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1.  Salvage surgery for local failures after stereotactic ablative radiotherapy for early stage non-small cell lung cancer 
The literature on surgical salvage, i.e. lung resections in patients who develop a local recurrence following stereotactic ablative radiotherapy (SABR), is limited. We describe our experience with salvage surgery in nine patients who developed a local recurrence following SABR for early stage non-small cell lung cancer (NSCLC).
Patients who underwent surgical salvage for a local recurrence following SABR for NSCLC were identified from two Dutch institutional databases. Complications were scored using the Dindo-Clavien-classification.
Nine patients who underwent surgery for a local recurrence were identified. Median time to local recurrence was 22 months. Recurrences were diagnosed with CT- and/or 18FDG-PET-imaging, with four patients also having a pre-surgical pathological diagnosis. Extensive adhesions were observed during two resections, requiring conversion from a thoracoscopic procedure to thoracotomy during one of these procedures. Three patients experienced complications post-surgery; grade 2 (N = 2) and grade 3a (N = 1), respectively. All resection specimens showed viable tumor cells. Median length of hospital stay was 8 days (range 5–15 days) and 30-day mortality was 0 %. Lymph node dissection revealed mediastinal metastases in 3 patients, all of whom received adjuvant therapy.
Our experience with nine surgical procedures for local recurrences post-SABR revealed two grade IIIa complications, and a 30-day mortality of 0 %, suggesting that salvage surgery can be safely performed after SABR.
PMCID: PMC5048455  PMID: 27716240
2.  Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer 
Cell Discovery  2016;2:16031-.
Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.
PMCID: PMC5037574  PMID: 27721983
metabolomics; glutathione; lung cancer; drug resistance; TKI
3.  [18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches 
Nitroglycerin (NTG) is a vasodilating drug, which increases tumor blood flow and consequently decreases hypoxia. Therefore, changes in [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG PET) uptake pattern may occur. In this analysis, we investigated the feasibility of [18F]FDG PET for response assessment to paclitaxel-carboplatin-bevacizumab (PCB) treatment with and without NTG patches. And we compared the [18F]FDG PET response assessment to RECIST response assessment and survival.
A total of 223 stage IV non-small cell lung cancer (NSCLC) patients were included in a phase II study (NCT01171170) randomizing between PCB treatment with or without NTG patches. For 60 participating patients, a baseline and a second [18F]FDG PET/computed tomography (CT) scan, performed between day 22 and 24 after the start of treatment, were available. Tumor response was defined as a 30 % decrease in CT and PET parameters, and was compared to RECIST response at week 6. The predictive value of these assessments for progression free survival (PFS) and overall survival (OS) was assessed with and without NTG.
A 30 % decrease in SUVpeak assessment identified more patients as responders compared to a 30 % decrease in CT diameter assessment (73 % vs. 18 %), however, this was not correlated to OS (SUVpeak30 p = 0.833; CTdiameter30 p = 0.557). Changes in PET parameters between the baseline and the second scan were not significantly different for the NTG group compared to the control group (p value range 0.159–0.634). The CT-based (part of the [18F]FDG PET/CT) parameters showed a significant difference between the baseline and the second scan for the NTG group compared to the control group (CT diameter decrease of 7 ± 23 % vs. 19 ± 14 %, p = 0.016, respectively).
The decrease in tumoral FDG uptake in advanced NSCLC patients treated with chemotherapy with and without NTG did not differ between both treatment arms. Early PET-based response assessment showed more tumor responders than CT-based response assessment (part of the [18F]FDG PET/CT); this was not correlated to survival. This might be due to timing of the [18F]FDG PET shortly after the bevacizumab infusion.
PMCID: PMC5121177  PMID: 27600280
[18F]FDG PET/CT; Response assessment; Nitroglycerin; Bevacizumab; Stage IV NSCLC
4.  Dabrafenib in BRAF V600E–Mutant Advanced Non-Small Cell Lung Cancer: an Open-label, Single arm, Multicenter, Phase 2 Trial 
The Lancet. Oncology  2016;17(5):642-650.
Activating BRAF V600E mutations are found in approximately 1–2% of adenocarcinomas of the lung offering an opportunity to test targeted therapy for this disease. Dabrafenib is an oral selective inhibitor of the BRAF kinase. The aim of this study was to assess the clinical activity of dabrafenib in patients with advanced BRAF V600E-mutant non-small cell lung cancer (NSCLC).
In this phase 2, multicenter, nonrandomized, open-label study of previously treated and untreated patients with stage IV, metastatic NSCLC and BRAF V600E mutation, we evaluated the antitumor activity and safety of oral dabrafenib (150 mg twice daily). The primary endpoint was investigator-assessed overall response rate (ORR) in patients receiving ≥ 1 dose of study drug. Safety analysis was performed on the all-treated population (all previously treated and untreated patients receiving ≥ 1 dose of study drug). The study is ongoing but not enrolling participants in this cohort. This trial is registered with, number NCT01336634.
Between August 2011 and February 2014 a total of 84 previously treated and untreated patients were enrolled. Investigator-assessed ORR for 78 pretreated patients was 33% (95% confidence interval [CI], 23·1 to 44·9). Independent review committee assessment of ORR was consistent with investigator-based assessment. Four of the six previously untreated patients had an objective response. One patient died on study due to intracranial hemorrhage that was considered by the investigator to be due to study drug. Serious adverse events were reported in 35 (42%) of 84 patients. The most frequent grade 3 or higher adverse events were cutaneous squamous cell carcinoma (10 [12%] of 84 patients), asthenia (4 [5%] of 84 patients), and basal cell carcinoma (4 [5%] of 84 patients).
This is, to our knowledge, the first prospective trial focusing on BRAF V600E-mutant NSCLC to show clinical activity of a BRAF inhibitor. The results presented here suggest that dabrafenib may represent a future treatment option for patients with BRAF V600E-mutant NSCLC, a population with limited therapeutic options.
This trial was funded by GlaxoSmithKline. Dabrafenib is an asset of Novartis AG as of March 2, 2015.
PMCID: PMC5006181  PMID: 27080216
5.  Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients 
Cell Reports  2016;16(3):631-643.
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.
Graphical Abstract
•NFIB drives tumor initiation and progression in mouse models of SCLC•NFIB enhances metastasis and changes the metastatic profile•NFIB promotes dedifferentiation and invasion in SCLC•NFIB marks stage III/IV high-grade neuroendocrine carcinomas in patients
SCLC is a highly malignant cancer with an unmet need for better intervention strategies. Semenova et al. report that the transcription factor NFIB drives SCLC growth and metastasis, defines an aggressive tumor compartment in mice, and marks a subgroup of high-grade pulmonary neuroendocrine tumors (pNETs) in patients.
PMCID: PMC4956617  PMID: 27373156
6.  Integrative genome analyses identify key somatic driver mutations of small cell lung cancer 
Peifer, Martin | Fernández-Cuesta, Lynnette | Sos, Martin L | George, Julie | Seidel, Danila | Kasper, Lawryn H | Plenker, Dennis | Leenders, Frauke | Sun, Ruping | Zander, Thomas | Menon, Roopika | Koker, Mirjam | Dahmen, Ilona | Müller, Christian | Di Cerbo, Vincenzo | Schildhaus, Hans-Ulrich | Altmüller, Janine | Baessmann, Ingelore | Becker, Christian | de Wilde, Bram | Vandesompele, Jo | Böhm, Diana | Ansén, Sascha | Gabler, Franziska | Wilkening, Ines | Heynck, Stefanie | Heuckmann, Johannes M | Lu, Xin | Carter, Scott L | Cibulskis, Kristian | Banerji, Shantanu | Getz, Gad | Park, Kwon-Sik | Rauh, Daniel | Grütter, Christian | Fischer, Matthias | Pasqualucci, Laura | Wright, Gavin | Wainer, Zoe | Russell, Prudence | Petersen, Iver | Chen, Yuan | Stoelben, Erich | Ludwig, Corinna | Schnabel, Philipp | Hoffmann, Hans | Muley, Thomas | Brockmann, Michael | Engel-Riedel, Walburga | Muscarella, Lucia A | Fazio, Vito M | Groen, Harry | Timens, Wim | Sietsma, Hannie | Thunnissen, Erik | Smit, Egbert | Heideman, Daniëlle AM | Snijders, Peter JF | Cappuzzo, Federico | Ligorio, Claudia | Damiani, Stefania | Field, John | Solberg, Steinar | Brustugun, Odd Terje | Lund-Iversen, Marius | Sänger, Jörg | Clement, Joachim H | Soltermann, Alex | Moch, Holger | Weder, Walter | Solomon, Benjamin | Soria, Jean-Charles | Validire, Pierre | Besse, Benjamin | Brambilla, Elisabeth | Brambilla, Christian | Lantuejoul, Sylvie | Lorimier, Philippe | Schneider, Peter M | Hallek, Michael | Pao, William | Meyerson, Matthew | Sage, Julien | Shendure, Jay | Schneider, Robert | Büttner, Reinhard | Wolf, Jürgen | Nürnberg, Peter | Perner, Sven | Heukamp, Lukas C | Brindle, Paul K | Haas, Stefan | Thomas, Roman K
Nature genetics  2012;44(10):1104-1110.
Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor survival1–3. We sequenced 29 SCLC exomes, two genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in histone-modifying genes, CREBBP, EP300, and MLL. Furthermore, we observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from p53/Rb1-deficient mice4. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genome alterations, and provides a generalizable framework for identification of biologically relevant genes in the context of high mutational background.
PMCID: PMC4915822  PMID: 22941188
small-cell lung cancer; cancer genome; integrated analysis
7.  Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials 
The Lancet. Oncology  2015;16(6):630-637.
The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials.
Eligible patients in the STARS and ROSEL studies were those with clinical T1–2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with (STARS: NCT00840749; ROSEL: NCT00687986).
58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40.2 months (IQR 23.0–47.3) for the SABR group and 35.4 months (18.9–40.7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85–100) in the SABR group compared with 79% (64–97) in the surgery group (hazard ratio [HR] 0.14 [95% CI 0.017–1.190], log-rank p=0.037). Recurrence-free survival at 3 years was 86% (95% CI 74–100) in the SABR group and 80% (65–97) in the surgery group (HR 0.69 [95% CI 0.21–2.29], log-rank p=0.54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three [10%] chest wall pain, two [6%] dyspnoea or cough, and one [3%] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3–4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four [15%] patients), chest pain (four [15%] patients), and lung infections (two [7%]).
SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted.
Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.
PMCID: PMC4489408  PMID: 25981812
8.  Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer 
Oncoimmunology  2015;4(7):e1014242.
Myeloid-derived suppressor cells (MDSCs) play an important role in immune suppression and accumulate under pathologic conditions such as cancer and chronic inflammation. They comprise a heterogeneous population of immature myeloid cells that exert their immunosuppressive function via a variety of mechanisms. Immunoglobulin-like transcript 3 (ILT3) is a receptor containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) that can be expressed on antigen-presenting cells and is an important regulator of dendritic cell tolerance. ILT3 exists in a membrane-bound and a soluble form and can interact with a yet unidentified ligand on T cells and thereby induce T-cell anergy, regulatory T cells, or T suppressor cells. In this study, we analyzed freshly isolated peripheral blood mononuclear cells (PBMCs) of 105 patients with non-small cell lung cancer and 20 healthy controls and demonstrated for the first time that ILT3 is expressed on MDSCs. We show that increased levels of circulating MDSCs correlate with reduced survival. On the basis of ILT3 cell surface expression, an ILT3low and ILT3high population of polymorphonuclear (PMN)-MDSCs could be distinguished. Interestingly, in line with the immunosuppressive function of ILT3 on dendritic cells, patients with an increased proportion of PMN-MDSCs and an increased fraction of the ILT3high subset had a shorter median survival than patients with elevated PMN-MDSC and a smaller ILT3high fraction. No correlation between the ILT3high subset and other immune variables was found. ILT3 expressed on MDSCs might reflect a previously unknown mechanism by which this cell population induces immune suppression and could therefore be an attractive target for immune intervention.
PMCID: PMC4485803  PMID: 26140237
CD85k; immunoglobulin-like transcript 3; immune suppression; LILRB4; LIR-5; myeloid-derived suppressor cells; non-small cell lung cancer; overall survival; APC, antigen-presenting cell; DC, dendritic cell; ELISA, enzyme-linked immunosorbent assay; HC, healthy control; ILT3, immunoglobulin-like transcript 3; MDSC, myeloid-derived suppressor cell; MFI, mean fluorescence intensity; MO-MDSC, monocytic MDSC; NFκB, nuclear factor κB; NSCLC, non-small cell lung carcinoma; PBMC, peripheral blood mononuclear cell; PMN-MDSC, polymorphonuclear MDSC; sILT3, soluble ILT3; Treg, regulatory T cell; Ts, T suppressor cell
9.  Repeatability of Radiomic Features in Non-Small-Cell Lung Cancer [18F]FDG-PET/CT Studies: Impact of Reconstruction and Delineation 
Molecular Imaging and Biology  2016;18(5):788-795.
To assess (1) the repeatability and (2) the impact of reconstruction methods and delineation on the repeatability of 105 radiomic features in non-small-cell lung cancer (NSCLC) 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomorgraphy/computed tomography (PET/CT) studies.
Eleven NSCLC patients received two baseline whole-body PET/CT scans. Each scan was reconstructed twice, once using the point spread function (PSF) and once complying with the European Association for Nuclear Medicine (EANM) guidelines for tumor PET imaging. Volumes of interest (n = 19) were delineated twice, once on PET and once on CT images.
Sixty-three features showed an intraclass correlation coefficient ≥ 0.90 independent of delineation or reconstruction. More features were sensitive to a change in delineation than to a change in reconstruction (25 and 3 features, respectively).
The majority of features in NSCLC [18F]FDG-PET/CT studies show a high level of repeatability that is similar or better compared to simple standardized uptake value measures.
Electronic supplementary material
The online version of this article (doi:10.1007/s11307-016-0940-2) contains supplementary material, which is available to authorized users.
PMCID: PMC5010602  PMID: 26920355
PET/CT; Repeatability; Radiomics; Tracer uptake heterogeneity; Non-small-cell lung cancer (NSCLC)
10.  Effects of erlotinib therapy on [11C]erlotinib uptake in EGFR mutated, advanced NSCLC 
EJNMMI Research  2016;6:10.
In non-small cell lung cancer (NSCLC) patients off erlotinib therapy, positron emission tomography (PET) using [11C]erlotinib distinguished epidermal growth factor receptor (EGFR) mutations from wild-type EGFR. However, tumor uptake of [11C]erlotinib during erlotinib therapy is unknown. Therefore, the aims of this study were to evaluate tumor [11C]erlotinib uptake in NSCLC patients both on and off erlotinib therapy, to evaluate the effect of erlotinib therapy on tumor perfusion and its correlation to tumor [11C]erlotinib uptake, and also, to investigate simplified uptake parameters using arterial and venous blood samples.
Ten patients were to be scanned twice with a 1–2-week interval, i.e., on (E+) and off (E−) erlotinib therapy. Each procedure consisted of a low-dose CT scan, a 10-min dynamic [15O]H2O PET scan, and a 60-min dynamic [11C]erlotinib PET scan with arterial and venous sampling at six time points. In patients(E+), the optimal compartment model was analyzed using Akaike information criterion. In patients(E−), the uptake parameter was the volume of distribution (VT), estimated by using metabolite-corrected plasma input curves based on image-derived input functions and discrete arterial and venous blood samples. Tumor blood flow (TBF) was determined by rate constant of influx (K1) of [15O]H2O using the 1T2k model and correlated with VT and K1 values of [11C]erlotinib. The investigated simplified parameters were standardized uptake value (SUV) and tumor-to-blood ratio (TBR) at 40–60 min pi interval.
Of the 13 patients included, ten were scanned twice. In patients(E+), [11C]erlotinib best fitted the 2T4k model with VT. In all patients, tumor VT(E+) was lower than VT(E−) (median VT(E−) = 1.61, range 0.77–3.01; median VT(E+) = 1.17, range 0.53–1.74; P = 0.004). Using [15O]H2O, five patients were scanned twice. TBF did not change with erlotinib therapy, TBF showed a positive trend towards correlation with [11C]erlotinib K1, but not with VT. TBR40–50 and TBR50–60, using both arterial and venous sampling, correlated with VT(E−) (all rs >0.9, P < 0.001), while SUV did not. In patients off and on therapy, venous TBR underestimated arterial TBR by 26 ± 12 and 9 ± 9 %, respectively.
In patients on erlotinib in therapeutic dose, tumor VT decreases with high variability, independent of tumor perfusion. For simplification of [11C]erlotinib PET scanning protocols, both arterial and venous TBR 40–60 min post injection can be used; however, arterial and venous TBR values should not be interchanged as venous values underestimate arterial values.
Trial registration
Registered at the Netherlands Trial Registry: NTR3670.
Electronic supplementary material
The online version of this article (doi:10.1186/s13550-016-0169-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4746207  PMID: 26857779
NSCLC; PET; [11C]Erlotinib; Erlotinib therapy
11.  Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer 
Oncotarget  2015;7(1):1066-1075.
Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers. Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival. Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK− platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression. Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.
PMCID: PMC4808052  PMID: 26544515
diagnostics; NSCLC; liquid biopsies; platelets; EML4-ALK
12.  A patient perspective on shared decision making in stage I non-small cell lung cancer: a mixed methods study 
BMC Cancer  2015;15:959.
Surgery and stereotactic ablative radiotherapy (SABR) are both curative treatment options for patients with a stage I non-small cell lung cancer (NSCLC). Consequently, there is growing interest in studying the role of patients in treatment decision making. We studied how patients with stage I NSCLC perceived shared decision making (SDM) in general, and how they viewed different aspects of SDM.
A sequential mixed methods design was used, consisting of qualitative interviews (N = 11), as well as a survey study (N = 76) focusing on different SDM-related aspects. Participants were interviewed to understand their own experience with treatment decision making. In the survey study, patients rated the importance of 20 aspects of shared decision making that were identified during interviews. Descriptive analysis and explorative factor analysis were performed.
We assessed six qualitative themes covering SDM aspects that were determined by patients to be important. The survey identified four SDM-related factors with sufficient internal consistency, namely (1) ‘guidance by clinician’ (α = .741), (2) ‘conduct of clinician’ (α = .774); (3) ‘preparation for treatment decision making’ (α = .864); and (4) ‘active role of patient in treatment decision making’ (α = .782). Of these, clinician guidance was rated as most important by patients (M = 3.61; SD = .44). Only 28.9 % of patients in the survey study reported that both treatment options were discussed with them.
Patients with a stage I NSCLC found clinician guidance to be important when making treatment decisions. Nevertheless, the majority of patients reported not being offered both treatment options, which might have influenced this finding.
PMCID: PMC4682255  PMID: 26673216
Shared decision making; Stereotactic ablative radiotherapy; Surgery; Patient perspective
13.  NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor 
Oncotarget  2015;6(40):42717-42732.
The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase-1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor. By integration of genetic and functional analyses in isogenic cell pairs we provide evidence of the crucial role played by NF-κB1 in driving CNX-2006 acquired resistance and show that NF-κB activation may replace the oncogenic EGFR signaling in NSCLC when effective and persistent inhibition of the target is achieved in the presence of the T790M mutation. In this context, we demonstrate that the sole, either genetic or pharmacologic, inhibition of NF-κB is sufficient to reduce the viability of cells that adapted to EGFR-TKIs. Overall, our findings support the rational inhibition of members of the NF-κB pathway as a promising therapeutic option for patients who progress after treatment with novel mutant-selective EGFR-TKIs.
PMCID: PMC4767465  PMID: 26015408
drug-resistance; EGFR-T790M; NSCLC; NF-κB; EMT
14.  RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics 
Cancer Cell  2015;28(5):666-676.
Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based “liquid biopsies”.
Graphical Abstract
•Tumors “educate” platelets (TEPs) by altering the platelet RNA profile•TEPs provide a RNA biosource for pan-cancer, multiclass, and companion diagnostics•TEP-based liquid biopsies may guide clinical diagnostics and therapy selection•A total of 100–500 pg of total platelet RNA is sufficient for TEP-based diagnostics
Best et al. show that mRNA sequencing of tumor-educated blood platelets distinguishes cancer patients from healthy individuals with 96% accuracy, differentiates between six primary tumor types of patients with 71% accuracy, and identifies several genetic alterations found in tumors.
PMCID: PMC4644263  PMID: 26525104
15.  A comparative PET imaging study with the reversible and irreversible EGFR tyrosine kinase inhibitors [11C]erlotinib and [18F]afatinib in lung cancer-bearing mice 
EJNMMI Research  2015;5:14.
Tyrosine kinase inhibitors (TKIs) have experienced a tremendous boost in the last decade, where more than 15 small molecule TKIs have been approved by the FDA. Unfortunately, despite their promising clinical successes, a large portion of patients remain unresponsive to these targeted drugs. For non-small cell lung cancer (NSCLC), the effectiveness of TKIs is dependent on the mutational status of epidermal growth factor receptor (EGFR). The exon 19 deletion as well as the L858R point mutation lead to excellent sensitivity to TKIs such as erlotinib and gefitinib; however, despite initial good response, most patients invariably develop resistance against these first-generation reversible TKIs, e.g., via T790M point mutation. Second-generation TKIs that irreversibly bind to EGFR wild-type and mutant isoforms have therefore been developed and one of these candidates, afatinib, has now reached the market. Whether irreversible TKIs differ from reversible TKIs in their in vivo tumor-targeting properties is, however, not known and is the subject of the present study.
Erlotinib was labeled with carbon-11 and afatinib with fluorine-18 without modifying the structure of these compounds. A preclinical positron emission tomography (PET) study was performed in mice bearing NSCLC xenografts with a representative panel of mutations: an EGFR-WT xenograft cell line (A549), an acquired treatment-resistant L858R/T790M mutant (H1975), and a treatment-sensitive exon 19 deleted mutant (HCC827). PET imaging was performed in these xenografts with both tracers. Additionally, the effect of drug efflux transporter permeability glycoprotein (P-gp) on the tumor uptake of tracers was explored by therapeutic blocking with tariquidar.
Both tracers only demonstrated selective tumor uptake in the HCC827 xenograft line (tumor-to-background ratio, [11C]erlotinib 1.9 ± 0.5 and [18F]afatinib 2.3 ± 0.4), thereby showing the ability to distinguish sensitizing mutations in vivo. No major differences were observed in the kinetics of the reversible and the irreversible tracers in each of the xenograft models. Under P-gp blocking conditions, no significant changes in tumor-to-background ratio were observed; however, [18F]afatinib demonstrated better tumor retention in all xenograft models.
TKI-PET provides a method to image sensitizing mutations and can be a valuable tool to compare the distinguished targeting properties of TKIs in vivo.
PMCID: PMC4385286  PMID: 25853020
Afatinib; Erlotinib; Activated EGFR; Radiochemistry; PET; Personalized medicine
16.  Adherence, exposure and patients’ experiences with the use of erlotinib in non-small cell lung cancer 
Erlotinib is an orally administered tyrosine kinase inhibitor used for treatment of non-small cell lung cancer. Understanding actual use of medication is essential for optimizing treatment conditions.
In this multicentre prospective observational study, patients starting erlotinib treatment were followed for 4 months. Adherence was assessed using a medication event monitoring system (MEMS). Area under the curve (AUC) was determined after 1, 2 and 4 months. Before start and at monthly intervals, patients filled out questionnaires about attitude towards medication and disease, quality of life, symptoms and use in daily practice.
Sixty-two patients (median age 63.5 years, 53 % male) were included of whom 15 were still on treatment after 4 months. MEMS data of 55 patients revealed a mean adherence of 96.8 ± 4.0 %. Over one-third of patients had an adherence rate <95 %. At 1 month, 21 % of patients did not always correctly take erlotinib without food. Associated risk factors were older age, suboptimal adherence, ocular symptoms and stomatitis (all p < 0.05). After 1 month of treatment, fatigue (91 %) and rash (86 %) were the most common symptoms reported. AUCss of erlotinib was higher in patients with rash and patients with moderate–severe anorexia (both p < 0.05).
Though adherence to erlotinib treatment is generally high, non-adherence might be an issue in a considerable number of patients. To support optimal erlotinib intake, clinicians need to take adequate measures to ameliorate symptoms and to address adherence and correct intake without food. Especially older patients and those who experience stomatitis may need extra attention.
PMCID: PMC4469769  PMID: 25743274
Erlotinib; Non-small cell lung cancer; Medication adherence; Symptoms; Patient-reported; Tyrosine kinase inhibitor
17.  Analysis of AKT and ERK1/2 protein kinases in extracellular vesicles isolated from blood of patients with cancer 
Journal of Extracellular Vesicles  2014;3:10.3402/jev.v3.25657.
Extracellular vesicles (EVs) are small nanometre-sized vesicles that are circulating in blood. They are released by multiple cells, including tumour cells. We hypothesized that circulating EVs contain protein kinases that may be assessed as biomarkers during treatment with tyrosine kinase inhibitors.
EVs released by U87 glioma cells, H3255 and H1650 non-small-cell lung cancer (NSCLC) cells were profiled by tandem mass spectrometry. Total AKT/protein kinase B and extracellular signal regulated kinase 1/2 (ERK1/2) levels as well as their relative phosphorylation were measured by western blot in isogenic U87 cells with or without mutant epidermal growth factor receptor (EGFRvIII) and their corresponding EVs. To assess biomarker potential, plasma samples from 24 healthy volunteers and 42 patients with cancer were used.
In total, 130 different protein kinases were found to be released in EVs including multiple drug targets, such as mammalian target of rapamycin (mTOR), AKT, ERK1/2, AXL and EGFR. Overexpression of EGFRvIII in U87 cells results in increased phosphorylation of EGFR, AKT and ERK1/2 in cells and EVs, whereas a decreased phosphorylation was noted upon treatment with the EGFR inhibitor erlotinib. EV samples derived from patients with cancer contained significantly more protein (p=0.0067) compared to healthy donors. Phosphorylation of AKT and ERK1/2 in plasma EVs from both healthy donors and patients with cancer was relatively low compared to levels in cancer cells. Preliminary analysis of total AKT and ERK1/2 levels in plasma EVs from patients with NSCLC before and after sorafenib/metformin treatment (n=12) shows a significant decrease in AKT levels among patients with a favourable treatment response (p<0.005).
Phosphorylation of protein kinases in EVs reflects their phosphorylation in tumour cells. Total AKT protein levels may allow monitoring of kinase inhibitor responses in patients with cancer.
PMCID: PMC4261239  PMID: 25491250
biomarker; cancer; kinase inhibitor; signalling; plasma
18.  Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer 
Cancer discovery  2014;4(5):606-619.
Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase activating protein encoded by the NF1 gene. Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MEK inhibitor restored sensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.
PMCID: PMC4011693  PMID: 24535670
NF1; EGFR; KRAS; MAPK pathway; drug resistance; erlotinib; gefitinib; lung adenocarcinoma
19.  Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer 
Cancer discovery  2014;4(5):606-619.
Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase activating protein encoded by the NF1 gene. Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MEK inhibitor restored sensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.
PMCID: PMC4011693  PMID: 24535670
NF1; EGFR; KRAS; MAPK pathway; drug resistance; erlotinib; gefitinib; lung adenocarcinoma
20.  Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor-Resistant EGFR-Mutant Lung Cancer With and Without T790M Mutations 
Cancer discovery  2014;4(9):1036-1045.
EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase Ib study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post-acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3–6.4); median duration of confirmed objective response was 5.7 months (range, 1.8–24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib/cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations, warranting further investigation.
PMCID: PMC4155006  PMID: 25074459
afatinib; cetuximab; acquired resistance
21.  Benefit of a second opinion: From metastatic disease to resectable lung cancer with sarcoid-like reaction 
Mediastinal lymphadenopathy in combination with lung cancer is suggestive for lymph node metastases but can also have other origins.
Case report
We describe a patient diagnosed with stage IV lung cancer presenting with parenchymal lesions and enlarged mediastinal lymph nodes. A second opinion including FDG-PET scan review and a mediastinoscopy followed by surgery revealed tumor specimens originating from a single primary tumor with a sarcoid-like reaction in the mediastinal lymph nodes, changing the diagnosis from metastasized to resectable lung cancer.
PET positive lesions are not always synonymous with metastatic disease in the presence of a malignant tumor. Conscientious review of FDG-PET scans and tissue sampling are therefore mandatory to determine definitive staging and subsequent interventions.
PMCID: PMC4246249  PMID: 26029554
Non-small cell lung cancer; Second opinion; Mediastinal enlargement; Sarcoid-like reaction
22.  Pilot study of 89Zr-bevacizumab positron emission tomography in patients with advanced non-small cell lung cancer 
EJNMMI Research  2014;4:35.
The aim of this pilot study was to evaluate whether the uptake of 89Zr-bevacizumab in non-small cell lung cancer (NSCLC) tumors could be visualized and quantified. The correlation between tumor 89Zr-bevacizumab uptake and tumor response to antitumor therapy with a bevacizumab-based regimen was explored.
Seven NSCLC patients underwent static PET scans at days 4 and 7 after injection of 36.4 ± 0.9 MBq (mean ± SD) 89Zr-bevacizumab, prior to commencing carboplatin-paclitaxel-bevacizumab chemotherapy (CPB). Overall survival (OS) and progression-free survival (PFS) to CPB followed by bevacizumab maintenance therapy was correlated to tumor tracer uptake, quantified using peak standardized uptake values (SUVpeak).
Zr-bevacizumab uptake (SUVpeak) was approximately four times higher in tumor tissues (primary tumor and metastases) than in non-tumor tissues (healthy muscle, lung, and fat) on days 4 and 7. A positive trend but no significant correlation could be found between SUVpeak and OS or PFS.
This pilot study shows that 89Zr-bevacizumab PET imaging in NSCLC is feasible. Further investigation to validate this technique as a predictive biomarker for selecting patients for bevacizumab treatment is warranted.
Electronic supplementary material
The online version of this article (doi:10.1186/s13550-014-0035-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4884046  PMID: 26055936
NSCLC; VEGF; Immuno-PET; 89Zr-bevacizumab
23.  Frequent and Focal FGFR1 Amplification Associates With Therapeutically Tractable FGFR1 Dependency in Squamous-cell Lung Cancer 
Science translational medicine  2010;2(62):62ra93.
Lung cancer remains one of the leading causes for cancer-related death in developed countries. In lung adenocarcinomas, EGFR mutations and EML4-ALK fusions are associated with response to EGFR and ALK inhibition. By contrast, therapeutically exploitable genetic alterations have been lacking in squamous-cell lung cancer. We conducted a systematic search for alterations that are therapeutically amenable and performed high-resolution gene-copy number analyses in a set of 232 lung cancer specimens. We identified frequent and focal FGFR1 amplification in squamous-cell lung cancer (n=155), but not in other lung cancer subtypes, and confirmed its presence in an independent cohort of squamous-cell lung cancer samples employing FISH (22% of cases). Using cell-based screening with the FGFR inhibitor (PD173074) in a large (n=83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth (p=0.0002) and induced apoptosis (p=0.008) specifically in those lung cancer cells carrying amplified FGFR1. We validated the dependency on FGFR1 of FGFR1-amplified cell lines by knockdown of FGFR1 and by ectopic expression of a resistance allele of FGFR1 (FGFR1V561M), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Focal FGFR1 amplification is common in squamous-cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.
PMCID: PMC3990281  PMID: 21160078
24.  Benefit of a Second Opinion for Lung Cancer: No Metastasis to the Kidney but a Synchronous Primary Renal Neoplasm 
Case Reports in Oncology  2014;7(1):122-125.
The finding of a renal mass on imaging is suggestive of metastatic non-small cell lung cancer in the presence of a lung tumor but can also have another origin.
Case Report
We describe the case of a patient diagnosed with stage IV lung cancer based on a renal metastasis. A second opinion including review of histopathological data and additional imaging followed by lung surgery and cryoablation of the kidney lesion revealed two tumors of different origins, non-small cell lung cancer and a renal cell carcinoma.
The presence of a renal mass diagnosed on a CT scan in a patient with lung cancer is not always synonymous with metastatic disease. Confirmation of diagnosis by tissue sampling is mandatory, especially if a synchronous primary tumor is possible.
PMCID: PMC3975755  PMID: 24707259
Non-small cell lung cancer; Second opinion; Renal cell carcinoma; Diagnosis/treatment; Metastatic disease; Synchronous primary tumor
25.  Why Do Patients and Caregivers Seek Answers From the Internet and Online Lung Specialists? A Qualitative Study 
Since its launch in 2003, the Dutch Lung Cancer Information Center’s (DLIC) website has become increasingly popular. The most popular page of the website is the section “Ask the Physician”, where visitors can ask an online lung specialist questions anonymously and receive an answer quickly. Most questions were not only asked by lung cancer patients but also by their informal caregivers. Most questions concerned specific information about lung cancer.
Our goal was to explore the reasons why lung cancer patients and caregivers search the Internet for information and ask online lung specialists questions on the DLIC’s interactive page, “Ask the Physician”, rather than consulting with their own specialist.
This research consisted of a qualitative study with semistructured telephone interviews about medical information-seeking behavior (eg, information needs, reasons for querying online specialists). The sample comprised 5 lung cancer patients and 20 caregivers who posed a question on the interactive page of the DLIC website.
Respondents used the Internet and the DLIC website to look for lung cancer–related information (general/specific to their personal situation) and to cope with cancer. They tried to achieve a better understanding of the information given by their own specialist and wanted to be prepared for the treatment trajectory and disease course. This mode of information supply helped them cope and gave them emotional support. The interactive webpage was also used as a second opinion. The absence of face-to-face contact made respondents feel freer to ask for any kind of information. By being able to pose a question instantly and receiving a relatively quick reply from the online specialist to urgent questions, respondents felt an easing of their anxiety as they did not have to wait until the next consultation with their own specialist.
The DLIC website with its interactive page is a valuable complementary mode of information supply and supportive care for lung cancer patients and caregivers.
PMCID: PMC3936275  PMID: 24496139
lung cancer; patients; caregivers; website; online lung specialists; reasons; Internet; information needs; coping; qualitative

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