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Background: Venous thromboembolism (VTE) is a common complication in patients starting cancer therapies for non-small-cell lung cancer (NSCLC). We examined the risk and timing of VTE in patients with stage IIIA, IIIB to C, and stage IV NSCLC according to received cancer treatments., Materials and Methods: A nationwide registry-based cohort study of patients recorded in the Danish Lung Cancer Registry (2010-2021) followed for 1 year after entry into the registry to assess the incidence of VTE. The Aalen-Johansen estimator was used to calculate the risk of VTE after treatment commencement with chemotherapy, radiotherapy, chemoradiation, immunotherapy, and targeted therapy., Results: Among the 3475 patients with stage IIIA, 4047 with stage IIIB to C, and 18,082 patients with stage IV cancer, the 1-year risk of VTE was highest in the first 6 months and varied markedly by cancer stage and cancer treatment. In stage IIIA, VTE risk was highest with chemotherapy (3.9%) and chemoradiation (4.1%). In stage IIIB to C, risks increased with chemotherapy (5.2%), immunotherapy (9.4%), and targeted therapy (6.0%). Stage IV NSCLC showed high risk with targeted therapy (12.5%) and immunotherapy (12.2%). The risk was consistently higher for pulmonary embolism than deep vein thrombosis., Conclusion: VTE risks vary substantially according to cancer treatments and cancer stages. The highest risk was observed in the initial 6 months of therapy initiation. These insights emphasize the need for tailored risk assessment and vigilance in managing VTE complications in patients with NSCLC. Further research is needed to optimize individual thromboprophylaxis strategies for patients with unresectable and metastatic NSCLC., Competing Interests: Disclosure Thomas Decker Christensen has been on the speaker bureaus for AstraZeneca, Boehringer–Ingelheim, Pfizer, Roche Diagnostics, Takeda, Merck Sharp & Dohme (MSD) and Bristol–Myers Squibb (BMS) and on Advisory Board for Bayer, Merck MSD, AstraZeneca, and Sanofi. René Horsleben Petersen has received a speaker's fee from Medtronic, AMBU, Medela, and AstraZeneca and on the advisory board for AstraZeneca, Roche, MSD, and BMS. Torben Bjerregaard Larsen reports a relationship with Bayer, Pfizer, Janssen Pharmaceuticals, Roche Diagnostics, and Bristol Meyers Squibb that includes: consulting or advisory. Peter Meldgaard has received research support from Astra Zeneca, MSD, Novartis, Roche, and Takeda; and on advisory board for MSD, Roche, Astra Zeneca, BMS, Takeda, Novartis, and Amgen. Flemming Skjøth has received consultancy fees from Bayer. Simon Noble had received research support and been on speakers bureau from Leo Pharma. Anette Arbjerg Højen has received research grants from the Danish Heart Foundation and The Novo Nordisk Foundation, been on the speaker bureaus for Bayer, Pfizer, MSD, Leo Pharma, and BMS; and on Advisory Board for Bayer and BMS. Other authors: None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest PM reports receiving consulting fees from AstraZeneca, Roche, MSD, and Takeda; honoraria from AstraZeneca and BMS; and travel support from MSD.

Background: Venous thromboembolism (VTE) is a potentially preventable serious complication in patients with lung cancer undergoing thoracic operation. We examined the risk and timing of VTE after surgery for primary non-small cell lung cancer (NSCLC)., Methods: All patients undergoing operation for NSCLC in Denmark between 2003 and 2021 were identified in the Danish Lung Cancer Registry. VTE events in the year after operation were assessed by stage, patient characteristics, and surgical procedure., Results: We identified 13,197 patients who underwent operation for NSCLC in 2003 to 2021 (mean age, 67.6 years; 50% female); 10,524 (79.7%) had stage I-II NSCLC, and 2673 (20.3%) had stage III-IV. During 1-year follow-up, there were 335 VTE events, yielding a rate of 2.87 events/100 person-years and an absolute risk of 3.3% (95% CI, 2.3-4.0). VTE risk increased with advancing cancer stage (1.8% for stage I vs 3.9% for stage IV) but varied little by pathologic type, sex, and comorbidity level. Bilobectomy was associated with highest VTE risk (4.8%; 95% CI, 3.2-6.9), followed by pneumonectomy (3.5%; 95% CI, 2.3-5.0). The hazard of VTE was highest during the first 3 months after operation, after which it declined. For stage IV cancer, hazards increased again after 6 months. At 1 year, all-cause death was 12.6% (95% CI, 12.0%-13.1%)., Conclusions: VTE developed in 3.3% of patients undergoing operation for NSCLC, most commonly within 3 months postoperatively. Prolonged thromboprophylaxis could be considered, particularly in those with advanced cancer stage and undergoing extended resections., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Reliable biomarkers are needed to identify tumor recurrence of non-small cell lung cancer (NSCLC) patients after chemoradiotherapy (CRT) with curative intent. This could improve consolidation therapy of progressing patients. However, the approach of existing studies has limited transferability to the clinic., Materials and Methods: A retrospective analysis of 135 plasma samples from 56 inoperable NSCLC patients who received CRT with curative intent was performed. Plasma samples collected at baseline, at the first check-up (average 1.6 months post-RT), and at the second check-up (average 4.5 months post-RT) were analyzed by deep sequencing with a commercially available cancer personalized profiling strategy (CAPP-Seq) using a tumor-agnostic approach., Results: Detection of circulating tumor DNA (ctDNA) at 4.5 months after therapy was significantly associated with higher odds of tumor recurrence (OR: 5.4 (CI: 1.1-31), Fisher's exact test: p-value = 0.022), and shorter recurrence-free survival (RFS) (HR: 4.1 (CI: 1.7-10); log-rank test: p-value = 9e-04). In contrast, detection of ctDNA at 1.6 months after therapy was not associated with higher odds of tumor recurrence (OR: 2.7 (CI: 0.67-12), Fisher's exact test: p-value = 0.13) or shorter RFS (HR: 1.5 (CI: 0.67-3.3); log-rank test: p-value = 0.32)., Conclusion: This study demonstrates that the detection of ctDNA can be used to identify minimal residual disease 4.5 months after CRT in NSCLC patients using a commercially available kit and a tumor-agnostic approach. Furthermore, the time point of collecting the plasma sample after CRT has decisive importance for the prognostic value of ctDNA., Micro Abstract: This study analysed 135 plasma samples from 56 NSCLC patients treated with curative intent chemoradiotherapy using a tumor-agnostic approach. Detecting ctDNA at 4.5 months post-treatment was linked to higher recurrence odds, indicating ctDNA's potential as a biomarker for identifying residual disease after treatment with curative intent. Importantly, the study emphasizes the importance of timing for accurate ctDNA analysis results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Intrinsic resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC) patients with an activating mutation in the epidermal growth factor receptor (EGFR). We investigated co-occurring genetic alterations in circulating tumor DNA (ctDNA) as predictive markers of clinical response to first-line erlotinib., Methods: Pretreatment plasma samples were collected from 76 patients with EGFR-mutated, advanced-stage NSCLC treated with first-line erlotinib. We isolated ctDNA from plasma for next-generation sequencing., Results: Co-occurring oncogenic drivers were detected in 21% of pretreatment samples and correlated with decreased progression-free survival (PFS) (6.9 months vs 14.4 months; hazard ratio [HR], 2.088; 95% confidence interval [CI], 0.8119-5.370; P = .0355). Concurrent MET amplification was identified in 9 samples (12%), predicting inferior PFS (5.5 months vs 14.4 months; HR, 4.750; 95% CI, 0.5923-38.10; P = .0007) and overall survival (7.6 months vs 28.3 months; HR, 3.952; 95% CI, 0.8441-18.50; P = .0005). Co-occurring non-MET-amplification oncogenic alterations showed a tendency for shorter PFS (9.9 months vs 14.4 months; HR, 1.199; 95% CI, 0.3373-4.265; P = .7586). Clearing EGFR-mutated ctDNA during erlotinib treatment is a positive predictor of clinical outcomes. Among patients who cleared the EGFR mutation, 12% had a co-occurring oncogenic driver, with a tendency toward inferior PFS (8.7 months vs 16.1 months; HR, 1.703; 95% CI, 0.5347-5.424; P = .2508)., Conclusion: Co-occurring MET amplification in pretreatment ctDNA samples predict inferior clinical response to first-line erlotinib in advanced-stage, EGFR-mutated NSCLC patients. Co-occurring oncogenic alterations were associated with inferior response and may be potential predictors of clinical outcome., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Comprehensive Geriatric Assessment (CGA) can identify health problems in older persons. In addition, CGA includes intervention towards the identified problems. With follow up, more problems may be identified and the interventions can be adjusted. We wanted to compare CGA with or without tailored follow-up in a randomised design., Patients and Methods: Patients 70+ years referred for oncology treatment with four primary tumour sites. Participants were randomised 1:1 to either control group with no follow-up or intervention group with a tailored follow-up by a multidisciplinary team. Primary outcome was adherence to cancer treatment. Secondary outcomes were daily life activities, physical performance and hospitalisation., Results: In total, 363 participants were randomised. After randomisation only 301 were planned to receive specific cancer treatment. Median age was 75 years. Among the 301 participants, 52% of control group vs. 61% of intervention group completed treatment. Risk Rate (RR): 1.16 (95% Confidence Interval (CI): 0.95-1.42), p = .14. The impact varied between the included tumour-sites, p < .01. We found no difference in 90 days physical performance or daily life activities between groups. During the study period, 55% of controls vs. 47% in the intervention group were admitted to hospital, RR: 0.86 (95%CI: 0.69-1.07), p = .19., Conclusion: In frail and vulnerable patients with cancer, a tailored follow-up on CGA showed no differences in ability to complete initially planned cancer treatment. The impact varied between the included tumour sites. We did not find any impact of tailored follow-up on daily life activities, physical performance or hospitalisation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite increased focus on prevention as well as improved treatment possibilities, lung cancer remains among the most frequent and deadliest cancer diagnoses worldwide. Even lung cancer patients treated with curative intent have a high risk of relapse, leading to a dismal prognosis. More knowledge on the efficacy of surveillance with both current and new technologies as well as on the impact on patient treatment, quality of life, and survival are urgently needed. We therefore designed a randomized phase 3 trial. In one arm, every other computed tomography (CT) scan is replaced by positron emission tomography/CT, the other arm is the standard follow-up scheme with CT. The standard arm is identical to the current national Danish follow-up program. The primary endpoint is to compare the number of relapses treatable with curative intent in the 2 arms. We aim to include 750 patients over a 3-year period. Additionally, we will test the feasibility of noninvasive lung cancer diagnostics and surveillance in the form of circulating tumor DNA analysis. For this purpose, blood samples are collected before treatment and at each following control. The blood samples are stored in a biobank for later analysis and will not be used for guiding patient treatment decisions., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with advanced-stage non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations are successfully treated with tyrosine kinase inhibitors (TKIs). However, treatment outcome varies significantly. Previously, we found the polymorphism 181946C>T (rs2293347) located in exon 25 of the EGFR gene to be a predictor of improved outcome. However, these data were based on a subgroup analysis. Furthermore, other minor studies have found conflicting data. Thus, the aim of this study was to demonstrate the association of 181946C>T with clinical outcome in an independent cohort of EGFR-mutated patients treated with erlotinib., Patients and Methods: Seventy-five patients were prospectively enrolled. Blood samples were collected, and genotype for 181946C>T was determined by allele-specific polymerase chain reaction. Genotype was correlated with outcome., Results: In 73 patients, 181946C>T was successfully measured. Patients harboring the 181946CT genotype had a significantly longer median progression-free survival compared with patients harboring the 181946CC genotype (49.9 months [95% confidence interval (CI), 5.9-93.9 months] versus 11.1 months (95% CI, 7.4-14.9 months); P = .020). Moreover, a significantly longer median overall survival of 65.6 months (95% CI, 11.0-120.3 months) versus 31.2 months (95% CI, 10.9-51.6 months) was found (P = .019). Both results remained significant in a multivariate analysis adjusting for potential confounders., Conclusion: We demonstrate that the 181946C>T polymorphism is a significant predictor of prolonged progression-free survival and overall survival in an independent cohort of EGFR mutation-positive patients treated with erlotinib. The polymorphism could be an important predictor of treatment response in these patients. A large multicenter cohort study involving other concurrent genetic alterations is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The reported prevalence of ALK receptor tyrosine kinase gene (ALK) rearrangement in NSCLC ranges from 2% to 7%. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proved to be a reproducible and sensitive technique. Reverse-transcriptase polymerase chain reaction (RT-PCR) has also been advocated, and most recently, the advent of targeted next-generation sequencing (NGS) for ALK and other fusions has become possible. This study compares anaplastic lymphoma kinase (ALK) evaluation with all four techniques in resected NSCLC from the large European Thoracic Oncology Platform Lungscape cohort., Methods: A total of 96 cases from the European Thoracic Oncology Platform Lungscape iBiobank, with any ALK immunoreactivity were examined by FISH, central RT-PCR, and NGS. An H-score higher than 120 defines IHC positivity. RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers covered the most frequent ALK translocations. For NGS, the Oncomine Solid Tumour Fusion Transcript Kit (Thermo Fisher Scientific, Waltham, MA) was used. The concordance was assessed using the Cohen κ coefficient (two-sided α ≤ 5%)., Results: NGS provided results for 77 of the 95 cases tested (81.1%), whereas RT-PCR provided results for 77 of 96 (80.2%). Concordance occurred in 55 cases of the 60 cases tested with all four methods (43 ALK negative and 12 ALK positive). Using ALK copositivity for IHC and FISH as the criterion standard, we derived a sensitivity for RT-PCR/NGS of 70.0%/85.0%, with a specificity of 87.1%/79.0%. When either RT-PCR or NGS was combined with IHC, the sensitivity remained the same, whereas the specificity increased to 88.7% and 83.9% respectively., Conclusion: NGS evaluation with the Oncomine Solid Tumour Fusion transcript kit and RT-PCR proved to have high sensitivity and specificity, advocating their use in routine practice. For maximal sensitivity and specificity, ALK status should be assessed by using two techniques and a third one in discordant cases. We therefore propose a customizable testing algorithm. These findings significantly influence existing testing paradigms and have clear clinical and economic impact., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival)., Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test., Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases., Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Comorbidity is a debated prognosticator in lung cancer. Results are conflicting, and the variety in study designs and inclusion criteria hampers direct comparison of available studies. So far, methods for generation of data on lung cancer comorbidity have attracted little attention. We evaluated whether self-reported comorbidity and register-based comorbidity are of comparable quality., Methods: In a prospective study, we evaluated paired data sets on self-reported versus register-based comorbidity to detect whether any data asymmetry could be related to the data collection methods. We evaluated the Charlson comorbidity index and the simplified comorbidity score as predictors of overall survival (OS) in lung cancer to test whether our findings would affect outcome., Results: In a cohort of 336 patients with lung cancer and 125 patients in whom cancer was suspected but who were determined to be cancer-free, we demonstrated a significant underreporting of self-reported comorbidities compared with register-based comorbidities. Furthermore, we demonstrated that an association between comorbidity and OS can be detected only by using register-based data and only by the simplified comorbidity score (hazard rate = 1.6, 95% confidence interval: 1.0-2.5, p = 0.03). The results remained significant after adjustment for the relevant clinicopathological characteristics (hazard rate = 1.8, 95% confidence interval: 1.1-3.3, p = 0.028). An association between comorbidity and OS could not be detected by using either the self-reported data or the Charlson comorbidity index., Conclusions: In this cohort of patients in whom cancer was suspected, comorbidity estimations varied depending on the data collection method used; similarly, the data collection method could affect the association between comorbidity and OS., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Programmed death ligand 1 (PD-L1) expression may predict response to anti-programmed death 1 (anti-PD-1) or anti-PD-L1 treatment. There is limited information on changes in PD-L1 expression over time in patients with non-small cell lung cancer (NSCLC)., Patients and Methods: Eligible patients with NSCLC who received surgery or underwent biopsy at Samsung Medical Center, Seoul, Republic of Korea, and Aarhus University Hospital, Aarhus, Denmark, between February 2004 and April 2012 were included. PD-L1 expression in paired tumor tissue samples from the same patients at different dates and lesions was measured using a laboratory-developed prototype immunohistochemistry assay (22C3 antibody). PD-L1 positivity was defined as tumor cell membrane positivity in ≥ 1% of tumor cells (proportion score). Concordance of PD-L1 expression was analyzed by treating proportion score as categoric or continuous variables., Results: Ninety-one patients were included in the analysis. The median interval between the 2 tumor collection dates was 20 months, with 91% of paired samples collected > 3 months apart. The concordance rate for PD-L1 classification between paired samples was 67% (95% confidence interval, 57%-77%). When treating the immunohistochemistry proportional score as a continuous variable, a significant correlation of PD-L1 expression was observed between the paired samples (Pearson correlation coefficient, 0.61; P < .001)., Conclusion: There are good correlations of PD-L1 expression from paired NSCLC samples. For patients whose PD-L1 status is negative, it may be valuable to obtain additional tissue samples for retesting PD-L1 expression when anti-PD-1 immunotherapy is considered., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial., Methods: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC., Results: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events., Conclusions: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study)., (Copyright © 2017 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: Exosomes have been suggested as promising biomarkers in NSCLC because they contain proteins from their originating cells and are readily available in plasma. In this study, we explored the potential of exosome protein profiling in diagnosing lung cancers of all stages and various histological subtypes in patients., Methods: Plasma was isolated from 581 patients (431 with lung cancer and 150 controls). The extracellular vesicle array was used to phenotype exosomes. The extracellular vesicle array contained 49 antibodies for capturing exosomes. Subsequently, a cocktail of biotin-conjugated CD9, CD81, and CD63 antibodies was used to detect and visualize captured exosomes. Multimarker models were made by combining two or more markers. The optimal multimarker model was evaluated by area under the curve (AUC) and random forests analysis., Results: The markers CD151, CD171, and tetraspanin 8 were the strongest separators of patients with cancer of all histological subtypes versus patients without cancer (CD151: AUC = 0.68, p = 0.0002; CD171: AUC = 0.60, p = 0.0002; and TSPAN8: AUC = 0.60, p = 0.0002). The multimarker models with the largest AUC in the cohort of patients with all lung cancer histological subtypes and in the cohort of patients with adenocarcinoma only covered 10 markers (all cancer: AUC = 0.74 [95% confidence interval: 0.70-0.80]; adenocarcinoma only: AUC = 0.76 [95% confidence interval: 0.70-0.83]). In squamous cell cancer and SCLC, multimarker models did not exceed CD151 as an individual marker in separating patients with cancer from controls., Conclusion: We have demonstrated exosome protein profiling to be a promising diagnostic tool in lung cancer independently of stage and histological subtype. Multimarker models could make a fair separation of patients, demonstrating the perspectives of exosome protein profiling as a biomarker., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The Lungscape project was designed to address the impact of clinical, pathological, and molecular characteristics on outcome in resected non-small- cell lung cancer (NSCLC)., Materials and Methods: A decentralized biobank with fully annotated tissue samples was established. Selection criteria for participating centers included sufficient number of cases, tissue microarray building capability, and documented ethical approval. Patient selection was based on availability of comprehensive clinical data, radical resection between 2003 and 2009 with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue., Results: Fifteen centers contributed 2449 cases. The 5-year overall survival (OS) was 69.6% and 63.6% for stages IA and IB, 51.6% and 47.7% for stages IIA and IIB, and 29.0% and 13.0% for stages IIIA and IIIB, respectively (p < 0.001). Median and 5-year relapse-free survival (RFS) were 52.8 months and 47.3%, respectively. Distant relapse was recorded for 44.4%, local for 26.0%, and both for 16.9% of patients. Based on multivariate analysis for the OS, RFS, and time to relapse, the factors significantly associated with all of them are performance status and pathological stage., Conclusion: The aim of this report is to present the results from Lungscape, the first large series reporting on NSCLC surgical outcome measured not only by OS but also by RFS and time to relapse and including multivariate analysis by significant clinical and pathological prognostic parameters. As tissue from all patients is preserved locally and is available for detailed molecular investigations, Lungscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome after radical resection, besides providing an overview of the molecular landscape of stage I to III NSCLC.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Patients with non-small cell lung cancer with a sensitizing mutation in the epidermal growth factor receptor (EGFR) are likely to respond to treatment with an EGFR inhibitor. In some patients, residual tumor tissue can be visualized for several years without any signs of progression., Methods: Two patients with pathologically verified adenocarcinoma of the lung and multiple bone metastases were monitored after start of treatment with erlotinib by examining clinical parameters and imaging of lung tumors and bone metastases. Pretreatment biopsies and blood samples were examined for the presence of EGFR mutations, and lobectomy was performed according to standard procedures after 10 months of treatment in one patient and 30 months in the other., Results: Both patients responded to treatment with erlotinib and displayed a mutated EGFR. At the time of surgery, tumor was still visible in the lungs of both patients, but cancer cells could not be identified in the resected lung tumor tissue. In one patient, blood samples were available and the EGFR mutation was detected in the circulating DNA in the pretreatment blood sample but was no longer detectable 4 weeks after start of treatment and could not be detected in any of the following 12 blood samples., Conclusions: Treatment with erlotinib may induce complete response in patients with metastatic non-small cell lung cancer. It remains to be shown whether treatment with erlotinib can be discontinued in such patients. The disappearance of EGFR mutations in the DNA of the blood sample early in treatment might be used as an indicator of response to erlotinib.

Introduction: Drugs directed toward the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva®) and gefitinib (Iressa®), are used for the treatment of patients with advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. However, whether erlotinib actually enters into brain metastases has not been adequately elucidated. In this study, we investigated the accumulation of [¹¹C]-erlotinib by positron emission tomography (PET) combined with computed tomography (CT) and magnetic resonance imaging (MRI)., Methods: A 32-year-old patient with NSCLC and multiple brain metastases was treated with first-line erlotinib. EGFR mutations were determined by analyzing a fine-needle lung tumor biopsy taken before the treatment. A PET/CT of the brain with [¹¹C]-erlotinib was performed during treatment, and a MRI of the head and a CT of the chest were performed pre- and posttreatment., Results: The primary lung tumor displayed an erlotinib-sensitizing exon 19 deletion in the EGFR gene, and [¹¹C]-erlotinib PET/CT showed accumulation in the brain metastases. Posttreatment MRI and CT demonstrated regression of both brain metastases and primary lung tumor., Conclusion: Our data demonstrated that erlotinib accumulated in brain metastases in a NSCLC patient who responded to the treatment.

Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU). TS mRNA and protein levels in colorectal tumours are among the most important determinants for tumour response to 5-FU. TS mRNA levels in blood leukocytes may give information on pharmacokinetic and pharmacodynamic actions of 5-FU on TS as it has previously been shown that inhibition of TS levels by 5-FU in bone marrow leukocytes resembles the degree of TS inhibition in colorectal tumours. The aim of this study was to develop a quantitative high-throughput RT-PCR assay for TS mRNA expression in blood leukocytes (CURT-PCR). Furthermore the TS mRNA levels in blood of patients with colorectal cancer and healthy controls was compared. TS mRNA levels in 17 patients with colorectal cancer did not differ from 20 matched controls whereas a group of 14 younger controls had significantly lower TS mRNA expression than patients and matched controls. In order to investigate the sensitivity of the assay towards cellular reactions such as proliferative stimuli, isolated blood leukocytes were stimulated with phytohemagglutinin both in mitogenic and non-mitogenic concentrations and an induction of TS mRNA expression was measured in both cases. TS activity and cellular proliferation also increased but only at mitogenic concentrations, suggesting that TS mRNA expression is an early leukocyte activation marker. This new CURT-PCR assay may allow improved studies of functional kinetics of drugs with impact upon TS. Further studies are required to establish the possible clinical benefit of TS mRNA measurements in blood leukocytes.