIIB/IV, performance status 0-2, enrolled in three randomised trials of first-line chemotherapy (n = 1305). Computed tomography (CT) images obtained before start of treatment were used for body composition analyses at the level of the third lumbar vertebra (L3). Skeletal muscle mass was assessed by measures of the cross sectional muscle area, from which the skeletal muscle index (SMI) was obtained. Skeletal muscle radiodensity (SMD) was measured as the mean Hounsfield unit (HU) of the measured muscle area. A high level of mean HU indicates a high SMD.
RESULTS: Complete data were available for 734 patients, mean age 65 years. Both skeletal muscle index (SMI) and muscle radiodensity (SMD) varied largely. Mean SMI and SMD were 47.7 cm2/m2 and 37.4 HU in men (n = 420), 39.6 cm2/m2 and 37.0 HU in women (n = 314). Multivariable Cox regression analyses, adjusted for established prognostic factors, showed that SMD was independently prognostic for survival (Hazard ratio (HR) 0.98, 95% CI 0.97-0.99, p = 0.001), whereas SMI was not (HR 0.99, 95% CI 0.98-1.01, p = 0.329).
CONCLUSION: Low SMD is associated with poorer survival in advanced NSCLC. Further research is warranted to establish whether muscle measures should be integrated into routine practice to improve prognostic accuracy.

PMID: 27102408 [PubMed - indexed for MEDLINE]

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

fre, 01/19/2018 - 10:30
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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]