Odd Terje Brustugun

• Sexton-Oates, Alexandra; Mathian, Émilie; Candeli, Noah; Lim, Yuliya; Voegele, Catherine & Genova, Alex Di [Vis alle 75 forfattere av denne artikkelen] (2026). Deep molecular profiling of lung neuroendocrine tumours and supra-carcinoids. Molecular Cancer. 25. doi: 10.1186/s12943-026-02721-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Lung neuroendocrine tumours (NETs, also known as carcinoids) are rapidly rising in incidence worldwide but have unknown aetiology and limited therapeutic options beyond surgery. The current WHO classification, based on mitotic count and presence or absence of necrosis, divides lung NETs into grade-1 typical, and grade-2 atypical tumours. This dichotomous classification however does not account for recently described molecular entities nor is it sufficient for clinical management. Methods Here we conducted integrative multi‐omic analyses on over 300 lung NETs including whole‐genome sequencing, transcriptome profiling, and DNA methylation arrays, followed by archetype analysis, to identify and characterise molecular groups. We further investigated molecular groups using spatial RNA sequencing and proteomics, and deep learning analysis of whole slide images. Results The integration of multi-omic data provided definitive proof of the existence of four strikingly different molecular groups that vary in patient characteristics, genomic and transcriptomic profiles, microenvironment, and morphology. Among these, we identified a new molecular group, enriched for highly aggressive supra‐carcinoids that displayed an immune‐rich microenvironment linked to tumour-macrophage crosstalk. We uncovered an undifferentiated cell population within supra-carcinoids and show the transcriptomic similarities between supra-carcinoids and the recently identified atypical small cell lung cancer tumours, further demonstrating their molecular link to high-grade lung neuroendocrine carcinomas. Multi-regional genomic analyses identified distinct evolutionary trajectories, suggesting that molecular groups are determined early in tumourigenesis by genomic events, and that transitions between groups, though infrequent, are possible for supra-carcinoids. Deep learning models accurately identified these groups based on morphology alone, outperforming current histological criteria. Together with the validation of a panel of immunohistochemistry markers, we demonstrated that these molecular groups can be accurately identified based on morphological features, facilitating their future implementation in the clinical setting. Our proposed morpho-molecular classification highlights potential group-specific therapeutic opportunities, with differences in expression to DLL3, EGFR, FGFR and TERT inhibitor targets. Conclusions Overall, our findings unify previously proposed molecular classifications and refine the lung cancer map by revealing novel tumour phenotypes with potential implications for prognosis and therapeutic management.

• Cáceres-Verschae, Albano; Hååg, Petra; Joelsson, Sofia; Hydbring, Per; Franzén, Bo & Végvári, Ákos [Vis alle 16 forfattere av denne artikkelen] (2026). Profiling of Extracellular Vesicles of Non-Small Cell Lung Cancer Reveals Proteins Associated With Osimertinib Resistance. Journal of Extracellular Vesicles. 15(1). doi: 10.1002/jev2.70219. Fulltekst i vitenarkiv
• Stensland, Elin Marie; Stensgaard, Simone; Eide, Inger Johanne; Nilssen, Yngvar; Horndalsveen, Henrik & Cicenas, Saulius [Vis alle 11 forfattere av denne artikkelen] (2026). Upfront treatment with osimertinib in lung cancer patients with and without active brain metastases, and the role of ctDNA as a biomarker; a phase II clinical trial (the FIOL study). Lung Cancer. ISSN 0169-5002. 214, s. 1–10. doi: 10.1016/j.lungcan.2026.109338. Fulltekst i vitenarkiv
• Riess, J. W.; Yu, H. A.; Le, X.; Langen, A. J. de; Cho, B. C. & Piotrowska, Z. [Vis alle 21 forfattere av denne artikkelen] (2026). Osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC after progression on first-line osimertinib: ORCHARD. Annals of Oncology. ISSN 0923-7534. doi: 10.1016/j.annonc.2026.02.014. Fulltekst i vitenarkiv
• Eide, Inger Johanne Zwicky; Dyrbekk, Anne Pernille Harlem; Bisha, Ina; Haberichter, Thomas; Lakis, Sotirios & Chan, Jessica [Vis alle 10 forfattere av denne artikkelen] (2026). CD73 expression as a resistance mechanism in advanced EGFR-mutated non-small cell lung cancer. Frontiers in Oncology. 16. doi: 10.3389/fonc.2026.1755595. Fulltekst i vitenarkiv Vis sammendrag

  Introduction The ectoenzyme CD73 induces an immune-evasive tumor microenvironment and has been proposed to be modulated by EGFR-TKI treatment. In this exploratory study, we analyzed CD73 expression and related immune markers during sequenced EGFR-TKI treatment, including osimertinib, to identify potential biomarkers for CD73-based therapeutic opportunities in EGFR-resistant tumors. Methods Tumor specimens from patients included in a clinical trial (NCT02504346) evaluating osimertinib in EGFR -mutated EGFR-TKI pretreated NSCLC patients were analyzed. Expression of CD73, CD39, HLA-E and NKp46 were mapped in tumor tissue from diagnosis, after progression on early-generation EGFR-TKIs and after progression on osimertinib given as next-line EGFR-therapy. Results Samples from 51 patients were evaluable. Upon progression after first line EGFR-TKI, 25 patients had T790M-postive disease, 18 cases were negative and 8 had unknown T790M-status. CD73 and HLA-E were significantly higher expressed in epithelium, while CD39 and NKp46 showed higher expression in the stroma of the tumors. There was no significant difference in expression pattern for any marker from diagnosis to progression after first line EGFR-treatment, but tumors with non-T790M-resistance to first- or second-generation TKIs had a significantly higher level of CD73 than T790M-positive tumors before commencing osimertinib. Paired tissue samples pre- and post-osimertinib were available in only four cases, of which three cases showed increased expression of HLA-E and NKp46 after osimertinib, while 2 cases had an increase in CD73 expression. Conclusion We demonstrated differential expression patterns among the immune markers and higher levels of CD73 in cases with non-T790M-resistance to EGFR-TKIs. Although a limited number of cases were included in these analyses, the results might point to a potential role of immune markers inducing an immunosuppressive environment and thereby contribute to development of resistance to TKIs, which in turn could have future therapeutic implications.

• Skrede, Ole-Johan; Pradhan, Manohar; Isaksen, Maria; Hveem, Tarjei Sveinsgjerd; Vlatkovic, Ljiljana & Nesbakken, Arild [Vis alle 23 forfattere av denne artikkelen] (2026). Generalisation of automatic tumour segmentation in histopathological whole-slide images across multiple cancer types. NPJ precision oncology. 10. doi: 10.1038/s41698-026-01311-6. Fulltekst i vitenarkiv Vis sammendrag

  Deep learning is expected to aid pathologists in tasks such as tumour segmentation. We developed a general tumour segmentation model for histopathological images and examined its performance in different cancer types. The model was developed using over 20,000 whole-slide images from over 4000 patients with colorectal, endometrial, lung, or prostate carcinoma. Performance was validated in pre-planned analyses on external cohorts with over 3000 patients across six cancer types. Exploratory analyses included over 1500 additional patients from The Cancer Genome Atlas. Average Dice coefficient was over 80% in all validation cohorts with en bloc resection specimens and in The Cancer Genome Atlas cohorts. No performance loss was observed when comparing the general model with single-cancer models specialised in cancer types from the development set. In conclusion, extensive and rigorous evaluations demonstrate that generic tumour segmentation by a single model is possible across cancer types, patient populations, sample preparations and slide scanners.

• Kalsnes, Joakim; Isaksen, Maria; Julbø, Frida Marie Ihle; Pradhan, Manohar; Kleppe, Andreas & Raedt, Sepp de [Vis alle 33 forfattere av denne artikkelen] (2026). Applicability of mitotic figure counting by deep learning: a development and pan‐cancer validation study. FEBS Open Bio. 16(7), s. 1259–1270. doi: 10.1002/2211-5463.70210. Fulltekst i vitenarkiv Vis sammendrag

  Mitotic figure counting is an established measure of cell proliferation that is included in grading systems. We developed a deep learning method for mitotic figure counting and evaluated its prognostic impact in multiple external validation datasets. The deep learning method was trained in whole slide images of tissue sections stained with haematoxylin and eosin from a publicly available breast cancer dataset where mitotic figures have been annotated by expert pathologists. The final model was externally validated according to a protocol with predefined analyses of 14 571 patient samples from 13 patient cohorts from seven different cancer types. The predefined primary analysis was univariable Cox survival analysis of the number of mitotic figures detected per mm 2 . Automatic mitotic figure counting correlated well with known proliferation rates, and patients with more mitotic figures per mm 2 had significantly worse patient outcome in all the studied cancer types except colorectal cancer. This study demonstrates the practical potential of automated, deep learning‐based mitotic figure counting, both by automating pathology work and by suggesting expanded use in more cancer types, such as prostate cancer.

• Solberg, Steinar Kristian; Slørdahl, Kathinka Schmidt; Aanerud, Marianne; Brustugun, Odd Terje; Grønberg, Bjørn Henning & Helbekkmo, Nina [Vis alle 8 forfattere av denne artikkelen] (2025). Too much or too little? The trajectory of systemic anti-cancer treatment throughout the last year of life of lung cancer patients in Norway. BJC Reports. 3, s. 1–8. doi: 10.1038/s44276-025-00183-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background The use of systemic anti-cancer treatment (SACT) at the end of life (EOL) is controversial. The evidence and detailed description of the dynamics of its use are deficient, especially after the introduction of targeted therapies and immunotherapy. Methods Clinical information about lung cancer patients dying in the years 2020–2023 was extracted from the Cancer Registry of Norway. Available data on intravenous and oral SACT enabled the calculation of the proportion of patients who received SACT each of the 360 days before death. Results A total of 8953 patients were eligible for this study. At day 30, 7, and 1 before death, 8.9%, 1.3%, and 0.4% respectively, received SACT. The reduction was mainly caused by reduced use of chemotherapy and immunotherapy closer to death. Independent predictors for receiving SACT at day 30 before death were young age, male sex, small-cell lung cancer, short time from diagnosis to death, and good performance status. Conclusion The presented low use of SACT at EOL has been achieved in a population where good survival has been documented. Patients with poor performance status and older age received less SACT than patients with good performance status and younger age.

• Hektoen, H. H.; Tsuruda, K. M.; Brustugun, O. T.; Neumann, K. & Andreassen, B. K. (2025). Real-world comparison of pembrolizumab alone and combined with chemotherapy in metastatic lung adenocarcinoma patients with PD-L1 expression ≥50%. ESMO Open. 10(5), s. 1–9. doi: 10.1016/j.esmoop.2025.105073. Fulltekst i vitenarkiv Vis sammendrag

  Objectives The frontline treatment of metastatic lung adenocarcinoma with high Programmed death-ligand 1 (PD-L1) expression (≥50%) includes immune checkpoint inhibitors (ICIs) either as monotherapy or combined with chemotherapy. The added benefit of chemotherapy in this context lacks direct comparison in head-to-head trials. We aimed to compare these two ICI treatment modalities both overall and within relevant patient subgroups in a real-world setting. Materials and methods This retrospective, nationwide study included 410 individuals diagnosed in Norway during 2017 to 2021 with stage IV non-small-cell lung adenocarcinoma, PD-L1 expression ≥50%, and treated first line with the ICI pembrolizumab, either as monotherapy (n = 317) or in combination with platinum-based chemotherapy (n = 93). We analyzed early (6-month) and overall (3-year) risk of death after treatment initiation using Cox regression, adjusted for and stratified by sex, age, stage, PD-L1 expression, performance status, and education. Results Patients treated with combination therapy had a higher median overall survival compared with monotherapy (22.6 months versus 14.2 months), and reduced risk of overall death, although not statistically significant after adjustment [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.54-1.00]. However, the risk of early death was significantly lower in patients receiving combination therapy, even after adjustment (HR 0.41, 95% CI 0.23-0.76). Across most subgroups, patients receiving combination therapy had comparable or superior survival outcomes relative to those receiving monotherapy. Particularly noteworthy were the observed benefits from combination therapy over monotherapy among females, individuals with stage IVB disease, and those with PD-L1 expression exceeding 75%. Conclusion Our real-world study demonstrates that combination therapy with ICI and chemotherapy provides superior early survival benefits over monotherapy in PD-L1-high patients. Additionally, certain subgroups showed enhanced overall survival. These findings challenge current treatment practices and underscore the need for further validation to optimize patient selection for monotherapy versus combination therapy, in particular to reassess the role of PD-L1 in treatment decisions.

• Nyen, Johanne Elise; Booth, Anja Ødegård; Husby, Øyvind; Bugge, Christoffer; Engebretsen, Ingrid & Oteiza, Francisco [Vis alle 10 forfattere av denne artikkelen] (2025). Targeted treatment and survival in advanced non-squamous non-small cell lung cancer patients – a nationwide and longitudinal study. Frontiers in Oncology. 15. doi: 10.3389/fonc.2025.1506041. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: We aimed to describe treatment patterns, time on treatment (ToT) and overall survival (OS) for patients with advanced non-squamous, EGFR+, ALK+ and ROS1+ NSCLC in Norway. Materials and methods: We extracted data on patients ≥ 18 years diagnosed with advanced non-squamous NSCLC between 2015 and 2022 from the Cancer Registry of Norway and data on cancer drug therapy from the Norwegian Patient Registry and the Norwegian Prescribed Drug Registry. ToT was measured from the date treatment was collected or administered until the last dispensing was depleted or last hospital drug administration. OS was measured from date of diagnosis until death. Results: In total, 5,279 patients were included, of whom 449 EGFR+, 131 ALK+ and 38 ROS1+. 75% of EGFR+ patients, 88% of ALK+ patients, and 58% of ROS1+ patients received at least one systemic treatment within the first three months after diagnosis. Median follow-up was 13, 19, and 4 months for EGFR+, ALK+, and ROS1+, respectively. The median ToT in first line (1L) for EGFR+ patients was 11 months for osimertinib (CI: 10.1-NA) and 9 months (CI: 8.2-11.2) for afatinib, dacomitinib, erlotinib and gefitinib. For ALK+ patients, median ToT in 1L was 20 months (CI: 14.7-23.7for alectinib, 11 months (CI: 4.7-NA) for brigatinib, and 7 months (CI: 2.9-21.6) for crizotinib. For the five ROS1+ patients treated with crizotinib in 1L, median ToT was 5 months (CI: 2.4-NA). For all patients with a targetable genomic alteration, unadjusted median OS was higher (p-value = 0.025) for patients diagnosed in 2020-2022 (median OS: 23 months, CI: 19.5-NA) compared to patients diagnosed in 2015-2019 (median: 19 months, CI: 16.5-21.2). Conclusions: ToT for targeted therapies was shorter than progression-free survival in clinical trials. However, patients eligible for targeted therapy still had a survival improvement during the study period.

• Grønberg, Bjørn Henning; Killingberg, Kristin Toftaker; Fløtten, Øystein; Bjaanæs, Maria Moksnes; Brustugun, Odd Terje & Madebo, Tesfaye [Vis alle 19 forfattere av denne artikkelen] (2025). High-Dose Versus Standard-Dose Twice-Daily Thoracic Radiotherapy in Limited-Stage SCLC: Final Survival Data, Long-Term Toxicity, and Relapse Patterns in a Randomized, Open-Label, Phase II Trial. Journal of Thoracic Oncology. ISSN 1556-0864. 20(8), s. 1108–1119. doi: 10.1016/j.jtho.2025.04.007. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Chemoradiotherapy is standard treatment for limited-stage SCLC. However, most patients relapse and there is a need for better treatment. We investigated whether twice-daily thoracic radiotherapy (TRT) of 60 Gy/40 fractions improves survival compared with the established schedule of 45 Gy/30 fractions. Here, we report final survival data and long-term toxicity. Methods Randomized, open-label, phase II trial. Eligible patients had performance status of 0 to 2, were above or equal to 18 years of age, underwent 18F-fluorodeoxyglucose positron emission tomography computed tomography and brain magnetic resonance imaging for staging, and were randomized 1:1 to TRT of 60 or 45 Gy. Patients were to receive four courses of platinum and etoposide chemotherapy, and responders were offered prophylactic cranial irradiation. Results A total of 170 patients were randomized (60 Gy: n = 89, 45 Gy: n = 81). Median age was 65 years, 31% above or equal to 70 years, 57% women, 89% had performance status of 0 to 1, 83% stage III disease, median planning target volume was 305 cm3, and 67% were treated with three-dimensional conformal radiotherapy. Median overall survival in the 60 Gy group was significantly longer (43.5 versus 22.5 mo, hazard ratio 0.68, 95% confidence interval 0.48–0.98, p = 0.037). The 60 Gy group did not experience more acute grades 3 to 4 esophagitis (60 Gy: 21%, 45 Gy: 18%, p = 0.83) or pneumonitis (60 Gy: 3%, 45 Gy: 0%, p = 0.39). Two patients, both in the 60 Gy group, developed esophageal strictures, whereas 11 patients (60 Gy: n = 5, 45 Gy: n = 6) developed severe long-term eating and swallowing dysfunction. Conclusion Twice-daily TRT of 60 Gy/40 fractions was well tolerated and prolonged survival compared with 45 Gy/30 fractions in patients with limited-stage SCLC.

• Nymoen, Hanne Marte Gjertsen; Alver, Tine Norman; Horndalsveen, Henrik; Eide, Hanne Astrid; Bjaanæs, Maria Moksnes & Brustugun, Odd Terje [Vis alle 9 forfattere av denne artikkelen] (2024). Thoracic radiation in combination with erlotinib—results from a phase 2 randomized trial. Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1412716. Fulltekst i vitenarkiv Vis sammendrag

  Background: Radiotherapy (RT) can be used to reduce symptoms and maintain open airways for patients with non-small cell lung cancer when systemic treatment is not sufficient. For some patients, tumor control is not achieved due to radioresistance. Concurrent inhibition of epidermal growth factor receptors has been proposed as a strategy to overcome radioresistance but may increase toxicity. We performed a randomized trial to assess the efficacy, tolerance, and quality of life of concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer. Methods: Patients were randomized 1:1 to RT alone (arm A) or in combination with erlotinib (arm B). A computed tomography (CT) scan at baseline and one at 4–12 weeks after inclusion was used to evaluate treatment response. Adverse events were registered during treatment and the subsequent 30 days. Health-related quality-of-life questionnaires were completed by the patients at baseline, weeks 2, 6, and 20. Results: A total of 114 patients were included. Of the 74 patients with CT scans available for evaluation of treatment effect, there were no significant differences in tumor size reduction between the two groups: median 14.5% reduction in the control arm A and 17.0% in the erlotinib arm B (p = 0.68). Overall survival was not significantly different between the two treatment arms: 7.0 and 7.8 months in arm A and arm B, respectively (log-rank p = 0.32). There was no significant increase in adverse events in the experimental arm, other than what is expected from erlotinib treatment alone. Overall, patients reported similar quality of life in both treatment arms. Conclusion: Concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer was well tolerated but did not improve the efficacy of the RT.

• Nilssen, Yngvar; Brustugun, Odd Terje; Fjellbirkeland, Lars; Helland, Åslaug; Møller, Bjørn & Wahl, Sissel Gyrid Freim [Vis alle 7 forfattere av denne artikkelen] (2024). Distribution and characteristics of malignant tumours by lung lobe. BMC Pulmonary Medicine. 24(1). doi: 10.1186/s12890-024-02918-w. Fulltekst i vitenarkiv Vis sammendrag

  Background The main focus on the characteristics of malignant lung tumours has been the size, position within the lobe, and infiltration into neighbouring structures. The aim of this study was to investigate the distribution and characteristics of malignant tumours between the lung lobes and whether the diagnosis, treatment, and outcome differed based on location. Methods This study is based on 10,849 lung cancer patients diagnosed in 2018–2022 with complete data on the location and characteristics of the tumours. The proportions of tumours in each lobe divided by its volume were termed the relative proportion. Results The right upper lobe comprised 31.2% of the tumours and 17.6% of the lung volume. The relative proportion of 1.77 was higher than in the other lobes (p < 0.001). The right middle lobe had a relative proportion of 0.64 but the highest proportion of neuroendocrine tumours (26.1% vs. 15.3 on average). Surgical resection was more often performed in patients with tumours in the lower lobes, and curative radiotherapy was more often performed in the upper lobes. After adjusting for age, sex, stage, and histology, the location of the tumour was found to be a significant independent predictor for resection but not for survival. Conclusion The main finding of the right upper lobe as a site of predilection for lung cancer is similar to tuberculosis and pneumoconiosis. This may be explained that most of the inhaled air, containing bacilli, inorganic particles or tobacco smoke goes to the upper and right parts of the lung.

• Hektoen, Helga; Tsuruda, Kaitlyn; Fjellbirkeland, Lars; Nilssen, Yngvar; Brustugun, Odd Terje & Kulle, Bettina (2024). Real-world evidence for pembrolizumab in non-small cell lung cancer: a nationwide cohort study. British Journal of Cancer. ISSN 0007-0920. 132, s. 93-102–93-102. doi: 10.1038/s41416-024-02895-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Based on favourable results from clinical trials, immune checkpoint inhibitors (ICI) have become the standard first line (1 L) systemic anticancer treatment (SACT) for advanced stage non-small cell lung cancer (NSCLC) without targetable mutations. We evaluate whether these results are generalizable to everyday clinical practice and compare overall survival (OS) of patients treated with ICI to a historical cohort of patients treated with chemotherapy and results from clinical trials. Methods Our study comprised all advanced NSCLC patients initiating SACT in 2012–21 in Norway. Clinical characteristics and treatment information was retrieved from Norwegian Health Registries. Results Survival for all 8416 advanced NSCLC patients treated with SACT increased concurrently with the gradual implementation of ICIs. Median OS of patients treated with 1 L pembrolizumab after 2017 was better (mono-/combination therapy: 13.8/12.8 months) than for patients treated with chemotherapy before 2017 (8.0 months). Although median OS for patients treated with pembrolizumab was lower in clinical practice than clinical trials (Keynote-024/189: 26.3/22.0 months), the survival benefit relative to chemotherapy was similar. Conclusion Our nationwide study demonstrated a survival benefit over conventional chemotherapy of a similar magnitude as observed in clinical trials and confirms the effectiveness of pembrolizumab in routine clinical practice.

• Nilssen, Yngvar; Brustugun, Odd Terje; Fjellbirkeland, Lars; Grønberg, Bjørn Henning; Haram, Per Magnus & Helbekkmo, Nina [Vis alle 10 forfattere av denne artikkelen] (2024). Small Cell Lung Cancer in Norway: Patterns of Care by Health Region and Survival Trends. Clinical Lung Cancer. ISSN 1525-7304. 25(5), s. e221–e228.e3. doi: 10.1016/j.cllc.2024.04.002. Fulltekst i vitenarkiv Vis sammendrag

  Introduction/Background: There has been a marked survival improvement for patients with non–small-cell lung cancer. We describe the national trends in characteristics and survival, and geographical differences in diagnostic workup, treatment, and survival for patients with small-cell lung cancer (SCLC). Materials and Methods: Patients registered with SCLC at the Cancer Registry of Norway in 2002 to 2022 were included. Trends in overall survival were estimated for all SCLC patients, patients with limited stage SCLC, patients undergoing surgery, and by health region. Adjusting for case-mix, a multivariable Cox regression was performed examining the association between health region and death. Results: The study included 8374 patients. The stage distribution remained unchanged during the study period. The 5-year overall survival increased from 7.7% to 22.8% for patients with limited stage. The use of multidisciplinary team meetings varied from 62.5% to 85.7%, and the use of positron emission tomography-computer tomography varied from 70.4% to 86.2% between the health regions. Treatment patterns differed markedly between the health regions, with the proportion dying without any registered treatment ranging from 1.2% to 10.9%. For limited stage patients in 2018 to 2022, the median overall survival ranged from 16.5 to 25.5 months across health regions, and the 5-year overall survival ranged from 18.7% to 28.7% (P = .019). Conclusion: The survival for patients with SCLC remains poor. The use of diagnostic procedures, treatment modalities, and survival differed between regions, warranting investigations to further explore the reasons.

• Lærum, Dan; Strand, Trond-Eirik; Brustugun, Odd Terje; Gallefoss, Frode; Falk, Ragnhild Sørum & Durheim, Michael Thomas [Vis alle 7 forfattere av denne artikkelen] (2024). Evaluation of sex inequity in lung-cancer-specific survival. Acta Oncologica. ISSN 0284-186X. 63(1), s. 343–350. doi: 10.2340/1651-226X.2024.27572. Fulltekst i vitenarkiv Vis sammendrag

  Background: Whether sex is an independent prognostic factor in lung cancer survival is the subject of ongoing debate. Both large national registries and single hospital studies have shown conflicting findings. In this study, we explore the impact of sex on lung-cancer-specific survival in an unselected population that is well-characterized with respect to stage and other covariates. Material and methods: All patients diagnosed with lung cancer at a single hospital serving a whole and defined region in Southern Norway during the 10 years 2007–2016 were included. Follow-up data were available for at least 56 months for all patients. Analyses were adjusted for stage, treatment, performance status, smoking, age, histology, epidermal growth factor receptor/anaplastic lymphoma kinase/immunotherapy treatment and period. Differences in lung-cancer-specific survival by sex were explored using restricted mean survival times (RMST). Results: Of the 1,261 patients diagnosed with lung cancer, 596 (47%) were females and 665 (53%) males, with mean ages of 68.5 and 69.5 years, respectively. The observed 5-year lung-cancer-specific survival rate was 27.4% (95% CI 23.7, 31.2) in females and 21.4% (95% CI 18.2, 24.8) in males. However, after adjustment for covariates, no significant differences by sex were observed. The 5-year RMST was 0.9 months shorter (95% CI −2.1, 0.31, p = 0.26) in males compared to females. Interpretation: In this cohort, sex was not associated with a difference in lung-cancer-specific survival after adjusting for clinical and biological factors. Imbalance in stage at diagnosis was the main contributor to the observed difference in lung-cancer-specific survival by sex.

• Dyrbekk, Anne Pernille Harlem; Warsam, Abdirashid Ali; Suhrke, Pål; Ludahl, Marianne Odnakk; Nermin, Zecic & Moe, Joakim Oliu [Vis alle 8 forfattere av denne artikkelen] (2024). Evaluation of NTRK expression and fusions in a large cohort of early-stage lung cancer. Clinical and Experimental Medicine. ISSN 1591-8890. 24(1). doi: 10.1007/s10238-023-01273-0. Fulltekst i vitenarkiv Vis sammendrag

  Tropomyosin receptor kinases (TRK) are attractive targets for cancer therapy. As TRK-inhibitors are approved for all solid cancers with detectable fusions involving the Neurotrophic tyrosine receptor kinase (NTRK)-genes, there has been an increased interest in optimizing testing regimes. In this project, we wanted to find the prevalence of NTRK fusions in a cohort of various histopathological types of early-stage lung cancer in Norway and to investigate the association between TRK protein expression and specific histopathological types, including their molecular and epidemiological characteristics. We used immunohistochemistry (IHC) as a screening tool for TRK expression, and next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) as confirmatory tests for underlying NTRK-fusion. Among 940 cases, 43 (4.6%) had positive TRK IHC, but in none of these could a NTRK fusion be confirmed by NGS or FISH. IHC-positive cases showed various staining intensities and patterns including cytoplasmatic or nuclear staining. IHC-positivity was more common in squamous cell carcinoma (LUSC) (10.3%) and adenoid cystic carcinoma (40.0%), where the majority showed heterogeneous staining intensity. In comparison, only 1.1% of the adenocarcinomas were positive. IHC-positivity was also more common in men, but this association could be explained by the dominance of LUSC in TRK IHC-positive cases. Protein expression was not associated with differences in time to relapse or overall survival. Our study indicates that NTRK fusion is rare in early-stage lung cancer. Due to the high level of false positive cases with IHC, Pan-TRK IHC is less suited as a screening tool for NTRK-fusions in LUSC and adenoid cystic carcinoma.

• Mathian, E.; Drouet, Y.; Sexton-Oates, A.; Papotti, M.G.; Pelosi, G. & Vignaud, J.-M. [Vis alle 47 forfattere av denne artikkelen] (2024). Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project. ESMO Open. 9(6), s. 1–12. doi: 10.1016/j.esmoop.2024.103591. Fulltekst i vitenarkiv Vis sammendrag

  Background Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. Patients and methods Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. Results The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. Conclusions This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

• Nilssen, Yngvar; Solberg, Steinar; Brustugun, Odd Terje; Møller, Bjørn; Sundset, Arve & Wahl, Sissel Gyrid Freim [Vis alle 7 forfattere av denne artikkelen] (2023). Tracheal cancer: a rare and deadly but potentially curable disease that also affects younger people. European Journal of Cardio-Thoracic Surgery. ISSN 1010-7940. 64(1). doi: 10.1093/ejcts/ezad244. Fulltekst i vitenarkiv Vis sammendrag

  OBJECTIVES The incidence of tracheal cancer is low, few clinicians get much experience and the awareness may be low. Recent data on the treatment and outcome are limited. The aim of the present study was to present updated, national data on the incidence, characteristics, treatment and outcome for patients with tracheal cancer. METHODS All tracheal cancers registered at the Cancer Registry of Norway in 2000–2020 were extracted. The patient and tumour characteristics age, sex, stage, histology and treatment modality (surgery and radiotherapy) were examined. Overall, median and relative survival were estimated. Cox regression models were used to identify independent prognostic factors. RESULTS The 77 patients diagnosed with tracheal cancer equals a crude incidence rate and an age-standardized incidence rate of 0.075 and 0.046 per 100,000 per year respectively. The mean age was 63.8 years (range: 26–94). The numerical preponderance of men (n = 41) is not statistically significant. Eighteen patients (23.4%) were diagnosed in the localized stage. The 5-year overall survival was 31.7% [95% confidence interval (CI): 21.0–42.9], and in those treated with surgical resection or curative radiotherapy, it was 53.7% (95% CI: 26.1–75.0) and 37.8% (95% CI: 18.8–56.7), respectively. Age, histological type and treatment modality were identified as independent prognostic factors. CONCLUSIONS Despite improved survival, the prognosis for patients with tracheal cancer is still poor. Few are diagnosed in the early stage and thus most are not eligible for curative treatment, mainly surgery. An increased awareness and diagnosis in the earlier stage is crucial.

• Dyrbekk, Anne Pernille Harlem; Warsam, Abdirashid Ali; Suhrke, Pål; Ludahl, Marianne Odnakk; Moe, Joakim Oliu & Eide, Inger Johanne [Vis alle 8 forfattere av denne artikkelen] (2023). “Evaluation of ROS1 expression and rearrangements in a large cohort of early-stage lung cancer”. Diagnostic Pathology. 18(1). doi: 10.1186/s13000-023-01357-1. Fulltekst i vitenarkiv Vis sammendrag

  Background ROS1 fusion is an infrequent, but attractive target for therapy in patients with metastatic non- small-cell lung cancer. In studies on mainly late-stage disease, the prevalence of ROS1 fusions is about 1–3%. In early-stage lung cancer ROS1 might also provide a fruitful target for neoadjuvant or adjuvant therapy. In the present study, we investigated the prevalence of ROS1 fusion in a Norwegian cohort of early-stage lung cancer. We also explored whether positive ROS1 immunohistochemical (IHC) stain was associated with certain mutations, clinical characteristics and outcomes. Methods The study was performed using biobank material from 921 lung cancer patients including 542 patients with adenocarcinoma surgically resected during 2006–2018. Initially, we screened the samples with two different IHC clones (D4D6 and SP384) targeting ROS1. All samples that showed more than weak or focal staining, as well as a subgroup of negative samples, were analyzed with ROS1 fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) with a comprehensive NGS DNA and RNA panel. Positive ROS1-fusion was defined as those samples positive in at least two of the three methods (IHC, FISH, NGS). Results Fifty cases were IHC positive. Of these, three samples were both NGS and FISH-positive and considered positive for ROS1 fusion. Two more samples were FISH positive only, and whilst IHC and NGS were negative. These were also negative with Reverse Transcription quantitative real time Polymerase Chain Reaction (RT-qPCR). The prevalence of ROS1 fusion in adenocarcinomas was 0.6%. All cases with ROS1 fusion had TP53 mutations. IHC-positivity was associated with adenocarcinoma. Among SP384-IHC positive cases we also found an association with never smoking status. There was no association between positive IHC and overall survival, time to relapse, age, stage, sex or pack-year of smoking. Conclusions ROS1 seems to be less frequent in early-stage disease than in advanced stages. IHC is a sensitive, but less specific method and the results need to be confirmed with another method like FISH or NGS.

• Eide, Inger Johanne; Nilssen, Yngvar; Stensland, Elin Marie & Brustugun, Odd Terje (2023). Real-World Data on EGFR and ALK Testing and TKI Usage in Norway—A Nation-Wide Population Study. Cancers. 15(5). doi: 10.3390/cancers15051505. Fulltekst i vitenarkiv Vis sammendrag

  Clinical studies have shown the efficacy of EGFR- and ALK-directed therapies in non-small cell lung cancer (NSCLC). Real-world data on, e.g., testing patterns, uptake, and duration of treatment are scarce. Reflex EGFR and ALK testing of non-squamous NSCLCs were implemented in Norwegian guidelines in 2010 and 2013, respectively. We present a complete national registry data on incidence, pathology procedures, and drug prescription in the period of 2013 to 2020. Test rates for both EGFR and ALK increased over time and were 85% and 89%, respectively, at the end of the study period, independent of age up to 85 years. The positivity rate for EGFR was higher among females and young patients, whereas no sex difference was observed for ALK. EGFR-treated patients were older than ALK-treated patients (71 vs. 63 years at start, p &lt; 0.001). Male ALK-treated patients were significantly younger than females at the start of treatment (58 vs. 65 years, p = 0.019). The time from the first dispensation to the last dispensation of TKI (as a surrogate for progression-free survival) was shorter for EGFR- than for ALK-TKI, and survival for both EGFR- and ALK-positive patients was substantially longer than for non-mutated patients. We found a high adherence to molecular testing guidelines, good concordance of mutation positivity and treatment, and the real-world replication of findings in clinical trials, indicating that the relevant patients are provided substantially life-prolonging therapy.

• Eide, Inger Johanne; Nilssen, Yngvar; Lund-Iversen, Marius & Brustugun, Odd Terje (2022). Factors affecting outcome in resected EGFR-mutated lung cancer. Acta Oncologica. ISSN 0284-186X. 61(6), s. 749–756. doi: 10.1080/0284186X.2022.2066984. Fulltekst i vitenarkiv
• Killingberg, Kristin Toftaker; Halvorsen, Tarje Onsøien; Fløtten, Øystein; Brustugun, Odd Terje; Langer, Seppo W. & Nyman, Jan [Vis alle 13 forfattere av denne artikkelen] (2022). Patient-reported health-related quality of life from a randomized phase II trial comparing standard-dose with high-dose twice daily thoracic radiotherapy in limited stage small-cell lung cancer. Lung Cancer. ISSN 0169-5002. 166, s. 49–57. doi: 10.1016/j.lungcan.2022.02.002. Fulltekst i vitenarkiv Vis sammendrag

  Objectives In a randomized phase II trial, twice daily (BID) thoracic radiotherapy (TRT) of 60 Gy/40 fractions improved survival compared with 45 Gy/30 fractions in limited stage small-cell lung cancer (LS SCLC). Notably, the higher dose did not cause more toxicity. Here we present health related quality of life (HRQoL) reported by the trial participants during the first 2 years. Materials and methods 170 patients were randomized 1:1 to TRT of 45 Gy or 60 Gy concurrently with cisplatin/etoposide chemotherapy. The 150 patients who commenced TRT and completed a minimum of one HRQoL-questionnaire were included in the present study. Patients reported HRQoL on the European Organization for Research and Treatment of Cancer Core 30 and Lung Cancer 13 Quality of Life Questionnaires. Questionnaires were completed weeks 0, 4 (before TRT), 8 (end of TRT), 12 (response evaluation after chemoradiotherapy) and 16 (end of prophylactic cranial irradiation), then every 10 weeks year one, and every 3 months year two. Primary HRQoL endpoints were dysphagia and dyspnea. A difference in mean score of ≥10 was defined as clinically significant. Results Maximum dysphagia was reported on week 8, with no significant difference between treatment arms (mean scores 45 Gy: 44.2, 60 Gy: 51.1). The 60 Gy arm had more dysphagia in the convalescence period, but dysphagia scores returned to baseline levels at week 16 in both arms. For dyspnea there were no significant changes, or differences between treatment arms, at any timepoint. There were no significant differences between treatment arms for any other HRQoL-scales. Conclusion TRT of 60 Gy did not cause significantly higher maximum dysphagia, though patients on the 60 Gy arm reported more dysphagia the first 8 weeks of convalescence. The higher dose was well tolerated and is an attractive alternative to current TRT schedules in LS SCLC.

• Alexeyenko, Andrey; Brustugun, Odd Terje; Eide, Inger Johanne; Gencheva, Radosveta; Kosibaty, Zeinab & Lai, Yi [Vis alle 14 forfattere av denne artikkelen] (2022). Plasma RNA profiling unveils transcriptional signatures associated with resistance to osimertinib in EGFR T790M positive non-small cell lung cancer patients. Translational Lung Cancer Research (TLCR). ISSN 2218-6751. 11(10), s. 2064–2078. doi: 10.21037/tlcr-22-236. Fulltekst i vitenarkiv Vis sammendrag

  Background: Targeted therapy with tyrosine kinases inhibitors (TKIs) against epidermal growth factor receptor (EGFR) is part of routine clinical practice for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. These patients eventually develop resistance, frequently accompanied by a gatekeeper mutation, T790M. Osimertinib is a third-generation EGFR TKI displaying potency to the T790M resistance mutation. Here we aimed to analyze if exosomal RNAs, isolated from longitudinally sampled plasma of osimertinib-treated EGFR T790M NSCLC patients, could provide biomarkers of acquired resistance to osimertinib. Methods: Plasma was collected at baseline and progression of disease from 20 patients treated with osimertinib in the multicenter phase II study TKI in Relapsed EGFR-mutated non-small cell lung cancer patients (TREM). Plasma was centrifuged at 16,000 g followed by exosomal RNA extraction using Qiagen exoRNeasy kit. RNA was subjected to transcriptomics analysis with Clariom D. Results: Transcriptome profiling revealed differential expression [log2(fold-change) >0.25, false discovery rate (FDR) P0.05] of 128 transcripts. We applied network enrichment analysis (NEA) at the pathway level in a large collection of functional gene sets. This overall enrichment analysis revealed alterations in pathways related to EGFR and PI3K as well as to syndecan and glypican pathways (NEA FDR 0.05 and NEA z-score exceeding 3 in at least one sample). Conclusions: Our study demonstrates a potential usability of plasma-derived exosomal RNAs to characterize molecular phenotypes of emerging osimertinib resistance. Furthermore, it highlights the involvement of multiple RNA species in shaping the transcriptome landscape of osimertinib-refractory NSCLC patients.

• Solberg, Steinar; Nilssen, Yngvar; Brustugun, Odd Terje; Haram, Per Magnus; Helland, Åslaug & Møller, Bjørn [Vis alle 9 forfattere av denne artikkelen] (2022). Concordance between clinical and pathology TNM-staging in lung cancer. Lung Cancer. ISSN 0169-5002. 171, s. 65–69. doi: 10.1016/j.lungcan.2022.07.014. Fulltekst i vitenarkiv Vis sammendrag

  Objectives - A prerequisite for utilizing the tumour, lymph-nodes, and metastases (TNM) for the staging of lung cancer patients is a high quality of the reported data on which the staging is based. The aim of this study was to investigate the concordance between the clinical, cTNM and the pathology, pTNM staging for lung cancer, version 8 as reported to the Cancer Registry of Norway (CRN). Materials and Methods - A total of 1284 patients who underwent surgery 2018–2019 with sufficient data regarding both clinical and pathology T and N descriptors were included. Results - The differences in tumour diameter reported in the clinical and the pathology notifications were ≤5 mm and ≤10 mm in 65.9 % and in 84.4 % of the cases, respectively. For the c- and pT categories, there was concordance in 53.4 % while 28.4 % were upstaged and 18.2 % were downstaged. For N categories there was concordance in 83.3 % while 13.7 % were upstaged and 3.0 % were downstaged. Unforeseen pN2 was found in 6.2 % of the cases. For TNM staging groups there was concordance in 48.1 % of the cases, while 33.4 % were upstaged and 18.5 % were downstaged. The calculated sensitivity and specificity for reported cTNM staging as diagnostic test for being eligible for adjuvant treatment (stage II–IIIA) were 0.65 and 0.91, respectively. Conclusions - These data on staging for lung cancer, as reported to the CRN, shows a disappointingly low precision and concordance in c- and pTNM staging. This urges a strategy for a marked improvement.

• Eide, Inger Johanne; Stensgaard, Simone; Helland, Åslaug; Ekman, Simon; Mellemgaard, Anders & Hansen, Karin Holmskov [Vis alle 11 forfattere av denne artikkelen] (2022). Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials. Translational Lung Cancer Research (TLCR). ISSN 2218-6751. 11(6), s. 953–963. doi: 10.21037/tlcr-21-995. Fulltekst i vitenarkiv Vis sammendrag

  Background: Osimertinib is standard of care for EGFR-mutated non-small cell lung cancer (NSCLC) patients. The efficacy of the drug in patients with mutations other than the common deletion in exon 19 and L858R in exon 21 is largely unknown. Methods: We identified patients with uncommon EGFR-mutations from two prospective clinical phase II, single-arm studies for previously treated patients and untreated patients, respectively, and pooled data for this analysis. All patients received treatment with osimertinib 80 mg daily until radiological progression or death. The primary endpoint of both trials was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS) and intracranial efficacy as key secondary endpoints. Circulating tumour DNA (ctDNA) was analysed before and two weeks after treatment initiation in the first line cohort. Results: Of 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I. Three of the 10 pretreated patients had the T790M resistance mutation. ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6% vs. 30.0% of 10 previously treated patients. The median PFS was 5.5 months in both groups. Patients with G719X-compound mutations had a higher response rate (62.5% vs. 38.5%), a longer median PFS (13.7 vs. 3.5 months) and median OS (29.3 vs. 7.5 months) than patients with other mutations. Most first line treated patients (81.8%) displayed a reduction in ctDNA after two weeks of treatment. Conclusions: Osimertinib demonstrates activity in patients with uncommon EGFR-mutations, and especially for G719X-compound mutations.

• Kaźmierczak, Dominika; Eide, Inger Johanne; Gencheva, Radosveta; Lai, Yi; Lewensohn, Rolf & Tsakonas, Georgios [Vis alle 12 forfattere av denne artikkelen] (2022). Elevated expression of miR-494-3p is associated with resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer. Translational Lung Cancer Research (TLCR). ISSN 2218-6751. 11(5), s. 722–734. doi: 10.21037/tlcr-21-955. Fulltekst i vitenarkiv Vis sammendrag

  Background: Non-small cell lung cancer (NSCLC) harboringactivating mutations in the gene encoding epidermal growth factor receptor (EGFR) is amenable for targeted therapy with tyrosine kinase inhibitors (TKIs). Eventually, resistance to TKI-therapy occurs resulting in disease progression. A substantial fraction of resistance mechanisms is unknown and may involve alterations in the RNA or protein landscape. MicroRNAs (miRNAs) have been frequently suggested to play roles in various forms of cancer including NSCLC. However, a role of miRNAs in acquired resistance to EGFR TKIs remains elusive. In this work, we aimed to investigate the potential involvement of miRNAs in acquired resistance to the third-generation EGFR TKI osimertinib in NSCLC. Methods: We combined miRNA expression profiling with miRNA-inhibitory screening to identify miRNAs involved in conferring resistance to osimertinib. Finally, we validated our top miRNA candidate by profiling longitudinal plasma exosomal RNA from patients receiving osimertinib as second-line therapy in a clinical trial. Results: Various miRNAs displayed differential expression in parental versus osimertinib-refractory NSCLC cells. miRNA-inhibitory screening revealed miR-494-3p to partially confer resistance to osimertinib in vitro. Expression of miR-494-3p was significantly elevated in plasma sampled at disease progression compared to plasma sampled at treatment baseline in a cohort of 21 EGFR T790M-mutation positive NSCLC patients receiving osimertinib. Conclusions: Our results highlight the need for further therapeutic exploration of miR-494-3p in in vivo models of EGFR-mutant NSCLC. Keywords: Non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); osimertinib; microRNA (miRNA); resistance

• Sørensen, Jens Benn; Horvat, Pia; Rosenlund, Mats; Kejs, Anne Mette; Patel, Dony & Juarez-Garcia, Ariadna [Vis alle 12 forfattere av denne artikkelen] (2022). Initial treatment and survival in Danish patients diagnosed with non-small-cell lung cancer (2005-2015): SCAN-LEAF study. Future Oncology. ISSN 1479-6694. 18(2), s. 205–214. doi: 10.2217/fon-2021-0746. Fulltekst i vitenarkiv
• Kosibaty, Zeinab; Brustugun, Odd Terje; Eide, Inger Johanne Zwicky; Tsakonas, Georgios; Grundberg, Oscar & Petris, Luigi De [Vis alle 9 forfattere av denne artikkelen] (2022). Ras-Related Protein Rab-32 and Thrombospondin 1 Confer Resistance to the EGFR Tyrosine Kinase Inhibitor Osimertinib by Activating Focal Adhesion Kinase in Non-Small Cell Lung Cancer. Cancers. 14(14). doi: 10.3390/cancers14143430. Fulltekst i vitenarkiv Vis sammendrag

  Treatment with the tyrosine kinase inhibitor (TKI) osimertinib is the standard of care for non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR). Osimertinib is also used in T790M-positive NSCLC that may occur de novo or be acquired following first-line treatment with other EGFR TKIs (i.e., gefitinib, erlotinib, afatinib, or dacomitinib). However, patients treated with osimertinib have a high risk of developing resistance to the treatment. A substantial fraction of the mechanisms for resistance is unknown and may involve RNA and/or protein alterations. In this study, we investigated the full transcriptome of parental and osimertinib-resistant cell lines, revealing 131 differentially expressed genes. Knockdown screening of the genes upregulated in resistant cell lines uncovered eight genes to partly confer resistance to osimertinib. Among them, we detected the expression of Ras-related protein Rab-32 (RAB32) and thrombospondin 1 (THBS1) in plasmas sampled at baseline and at disease progression from EGFR-positive NSCLC patients treated with osimertinib. Both genes were upregulated in progression samples. Moreover, we found that knockdown of RAB32 and THBS1 reduced the expression of phosphorylated focal adhesion kinase (FAK). Combination of osimertinib with a FAK inhibitor resulted in synergistic toxicity in osimertinib-resistant cells, suggesting a potential therapeutic drug combination for overcoming resistance to osimertinib in NSCLC patients.

• Khadse, Anand; Haakensen, Vilde Drageset; Silwal-Pandit, Laxmi; Hamfjord, Julian; Micke, Patrick & Botling, Johan [Vis alle 10 forfattere av denne artikkelen] (2022). Prognostic Significance of the Loss of Heterozygosity of KRAS in Early-Stage Lung Adenocarcinoma. Frontiers in Oncology. 12. doi: 10.3389/fonc.2022.873532. Fulltekst i vitenarkiv Vis sammendrag

  Lung cancer is a common disease with a poor prognosis. Genomic alterations involving the KRAS gene are common in lung carcinomas, although much is unknown about how different mutations, deletions, and expressions influence the disease course. The first approval of a KRAS-directed inhibitor was recently approved by the FDA. Mutations in the KRAS gene have been associated with poor prognosis for lung adenocarcinomas, but implications of the loss of heterozygosity (LOH) of KRAS have not been investigated. In this study, we have assessed the LOH of KRAS in early-stage lung adenocarcinoma by analyzing DNA copy number profiles and have investigated the effect on patient outcome in association with mRNA expression and somatic hotspot mutations. KRAS mutation was present in 36% of cases and was associated with elevated mRNA expression. LOH in KRAS was associated with a favorable prognosis, more prominently in KRAS mutated than in wild-type patients. The presence of both LOH and mutation in KRAS conferred a better prognosis than KRAS mutation alone. For wild-type tumors, no difference in prognosis was observed between patients with and without LOH in KRAS. Our study indicates that LOH in KRAS is an independent prognostic factor that may refine the existing prognostic groups of lung adenocarcinomas.

• Agbarya, Abed; Shalata, Walid; Addeo, Alfredo; Charpidou, Andriani; Cuppens, Kristof & Brustugun, Odd Terje [Vis alle 12 forfattere av denne artikkelen] (2022). Real-World Journey of Unresectable Stage III NSCLC Patients: Current Dilemmas for Disease Staging and Treatment. Journal of Clinical Medicine. 11(6). doi: 10.3390/jcm11061738. Fulltekst i vitenarkiv
• Nilssen, Yngvar; Brustugun, Odd Terje; Eriksen, Morten Tandberg; Guren, Marianne; Haug, Erik Skaaheim & Naume, Bjørn [Vis alle 8 forfattere av denne artikkelen] (2022). Compliance with recommended cancer patient pathway timeframes and choice of treatment differed by cancer type and place of residence among cancer patients in Norway in 2015–2016. BMC Cancer. 22(220). doi: 10.1186/s12885-022-09306-9. Fulltekst i vitenarkiv Vis sammendrag

  Background Cancer patient pathways (CPPs) were implemented in Norway to reduce unnecessary waiting times, regional variations, and to increase the predictability of cancer care for the patients. This study aimed to determine if 70% of cancer patients started treatment within the recommended time frames, and to identify potential delays. Methods Patients registered with a colorectal, lung, breast, or prostate cancer diagnosis at the Cancer Registry of Norway in 2015–2016 were linked with the Norwegian Patient Registry and Statistics Norway. Adjusting for sociodemographic variables, multivariable quantile (median) regressions were used to examine the association between place of residence and median time to start of examination, treatment decision, and start of treatment. Results The study included 20 668 patients. The proportions of patients who went through the CPP within the recommended time frames were highest among colon (84%) and breast (76%) cancer patients who underwent surgery and lung cancer patients who started systemic anticancer treatment (76%), and lowest for prostate cancer patients who underwent surgery (43%). The time from treatment decision to start of treatment was the main source of delay for all cancers. Travelling outside the resident health trust prolonged waiting time and was associated with a reduced odds of receiving surgery and radiotherapy for lung and rectal cancer patients, respectively. Conclusions Achievement of national recommendations of the CCP times differed by cancer type and treatment. Identified bottlenecks in the pathway should be targeted to decrease waiting times. Further, CPP guidelines should be re-examined to determine their ongoing relevance.

• Ekman, Simon; Horvat, Pia; Rosenlund, Mats; Kejs, Anne Mette; Patel, Dony & Juarez-Garcia, Ariadna [Vis alle 11 forfattere av denne artikkelen] (2021). Epidemiology and Survival Outcomes for Patients With NSCLC in Scandinavia in the Preimmunotherapy Era: A SCAN-LEAF Retrospective Analysis From the I-O Optimise Initiative. JTO Clinical and Research Reports. 2(5). doi: 10.1016/j.jtocrr.2021.100165. Fulltekst i vitenarkiv
• Brustugun, Odd Terje; Nilssen, Yngvar & Eide, Inger Johanne (2021). Epidemiology and outcome of peritoneal and pleural mesothelioma subtypes in Norway. A 20 year nation-wide study. Acta Oncologica. ISSN 0284-186X. doi: 10.1080/0284186X.2021.1955971. Fulltekst i vitenarkiv Vis sammendrag

  Background Mesothelioma of the pleural or peritoneal cavities is one of the deadliest cancer types. The incidence of pleural subtypes has decreased over time due to decrease in asbestos exposure, and the current treatment landscape is changing due to introduction of novel therapies. In this study we have analysed contemporary epidemiological data of mesothelioma on a national level before the advent of immunotherapy. Material and methods Complete national data on 1509 pleural and peritoneal malignant mesothelioma from the Cancer Registry of Norway from 2000 to 2019 are presented. Age standardised incidence and median survival were calculated. Results The age-standardised incidence of pleural mesothelioma among males has decreased from 1.7 per 100 000 in 2000–2004 to 1.1 in 2015–2019, whereas the incidence for females has been stable, lower than 0.3 per 100 000 throughout the period. Incidence of peritoneal mesotheliomas remained low, below 0.08 per 100 000. The female to male ratio among pleural mesotheliomas was 1:7 with no differences among morphological subtypes, whereas this ratio was 1:1.2 in peritoneal mesotheliomas. Median age at diagnosis for pleural mesothelioma was 73 years and 76 years for females and males respectively in the last 5-year period, and 67 years for peritoneal mesotheliomas of both sexes. Median survival among pleural mesotheliomas has been stable, with significantly worse prognosis among sarcomatoid subtype (5.4 months) compared to epithelioid subtype (15.8 months). Peritoneal mesothelioma of the epithelioid subtype, representing 38% of cases, had a median survival of 43.3 months, contrasting the non-epithelioid subtype of 5.1 months. Discussion Mesothelioma is still a significant disease with a dismal prognosis. Improvement in treatment is warranted.

• Nilssen, Yngvar; Brustugun, Odd Terje & Møller, Bjørn (2021). Factors associated with emergency-related diagnosis, time to treatment and type of treatment in 5713 lung cancer patients. European Journal of Public Health. ISSN 1101-1262. 31(5), s. 967–974. doi: 10.1093/eurpub/ckab071. Fulltekst i vitenarkiv
• Berg, Janna; Ramberg, Christina; Haugstvedt, Jon Olav Sulheim; Bengtson, May-Bente; Gabrielsen, Anne Marie & Brustugun, Odd [Vis alle 8 forfattere av denne artikkelen] (2021). Lung Function After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer, Changes and Predictive Markers. Frontiers in Oncology. 11. doi: 10.3389/fonc.2021.674731. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: The aim was to describe causal factors in children with postneonatal cerebral palsy (PNCP), compare clinical characteristics in children with PNCP to children with congenital CP, and compare congenital CP risk factors in children with PNCP to the general population. Patients and Methods: The Norwegian CP Registry was linked to the Medical Birth Registry for children born 1999 to 2013 (893,864 livebirths). Among 1710 children with CP, 67 (3.9%) had PNCP and 1643 congenital CP. Chi-Square tests were used to compare clinical characteristics in children with PNCP and congenital CP, and prevalence rates to compare risk factors in children with PNCP and the general population. Results: The leading causes of PNCP were cerebrovascular diseases (33%), accidents/trauma (22%) and infections (19%). More children with PNCP had spastic hemiplegic (54%) and quadriplegic/dyskinetic (31%) CP compared to congenital CP (42%; 20%, respectively) (p<0.001). More children with PNCP were unable to walk (GMFCS IV–V) (35%), had difficulty handling objects (MACS IV–V) (29%) compared to children with congenital CP (24%, p = 0.037; 19%, p = 0.008, respectively), and had significantly more associated impairments. Compared to the general population, children with PNCP were more likely to be born preterm, with a lower birthweight for gestational age and Apgar score, as a multiple, and with a congenital malformation.

• Frafjord, Astri; Buer, Linn; Hammarström, Clara Louise; Aamodt, Henrik; Woldbæk, Per R & Brustugun, Odd Terje [Vis alle 9 forfattere av denne artikkelen] (2021). The Immune Landscape of Human Primary Lung Tumors Is Th2 Skewed. Frontiers in Immunology. 12:764596, s. 1–15. doi: 10.3389/fimmu.2021.764596. Fulltekst i vitenarkiv Vis sammendrag

  Tumor-specific T helper (Th) cells have a central role in the immune response against cancer. However, there exist distinct Th cell subsets with very different and antagonizing properties. Some Th subsets such as Th1 protect against cancer, while others (Th2, T regulatory/Treg) are considered detrimental or of unknown significance (T follicular helper/Tfh, Th17). The Th composition of human solid tumors remains poorly characterized. Therefore, we established a four-color multiplex chromogenic immunohistochemical assay for detection of Th1, Th2, Th17, Tfh and Treg cells in human tumor sections. The method was used to analyze resected primary lung tumors from 11 patients with non-small cell lung cancer (NSCLC). Four microanatomical regions were investigated: tumor epithelium, tumor stroma, peritumoral tertiary lymphoid structures (TLS) and non-cancerous distal lung tissue. In tumor epithelium and stroma, most CD4 + T cells identified had either a Th2 (GATA-3 + CD3 + CD8 - ) or Treg (FOXP3 + CD3 + CD8 - ) phenotype, whereas only low numbers of Th1, Th17, and Tfh cells were observed. Similarly, Th2 was the most abundant Th subset in TLS, followed by Treg cells. In sharp contrast, Th1 was the most frequently detected Th subset in non-cancerous lung tissue from the same patients. A higher Th1:Th2 ratio in tumor stroma was found to be associated with increased numbers of intratumoral CD8 + T cells. The predominance of Th2 and Treg cells in both tumor stroma and tumor epithelium was consistent for all the 11 patients investigated. We conclude that human primary NSCLC tumors are Th2-skewed and contain numerous Treg cells. If human tumors are Th2-skewed, as our data in NSCLC suggest, reprogramming the type of immune response from a detrimental Th2 to a beneficial Th1 may be critical to increase the response rate of immunotherapy.

• Lehtiö, Janne; Arslan, Taner; Siavelis, Ioannis; Pan, Yanbo; Socciarelli, Fabio & Berkovska, Olena [Vis alle 29 forfattere av denne artikkelen] (2021). Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms. Cancer. ISSN 0008-543X. doi: 10.1038/s43018-021-00259-9. Fulltekst i vitenarkiv
• Wahl, Sissel Gyrid Freim; Hong, Yan Dai; Emdal, Elisabeth Fritzke; Berg, Thomas; Halvorsen, Tarje Onsøien & Ottestad, Anine Larsen [Vis alle 14 forfattere av denne artikkelen] (2021). The prognostic effect of KRAS mutations in non-small cell lung carcinoma revisited: A norwegian multicentre study. Cancers. 13(17), s. 1–19. doi: 10.3390/cancers13174294. Fulltekst i vitenarkiv Vis sammendrag

  Background: due to emerging therapeutics targeting KRAS G12C and previous reports with conflicting results regarding the prognostic impact of KRAS and KRAS G12C in non-small cell lung cancer (NSCLC), we aimed to investigate the frequency of KRAS mutations and their associations with clinical characteristics and outcome. Since mutation subtypes have different preferences for downstream pathways, we also aimed to investigate whether there were differences in outcome according to mutation preference for the Raf, PI3K/Akt, or RalGDS/Ral pathways. Methods: retrospectively, clinicopathological data from 1233 stage I–IV non-squamous NSCLC patients with known KRAS status were reviewed. KRAS’ associations with clinical characteristics were analysed. Progression free survival (PFS) and overall survival (OS) were assessed for the following groups: KRAS wild type (wt) versus mutated, KRAS wt versus KRAS G12C versus KRAS non-G12C, among KRAS mutation subtypes and among mutation subtypes grouped according to preference for downstream pathways. Results: a total of 1117 patients were included; 38% had KRAS mutated tumours, 17% had G12C. Among KRAS mutated, G12C was the most frequent mutation in former/current smokers (45%) and G12D in never smokers (46%). There were no significant differences in survival according to KRAS status, G12C status, among KRAS mutation subtypes or mutation preference for downstream pathways. Conclusion: KRAS status or KRAS mutation subtype did not have any significant influence on PFS or OS.

• Bugge, Christoffer; Brustugun, Odd Terje; Sæther, Erik Magnus & Kristiansen, Ivar Sønbø (2021). Phase- and gender-specific, lifetime, and future costs of cancer: A retrospective population-based registry study. Medicine. ISSN 0025-7974. 100(26), s. 1–8. doi: 10.1097/MD.0000000000026523. Fulltekst i vitenarkiv
• Eide, Inger Johanne; Grut, Harald; Helland, Åslaug; Ekman, Simon; Sørensen, Jens Benn & Hansen, Karin Holmskov [Vis alle 11 forfattere av denne artikkelen] (2021). Intracranial effect of osimertinib in relapsed EGFR-mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study. Acta Oncologica. ISSN 0284-186X. doi: 10.1080/0284186X.2021.1973092. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Osimertinib is effective for relapsed T790M-positive patients with brain metastases. The high brain permeability suggests that also such patients without T790M could benefit. Therefore, we evaluated the effect of osimertinib on brain metastases in both T790M-positive and -negative patients. Methods The TREM-study was an investigator-initiated phase II, single-arm, multi-institutional clinical trial conducted in Northern Europe. Patients with resistance to prior EGFR-TKIs received osimertinib until radiological progression, unacceptable toxicity or death. Baseline brain scans were performed in patients with known or suspected brain metastases and repeated every 8–12 weeks. We assessed intracranial efficacy in patients with baseline brain metastases. Results Brain metastases were detected in 48/199 patients at baseline. Of these, 63% were T790M-positive, 27% -negative and 10% had unknown T790M-status. The majority (73%) of the patients had received prior whole brain radiotherapy and additionally 8% had received stereotactic radiosurgery (SRS). Brain scans were available for review for 42 patients. The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively (p < 0.001). The overall intracranial disease control rate (iDCR) was 81%, and for T790M + and T790M- patients the DCR was 89% versus 55%, respectively. The estimated risk of CNS progression was 0.8% at 6 months and 6% at 12 months for T790M-positive patients, and 14% and 17% at 6 and 12 months, respectively, for the T790M-negative. Conclusion This subgroup analysis confirms CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.

• Lærum, Dan; Brustugun, Odd Terje; Gallefoss, Frode; Falk, Ragnhild Sørum; Strand, Trond-Eirik & Fjellbirkeland, Lars (2021). Factors associated with delayed treatment initiation in an unselected cohort of patients with small-cell lung cancer. Cancer Treatment and Research Communications. ISSN 2468-2942. 29. doi: 10.1016/j.ctarc.2021.100477. Fulltekst i vitenarkiv Vis sammendrag

  Background Small-cell lung cancer (SCLC) is an aggressive, rapidly progressive malignancy. Thus, expedient diagnosis and treatment initiation is important. This study identifies and quantifies factors associated with delayed diagnosis and treatment initiation in patients with SCLC and compares time to treatment in SCLC with a cohort of patients with non-small cell lung cancer (NSCLC). Materials and Methods The study included all patients diagnosed with SCLC at a hospital in southern Norway in a ten-year period (2007–2016), and all NSCLC patients during the period 2013–2016. Total time to treatment (TTT), was defined as the number of days from date of referral due to suspicion of lung cancer to first day of treatment. Factors associated with prolonged TTT were estimated using multivariate median regression analysis. Results The median TTT and interquartile range (IQR) for the 183 patients with SCLC was 16 (10–23) days. Factors associated with delayed TTT included outpatient versus inpatient evaluation (+8.4 days), number of diagnostic procedures (+4.3 days per procedure), stage I-III versus stage IV (+3.6 days) and age (+2.1 days per 10 years). In 2013–16, TTT in SCLC was 3.5 days shorter than in the period before and less than half that of NSCLC in the same period, 15 (9–22) versus 33 (22–50) days (p = 0.001). Conclusion Shorter TTT is seen in higher stage, while longer TTT is a result of increasing complexity of the diagnostic process and treatment decisions of patients with curative intent treatment. Knowledge on delaying factors can shorten TTT and improve clinical practice.

• Bjaanæs, Maria Moksnes; Nilsen, Gro; Halvorsen, Ann Rita; Russnes, Hege Elisabeth Giercksky; Solberg, Steinar & Jørgensen, Lars [Vis alle 9 forfattere av denne artikkelen] (2021). Whole genome copy number analyses reveal a highly aberrant genome in TP53 mutant lung adenocarcinoma tumors. BMC Cancer. 21(1). doi: 10.1186/s12885-021-08811-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Genetic alterations are common in non-small cell lung cancer (NSCLC), and DNA mutations and translocations are targets for therapy. Copy number aberrations occur frequently in NSCLC tumors and may influence gene expression and further alter signaling pathways. In this study we aimed to characterize the genomic architecture of NSCLC tumors and to identify genomic differences between tumors stratified by histology and mutation status. Furthermore, we sought to integrate DNA copy number data with mRNA expression to find genes with expression putatively regulated by copy number aberrations and the oncogenic pathways associated with these affected genes. Methods Copy number data were obtained from 190 resected early-stage NSCLC tumors and gene expression data were available from 113 of the adenocarcinomas. Clinical and histopathological data were known, and EGFR-, KRAS- and TP53 mutation status was determined. Allele-specific copy number profiles were calculated using ASCAT, and regional copy number aberration were subsequently obtained and analyzed jointly with the gene expression data. Results The NSCLC tumors tissue displayed overall complex DNA copy number profiles with numerous recurrent aberrations. Despite histological differences, tissue samples from squamous cell carcinomas and adenocarcinomas had remarkably similar copy number patterns. The TP53-mutated lung adenocarcinomas displayed a highly aberrant genome, with significantly altered copy number profiles including gains, losses and focal complex events. The EGFR-mutant lung adenocarcinomas had specific arm-wise aberrations particularly at chromosome7p and 9q. A large number of genes displayed correlation between copy number and expression level, and the PI(3)K-mTOR pathway was highly enriched for such genes. Conclusions The genomic architecture in NSCLC tumors is complex, and particularly TP53-mutated lung adenocarcinomas displayed highly aberrant copy number profiles. We suggest to always include TP53-mutation status when studying copy number aberrations in NSCLC tumors. Copy number may further impact gene expression and alter cellular signaling pathways.

• Grønberg, Bjørn Henning; Killingberg, Kristin Toftaker; Fløtten, Øystein; Brustugun, Odd; HORNSLIEN, KJERSTI & Madebo, Tesfaye [Vis alle 13 forfattere av denne artikkelen] (2021). High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial. The Lancet Oncology. ISSN 1470-2045. 22(3), s. 321–331. doi: 10.1016/S1470-2045(20)30742-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival. Methods This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 mg/m2 or carboplatin (area under the curve 5–6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m2 on days 1–3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20–28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25–30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at ClinicalTrials.gov, NCT02041845. Findings Between July 8, 2014, and June 6, 2018, 176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38–56). At 2 years, 66 (74·2% [95% CI 63·8–82·9]) patients in the 60 Gy group were alive, compared with 39 (48·1% [36·9–59·5]) patients in the 45 Gy group (odds ratio 3·09 [95% CI 1·62–5·89]; p=0·0005). The most common grade 3–4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 [81%] of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%]), thrombocytopenia (21 [24%] vs 19 [25%]), anaemia (14 [16%] vs 15 [20%]), and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group). Interpretation The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules.

• Brustugun, Odd & Heggelund, Lars (2021). Koronavaksinering av kreftpasienter. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(3). doi: 10.4045/tidsskr.21.0026. Fulltekst i vitenarkiv
• Eide, Inger Johanne & Brustugun, Odd Terje (2021). Lungekreft behandlet med reseptortyrosinkinasehemmer i utlandet. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(12), s. 1–4. doi: 10.4045/tidsskr.21.0147. Fulltekst i vitenarkiv
• Bugge, Christoffer; Sæther, Erik Magnus; Brustugun, Odd & Kristiansen, Ivar Sønbø (2021). Societal cost of cancer in Norway –Results of taking a broader cost perspective. Health Policy. ISSN 0168-8510. doi: 10.1016/j.healthpol.2021.05.008. Fulltekst i vitenarkiv
• Popat, Sanjay; Brustugun, Odd; Cadranel, Jacques; Felip, Enriqueta; Garassino, Marina Chiara & Griesinger, Frank [Vis alle 12 forfattere av denne artikkelen] (2021). Real-world treatment outcomes with brigatinib in patients with pretreated ALK+ metastatic non-small cell lung cancer. Lung Cancer. ISSN 0169-5002. 157, s. 9–16. doi: 10.1016/j.lungcan.2021.05.017. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background The next-generation ALK inhibitor brigatinib is approved for use in patients with ALK inhibitor-naïve ALK-positive advanced NSCLC and in patients previously treated with crizotinib. A phase II trial showed that brigatinib is active in patients with ALK-positive metastatic NSCLC (mNSCLC) who had progressed on prior crizotinib (response rate 56 %, median PFS 16.7 months, median OS 34.1 months). We report final data from the UVEA-Brig study of brigatinib in ALK inhibitor-pretreated ALK-positive mNSCLC in clinical practice. Methods UVEA-Brig was a retrospective chart review of patients treated with brigatinib in Italy, Norway, Spain and the UK in an expanded access program. Adults with ALK-positive mNSCLC, including those with brain lesions, resistant to or intolerant of ≥1 prior ALK inhibitor and ECOG performance status ≤3 were eligible. Patients received brigatinib 180 mg once daily with a 7-day lead-in at 90 mg. The objectives were to describe patient characteristics, clinical disease presentation, treatment regimens used and clinical outcomes. Results Data for 104 patients (male: 43 %; median age: 53 [29–80] years; ECOG performance status 0/1/2/3: 41/41/10/5 %; brain/CNS metastases: 63 %) were analyzed. Patients had received a median of 2 (1–6) lines of systemic therapy prior to brigatinib (37.5 % received ≥3) and a median of 1 (1–5) lines of prior ALK inhibitor-containing therapy (crizotinib 83.6 %; ceritinib 50.0 %; alectinib 6.7 %; lorlatinib 4.8 %). At the time of analysis, 77 patients had discontinued brigatinib. Overall, the response rate was 39.8 %, median PFS was 11.3 (95 % CI:8.6–12.9) months and median OS was 23.3 (95 % CI: 16.0–NR) months. Four patients discontinued brigatinib treatment due to adverse events. 53 patients received systemic therapy after brigatinib, 42 with an ALK inhibitor (lorlatinib, n = 34). Conclusions These real-world data indicate the activity and tolerability of brigatinib in patients with ALK-positive mNSCLC who were more heavily pretreated than patients included in clinical trials.

• Haakensen, Vilde Drageset; Khadse, Anand; Sandhu, Vandana; Halvorsen, Ann Rita; Solberg, Steinar & Jørgensen, Lars Hilmar [Vis alle 9 forfattere av denne artikkelen] (2020). Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy. International Journal of Cancer. ISSN 0020-7136. 147(10), s. 2957–2966. doi: 10.1002/ijc.33121. Fulltekst i vitenarkiv Vis sammendrag

  Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild‐type samples and a 17%‐fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes.

• Frafjord, Astri; Skarshaug, Renate; Hammarström, Clara Louise; Stankovic, Branislava; Dorg, Linda Trobe & Aamodt, Henrik [Vis alle 11 forfattere av denne artikkelen] (2020). Antibody combinations for optimized staining of macrophages in human lung tumours. Scandinavian Journal of Immunology. ISSN 0300-9475. 92:e12889(1), s. 1–24. doi: 10.1111/sji.12889. Fulltekst i vitenarkiv Vis sammendrag

  The analysis of tumour‐associated macrophages (TAMs) has a high potential to predict cancer recurrence and response to immunotherapy. However, the heterogeneity of TAMs poses a challenge for quantitative and qualitative measurements. Here, we critically evaluated by immunohistochemistry and flow cytometry two commonly used pan‐macrophage markers (CD14 and CD68) as well as some suggested markers for tumour‐promoting M2 macrophages (CD163, CD204, CD206 and CD209) in human non–small cell lung cancer (NSCLC). Tumour, non‐cancerous lung tissue and blood were investigated. For immunohistochemistry, CD68 was confirmed to be a useful pan‐macrophage marker although careful selection of antibody was found to be critical. The widely used anti‐CD68 antibody clone KP‐1 stains both macrophages and neutrophils, which is problematic for TAM quantification because lung tumours contain many neutrophils. For TAM counting in tumour sections, we recommend combined labelling of CD68 with a cell membrane marker such as CD14, CD163 or CD206. In flow cytometry, the commonly used combination of CD14 and HLA‐DR was found to not be optimal because some TAMs do not express CD14. Instead, combined staining of CD68 and HLA‐DR is preferable to gate all TAMs. Concerning macrophage phenotypic markers, the scavenger receptor CD163 was found to be expressed by a substantial fraction (50%‐86%) of TAMs with a large patient‐to‐patient variation. Approximately 50% of TAMs were positive for CD206. Surprisingly, there was no clear overlap between CD163 and CD206 positivity, and three distinct TAM sub‐populations were identified in NSCLC tumours: CD163+CD206+, CD163+CD206− and CD163−CD206−. This work should help develop macrophage‐based prognostic tools for cancer.

• Halvorsen, Ann Rita; Haugen, Mads Haugland; Øjlert, Åsa Kristina; Lund-Iversen, Marius; Jørgensen, Lars Hilmar & Solberg, Steinar [Vis alle 9 forfattere av denne artikkelen] (2020). Protein kinase C isozymes associated with relapse free survival in non-small cell lung cancer patients. Frontiers in Oncology. 10:590755, s. 1–11. doi: 10.3389/fonc.2020.590755. Fulltekst i vitenarkiv Vis sammendrag

  <i>Introduction</i>: Protein expression is deregulated in cancer, and the proteomic changes observed in lung cancer may be a consequence of mutations in essential genes. The purpose of this study was to identify protein expression associated with prognosis in lung cancers stratified by smoking status, molecular subtypes, and EGFR-, TP53-, and KRAS-mutations.<p> <p><i>Methods</i>: We performed profiling of 295 cancer-relevant phosphorylated and non-phosphorylated proteins, using reverse phase protein arrays. Biopsies from 80 patients with operable lung adenocarcinomas were analyzed for protein expression and association with relapse free survival (RFS) were studied.<p> <p><i>Results</i>: Spearman’s rank correlation analysis identified 46 proteins with significant association to RFS (p<0.05). High expression of protein kinase C (PKC)-α and the phosporylated state of PKC-α, PKC-β, and PKC-δ, showed the strongest positive correlation to RFS, especially in the wild type samples. This was confirmed in gene expression data from 172 samples. Based on protein expression, unsupervised hierarchical clustering separated the samples into four subclusters enriched with the molecular subtypes terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI) (p=0.0001). Subcluster 2 contained a smaller cluster (2a) enriched with samples of the subtype PP, low expression of the PKC isozymes, and associated with poor RFS (p=0.003) compared to the other samples. Low expression of the PKC isozymes in the subtype PP and a reduced relapse free survival was confirmed with The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) samples.<p> <p><i>Conclusion</i>: This study identified different proteins associated with RFS depending on molecular subtype, smoking- and mutational-status, with PKC-α, PKC-β, and PKC-δ showing the strongest correlation.

• Nilssen, Yngvar; Brustugun, Odd Terje; Eriksen, Morten Tandberg; Haug, Erik Skaaheim; Naume, Bjørn & Møller, Bjørn (2020). Patient and tumour characteristics associated with inclusion in Cancer patient pathways in Norway in 2015-2016. BMC Cancer. 20(1), s. 1–11. doi: 10.1186/s12885-020-06979-y. Fulltekst i vitenarkiv Vis sammendrag

  Background Cancer patient pathways (CPPs) were implemented in 2015 to reduce waiting time, regional variation in waiting time, and to increase the predictability of cancer care for the patients. The aims of this study were to see if the national target of 70% of all cancer patients being included in a CPP was met, and to identify factors associated with CPP inclusion. Methods All patients registered with a colorectal, lung, breast or prostate cancer diagnosis at the Cancer Registry of Norway in the period 2015–2016 were linked with the Norwegian Patient Registry for CPP information and with Statistics Norway for sociodemographic variables. Multivariable logistic regression examined if the odds of not being included in a CPP were associated with year of diagnosis, age, sex, tumour stage, marital status, education, income, region of residence and comorbidity. Results From 2015 to 2016, 30,747 patients were diagnosed with colorectal, lung, breast or prostate cancer, of whom 24,429 (79.5%) were included in a CPP. Significant increases in the probability of being included in a CPP were observed for colorectal (79.1 to 86.2%), lung (79.0 to 87.3%), breast (91.5 to 97.2%) and prostate cancer (62.2 to 76.2%) patients (p < 0.001). Increasing age was associated with an increased odds of not being included in a CPP for lung (p < 0.001) and prostate cancer (p < 0.001) patients. Colorectal cancer patients < 50 years of age had a two-fold increase (OR = 2.23, 95% CI: 1.70–2.91) in the odds of not being included in a CPP. The odds of no CPP inclusion were significantly increased for low income colorectal (OR = 1.24, 95%CI: 1.00–1.54) and lung (OR = 1.52, 95%CI: 1.16–1.99) cancer patients. Region of residence was significantly associated with CPP inclusion (p < 0.001) and the probability, adjusted for case-mix ranged from 62.4% in region West among prostate cancer patients to 97.6% in region North among breast cancer patients. Conclusions The national target of 70% was met within 1 year of CPP implementation in Norway. Although all patients should have equal access to CPPs, a prostate cancer diagnosis, older age, high level of comorbidity or low income were significantly associated with an increased odds of not being included in a CPP.

• Eide, Inger Johanne; Helland, Åslaug; Ekman, Simon; Mellemgaard, Anders; Hansen, Karin Holmskov & Cicenas, Saulius [Vis alle 9 forfattere av denne artikkelen] (2020). Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study). Lung Cancer. ISSN 0169-5002. 143, s. 27–35. doi: 10.1016/j.lungcan.2020.03.009. Fulltekst i vitenarkiv Vis sammendrag

  Objectives In non-small cell lung cancer patients with acquired resistance to first- or second-generation EGFR-TKIs, osimertinib is approved in the presence of the T790 M resistance mutation. We assessed the efficacy of osimertinib in both T790M-positive and T790M-negative patients. Materials and methods The TREM-study is an investigator-initiated, multi-centre, single-arm, phase 2 clinical trial conducted in five Northern European countries. Patients with progression on at least one previous EGFR-TKI were assigned to treatment with 80 mg of osimertinib daily until radiological progression or death. Patients were included regardless of the presence of T790 M. The primary endpoint was objective response rate (ORR). Results Of 199 included patients, 120 (60 %) were T790M-positive, 52 (26 %) were T790M-negative and 27 (14 %) had unknown T790M-status. 24 % had brain metastases and 15 % had an ECOG performance status of 2. Overall ORR was 48 % (95 % CI, 41 %–55 %), 60 % (51 %–69 %) for T790M-positive patients and 28 % (15 %–41 %) for T790M-negative patients, p < 0.001. ORR for patients with co-occurring del19 vs L858R was 61 % vs 32 %, p = 0.001. Duration of response was similar between the T790M-positive and –negative groups (11.8 vs 10.7 months, p = 0.229). Overall median progression-free survival (PFS) was 8.9 months (95 % CI, 7.4–10.5), and 10.8 vs 5.1 months for T790M-positive vs –negative patients (HR 0.62, p = 0.007). Median overall survival (OS) was 17.9 months (95 % CI, 14.4–21.3). For T790M-positive vs –negative median OS was 22.5 vs 13.4 months, (HR 0.55, p = 0.002). Conclusions This study confirms the efficacy of osimertinib for T790M-positive patients. There was also clinically significant activity of osimertinib in a proportion of T790M-negative patients.

• Lærum, Dan; Brustugun, Odd Terje; Gallefoss, Frode; Falk, Ragnhild Sørum; Strand, Trond-Eirik & Fjellbirkeland, Lars (2020). Reduced delays in diagnostic pathways for non-small cell lung cancer after local and National initiatives. Cancer Treatment and Research Communications. ISSN 2468-2942. 23. doi: 10.1016/j.ctarc.2020.100168. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Patients with non-small cell lung cancer (NSCLC) may experience progression and stage shift due to delays in a complex and time-consuming diagnostic work-up. We have analyzed the impact of both a local and national intervention on total time to treatment (TTT). Material and Methods All patients diagnosed with NSCLC at a Norwegian county hospital from 2007 to 2016 were reviewed. Logistic bottlenecks and delays were identified (2007–12) resulting in implementation of a local initiative with new diagnostic algorithm introduced by the beginning of 2013. In 2015, national diagnostic cancer pathways were implemented. TTT defined as time from received referral from the primary physician to start of treatment was compared in the three diagnostic time periods; baseline (2007–12), local (2013–14) and national (2015–16). Results A total of 780 patients were included. Among patients treated with curative intent the median TTT decreased by 21 days, from 64 to 43 days (p < 0.001) while the mean number of diagnostic procedures increased from 3.5 to 3.9. In median regression analysis, the local initiative was associated with a reduction of estimated 7.8 days (95% CI 3.2, 12.3) in TTT, while the national initiative correlated with a reduction of estimated 14.9 days (95% CI 10.2, 19.6) compared to time at baseline. Covariates associated with longer TTT were stage I, use of PET-CT, diagnostic procedure at external hospital, and number of diagnostic procedures. Conclusion Local and national initiatives significantly reduced TTT in NSCLC. The effect was most pronounced among patients with disease available for curative treatment.

• Garon, Edward B.; Scagliotti, Giorgio Vittorio; Gautschi, Oliver; Reck, Martin; Thomas, Michael & Docampo, Lara Iglesias [Vis alle 20 forfattere av denne artikkelen] (2020). Exploratory analysis of front-line therapies in REVEL: A randomised phase 3 study of ramucirumab plus docetaxel versus docetaxel for the treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy. ESMO Open. 5(1). doi: 10.1136/esmoopen-2019-000567. Fulltekst i vitenarkiv
• Øjlert, Åsa Kristina; Nebdal, Daniel J.H.; Lund-Iversen, Marius; Ellefsen, Renée Åstrøm; Brustugun, Odd Terje & Gran, Jon Michael [Vis alle 8 forfattere av denne artikkelen] (2020). Immune checkpoint blockade in the treatment of advanced non-small cell lung cancer–predictors of response and impact of previous radiotherapy. Acta Oncologica. ISSN 0284-186X. s. 1–9. doi: 10.1080/0284186X.2020.1854851. Fulltekst i vitenarkiv Vis sammendrag

  Background The implementation of immune checkpoint inhibitors (ICI) into the standard care of advanced non-small cell lung cancer (NSCLC) has improved prognosis for this group of patients. However, long-term survival is rare. The aim of the study was to identify predictors of response and, especially, to investigate the impact radiotherapy might have on duration of response. Material and methods The association between pretreatment patient/tumor characteristics and progression-free survival (PFS), overall survival (OS), and lung cancer-specific survival was investigated in 78 patients receiving an ICI as ≥2nd line treatment for advanced NSCLC, using Cox regression analysis. Due to competing risk, cause-specific deaths were also examined with cumulative incidence plots. Results Median OS was 12.6 months (95% CI 7.8–18.2) and median PFS 4.1 months (95% CI 3.0–6.2), after median follow-up time of 49.7 months (range 20.9–51.5). Increasing CRP and neutrophil/lymphocyte ratio (NLR), were associated with poor PFS (CRP: HR 1.49, 95% CI 1.12–1.98; NLR: HR 1.59, 95% CI 1.22–1.85) and OS (CRP: HR 1.94, 95% CI 1.47–2.56; NLR: HR 1.54, 95% CI 1.27–1.87). Radiotherapy prior to immunotherapy was not significantly associated with patient outcome. However, when the dataset was split at 6 months of follow-up, to be able to identify early and late predictors of prognosis, we found that patients receiving radiotherapy <6 months prior to immunotherapy had better PFS (HR: 0.27, 95% CI 0.09–0.84) and lung cancer-specific survival (HR: 0.41, 95% CI 0.18–0.95) after the first 6 months of follow-up, while increasing CRP (PFS: HR1.61, 95% CI 1.21–2.14; OS: HR2.04, 95% CI 1.51–2.74) and NLR (PFS: HR 1.57, 95% CI 1.29–1.91; OS: HR 1.63, 95% CI 1.35–1.97) were predictors of poor short-term prognosis. Conclusions Radiotherapy may be of importance to achieve a long-lasting response to immunotherapy, while indicators of systemic inflammation can help in identifying patients with poor short-term prognosis.

• Stankovic, Branislava; Aamodt, Henrik; Bjørhovde, Heidi Anine Korsmo; Müller, Elisabeth; Hammarström, Clara Louise & Brustugun, Odd Terje [Vis alle 9 forfattere av denne artikkelen] (2020). The immune microenvironment in typical carcinoid lung tumour, a brief report of four cases. Scandinavian Journal of Immunology. ISSN 0300-9475. 92:e12893(2), s. 1–12. doi: 10.1111/sji.12893. Fulltekst i vitenarkiv Vis sammendrag

  Pulmonary typical carcinoid (TC) is a low‐grade, rare lung cancer of neuroendocrine origin. Currently, there is very little information available about the immune cell composition in TC tumours. Here, we analysed by flow cytometry resected tumours from four never‐smoker female patients with TC. Twelve distinct immune cell types were identified in TC tumours. The most abundant immune cells were CD8+ T cells, CD4+ T cells, B cells and macrophages, which represented 19.8%, 17.7%, 11.5% and 11% of all tumour‐infiltrating CD45+ leucocytes, respectively. Natural killer (NK) cells (8.8%) and neutrophils (3.9%) were also common. Three types of dendritic cells (DCs) were identified (plasmacytoid DCs, CD1c DCs, and CD141 DCs) which together constituted 1.4% of all immune cells in TC tumours. Small populations of basophils (1.2%), mast cells (0.8%) and eosinophils (0.6%) were also present. Notably, the percentage of leucocytes (of all living cells) was much lower in TC tumours compared to high‐grade non‐small cell lung cancer (NSCLC) tumours and also compared to non‐cancerous lung tissue. We conclude that TC tumours are relatively non‐inflammatory, although the immune landscape was found to be very complex.

• Yu, Hui; Brustugun, Odd Terje; Ekman, Simon; Botling, Johan; Fleur, Linnea La & Micke, Patrick [Vis alle 10 forfattere av denne artikkelen] (2020). Programmed cell death ligand 1 expression in resected non–small cell lung cancer. Clinical Lung Cancer. ISSN 1525-7304. s. 1–8. doi: 10.1016/j.cllc.2020.09.018. Fulltekst i vitenarkiv
• Halvorsen, Tarje Onsøien; Stokke, Kristin; Killingberg, Kristin Toftaker; Raj, Sunil Xavier; Sørhaug, Sveinung & Brustugun, Odd Terje [Vis alle 12 forfattere av denne artikkelen] (2020). Randomized phase III trial comparing switch-maintenance pemetrexed with observation followed by pemetrexed at progression in advanced NSCLC. Acta Oncologica. ISSN 0284-186X. doi: 10.1080/0284186X.2020.1778179. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: Two phase III trials show that maintenance pemetrexed therapy after platinum-doublet chemotherapy prolongs overall survival (OS) and progression free survival (PFS) in advanced non-squamous non-small-cell lung cancer (NSCLC). However, few patients in the control arms received pemetrexed at progression in these trials, performance status (PS) two patients were ineligible and few of the participants were elderly. Thus, we designed this study comparing immediate switch-maintenance pemetrexed therapy with pemetrexed at progression after platinum-doublet chemotherapy. Methods: Patients with stage IIIB/IV non-squamous NSCLC, ≥18 years, PS 0–2, and non-progression after four courses of carboplatin/vinorelbine were randomized to receive immediate maintenance pemetrexed therapy or observation followed by pemetrexed at progression. The primary endpoint was OS, secondary endpoints were PFS, toxicity and health related quality of life (HRQoL). Results: 105 patients were randomized between May 2014 and September 2017. Median age was 67 years, 36% were >70 years, 9% had PS 2, 91% stage IV and 47% were women. In the observation arm, 73% received pemetrexed at progression. Patients in the maintenance arm had a numerically longer OS (median 12.0 vs. 10.0 months; p = .10) and a statistically significant longer PFS (median 3.1 vs. 1.9 months; p < .01). In multivariable analyses adjusting for baseline characteristics, there was a trend toward improved OS (HR 0.65, 95% CI 0.42–1.01); p = .05), and a significantly improved PFS (HR 0.53, 95% CI 0.35–0.80; p < .01). There were no significant differences in toxicity or HRQoL between the treatment arms. Conclusion: There was a trend toward prolonged OS and significantly longer PFS from switch- maintenance pemetrexed therapy when 73% of patients in the control arm received pemetrexed at progression.

• Øjlert, Åsa Kristina; Halvorsen, Ann Rita; Nebdal, Daniel J.H.; Lund-Iversen, Marius; Solberg, Steinar & Brustugun, Odd Terje [Vis alle 8 forfattere av denne artikkelen] (2019). The immune microenvironment in non‐small cell lung cancer is predictive of prognosis after surgery. Molecular Oncology. ISSN 1574-7891. 13(5), s. 1166–1179. doi: 10.1002/1878-0261.12475. Fulltekst i vitenarkiv Vis sammendrag

  The impact of the tumor immune microenvironment on overall survival in non‐small cell lung cancer (NSCLC) has been studied, but there is little information on its relevance for risk of relapse after surgery. Understanding more about the immune microenvironment in previously untreated NSCLC could help in identifying high‐risk patients and patients more likely to benefit from neoadjuvant/adjuvant immunotherapy. Here, we examined gene expression in 399 surgically derived NSCLC samples and 47 samples from normal lung, using Agilent microarray and RNA sequencing. In 335 of the tumor samples, programmed death‐ligand 1 (PD‐L1) expression was evaluated by immunohistochemistry. Gene expression was used to estimate content of immune cells and to calculate an immune score. Properties of the immune microenvironment, and its impact on prognosis, were compared in histological subgroups and gene expression subtypes. Tumors with an active immune microenvironment were found for both adenocarcinomas (AD) and squamous cell carcinomas (SCC). In AD, high immune score and high estimates of several immune cell types belonging to the adaptive immune system were associated with better progression‐free survival (PFS), while in SCC, no association between immune characteristics and PFS was found. The immune microenvironment, including PD‐L1 expression, and its impact on prognosis showed clear differences in AD and SCC gene expression subtypes. In conclusion, the NSCLC immune microenvironment is predictive of prognosis after surgery. Lung AD and SCC gene expression subtypes should be investigated as potential prognostic biomarkers in patients treated with immune checkpoint inhibitors.

• Menon, Usha; Vedsted, Peter; Falborg, Alina Zalounina; Jensen, Henry; Harrison, Samantha & Reguilon, Irene [Vis alle 26 forfattere av denne artikkelen] (2019). Time intervals and routes to diagnosis for lung cancer in 10 jurisdictions: Cross-sectional study findings from the International Cancer Benchmarking Partnership (ICBP). BMJ Open. 9:e025895(11), s. 1–20. doi: 10.1136/bmjopen-2018-025895. Fulltekst i vitenarkiv Vis sammendrag

  Differences in time intervals to diagnosis and treatment between jurisdictions may contribute to previously reported differences in stage at diagnosis and survival. The International Cancer Benchmarking Partnership Module 4 reports the first international comparison of routes to diagnosis and time intervals from symptom onset until treatment start for patients with lung cancer.Newly diagnosed patients with lung cancer, their primary care physicians (PCPs) and cancer treatment specialists (CTSs) were surveyed in Victoria (Australia), Manitoba and Ontario (Canada), Northern Ireland, England, Scotland and Wales (UK), Denmark, Norway and Sweden. Using Wales as the reference jurisdiction, the 50th, 75th and 90th percentiles for intervals were compared using quantile regression adjusted for age, gender and comorbidity.Consecutive newly diagnosed patients with lung cancer, aged ≥40 years, diagnosed between October 2012 and March 2015 were identified through cancer registries. Of 10 203 eligible symptomatic patients contacted, 2631 (27.5%) responded and 2143 (21.0%) were included in the analysis. Data were also available from 1211 (56.6%) of their PCPs and 643 (37.0%) of their CTS.Primary and secondary outcome measuresInterval lengths (days; primary), routes to diagnosis and symptoms (secondary).With the exception of Denmark (−49 days), in all other jurisdictions, the median adjusted total interval from symptom onset to treatment, for respondents diagnosed in 2012–2015, was similar to that of Wales (116 days). Denmark had shorter median adjusted primary care interval (−11 days) than Wales (20 days); Sweden had shorter (−20) and Manitoba longer (+40) median adjusted diagnostic intervals compared with Wales (45 days). Denmark (−13), Manitoba (−11), England (−9) and Northern Ireland (−4) had shorter median adjusted treatment intervals than Wales (43 days). The differences were greater for the 10% of patients who waited the longest. Based on overall trends, jurisdictions could be grouped into those with trends of reduced, longer and similar intervals to Wales. The proportion of patients diagnosed following presentation to the PCP ranged from 35% to 75%.There are differences between jurisdictions in interval to treatment, which are magnified in patients with lung cancer who wait the longest. The data could help jurisdictions develop more focused lung cancer policy and targeted clinical initiatives. Future analysis will explore if these differences in intervals impact on stage or survival.

• Alcala, Nicolas; Leblay, N; Gabriel, AAG; Mangiante, L; Hervas, D & Giffon, T [Vis alle 70 forfattere av denne artikkelen] (2019). Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nature Communications. 10:3407, s. 1–21. doi: 10.1038/s41467-019-11276-9. Fulltekst i vitenarkiv
• Nilssen, Yngvar; Brustugun, Odd Terje; Eriksen, Morten Tandberg; Gulbrandsen, Johanne; Haug, Erik Skaaheim & Naume, Bjørn [Vis alle 7 forfattere av denne artikkelen] (2019). Decreasing waiting time for treatment before and during implementation of cancer patient pathways in Norway. Cancer Epidemiology. ISSN 1877-7821. 61, s. 59–69. doi: 10.1016/j.canep.2019.05.004. Fulltekst i vitenarkiv Vis sammendrag

  Background: In 2015, Norway implemented cancer patient pathways to reduce waiting times for treatment. The aims of this paper were to describe patterns in waiting time and their association with patient characteristics for colorectal, lung, breast and prostate cancers. Methods: National, population-based data from 2007 to 2016 were used. A multivariable quantile regression examined the association between treatment period, age, stage, sex, place of residence, and median waiting times. Results: Reduction in median waiting times for radiotherapy among colorectal, lung and prostate cancer patients ranged from 14 to 50 days. Median waiting time for surgery remained approximately 21 days for both colorectal and breast cancers, while it decreased by 7 and 36 days for lung and prostate cancers, respectively. The proportion of lung and prostate cancer patients with metastatic disease at the time of diagnosis decreased, while the proportion of colorectal patients with localised disease and patients with stage I breast cancer increased (p < 0.001). After adjusting for case-mix, a patient’s place of residence was significantly associated with waiting time for treatment (p < 0.001), however, differences in waiting time to treatment decreased over the study period. Conclusions: Between 2007 and 2016, Norway experienced improved stage distributions and consistently decreasing waiting times for treatment. While these improvements occurred gradually, no significant change was observed from the time of cancer patient pathway implementation.

• Solberg, Steinar; Nilssen, Yngvar; Brustugun, Odd Terje; Grimsrud, Tom Kristian; Haram, Per Magnus & Helbekkmo, Nina [Vis alle 15 forfattere av denne artikkelen] (2019). Increase in curative treatment and survival of lung cancer in Norway 2001-2016. European Journal of Epidemiology (EJE). ISSN 0393-2990. 34(10), s. 951–955. doi: 10.1007/s10654-019-00536-z. Fulltekst i vitenarkiv Vis sammendrag

  We have studied the alterations in the use of curative treatment and the outcome for lung cancer patients in Norway 2001–2016. The Cancer Registry of Norway has a practically complete registration of all cancer diagnoses, treatments given and deaths. For the years 2001–2016, 43,137 patients were diagnosed with lung cancer. Stereotactic radiotherapy was established nationwide from 2008 and its use has increased, and in 2016, 8.8% were given this treatment. In addition 20.6% were operated and 8.5% were treated with conventional radiotherapy. Thus 37.9% of those diagnosed were treated with intention to cure, compared to 22.9% in 2001 (p < 0.0001). Further, the median survival for the whole group diagnosed with lung cancer increased from 6.0 (95% CI 5.6–6.7) months in 2001 to 11.8 (95% CI 10.9–12.7) in 2016. The 5 year survival increased from 9.4 (95% CI 8.1–10.8)% to 19.9 (95% CI 19.2–20.6)% in the same period. In 2016 the age adjusted incidence rate was 59.5 per 100,000 (Norwegian standard) and had increased significantly in both sexes. There had also been an increase in mean age at diagnosis and the proportion diagnosed in an early stage. The increase in curative treatment has been paralleled with a doubling in both the median and 5-year survival. The present results are used for surveillance and as a benchmark, and we are looking forward to reaching a proportion of 40% of patients given curative treatment.

• Halvorsen, Ann Rita; Aure, Miriam Ragle; Øjlert, Åsa Kristina; Brustugun, Odd Terje; Solberg, Steinar & Nebdal, Daniel J.H. [Vis alle 7 forfattere av denne artikkelen] (2019). Identification of microRNAs involved in pathways which characterize the expression subtypes of NSCLC. Molecular Oncology. ISSN 1574-7891. doi: 10.1002/1878-0261.12571. Fulltekst i vitenarkiv Vis sammendrag

  Dysregulation of microRNAs is a common mechanism in the development of lung cancer, but the relationship between microRNAs and expression subtypes in non‐small‐cell lung cancer (NSCLC) is poorly explored. Here, we analyzed microRNA expression from 241 NSCLC samples and correlated this with the expression subtypes of adenocarcinomas (AD) and squamous cell carcinomas (SCC) to identify microRNAs specific for each subtype. Gene set variation analysis and the hallmark gene set were utilized to calculate gene set scores specific for each sample, and these were further correlated with the expression of the subtype‐specific microRNAs. In ADs, we identified nine aberrantly regulated microRNAs in the terminal respiratory unit (TRU), three in the proximal inflammatory (PI), and nine in the proximal proliferative subtype (PP). In SCCs, 1, 5, 5, and 9 microRNAs were significantly dysregulated in the basal, primitive, classical, and secretory subtypes, respectively. The subtype‐specific microRNAs were highly correlated to specific gene sets, and a distinct pattern of biological processes with high immune activity for the AD PI and SCC secretory subtypes, and upregulation of cell cycle‐related processes in AD PP, SCC primitive, and SCC classical subtypes were found. Several in silico predicted targets within the gene sets were identified for the subtype‐specific microRNAs, underpinning the findings. The results were significantly validated in the LUAD (n = 492) and LUSC (n = 380) TCGA dataset (False discovery rates‐corrected P‐value < 0.05). Our study provides novel insight into how expression subtypes determined with discrete biological processes may be regulated by subtype‐specific microRNAs. These results may have importance for the development of combinatory therapeutic strategies for lung cancer patients.

• Eide, Hanne Astrid; Knudtsen, Ingerid Skjei; Sandhu, Vandana; Løndalen, Ayca; Halvorsen, Ann Rita & Abravan, Azadeh [Vis alle 12 forfattere av denne artikkelen] (2018). Serum cytokine profiles and metabolic tumor burden in patients with non-small cell lung cancer undergoing palliative thoracic radiation therapy. Advances in Radiation Oncology. ISSN 2452-1094. 3(2), s. 130–138. doi: 10.1016/j.adro.2017.12.007. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Radiation therapy effectively kills cancer cells and elicits local effects in the irradiated tissue. The aim of this study was to investigate the kinetics of cytokines in the serum of patients with lung cancer undergoing radiation therapy and to identify associations with metabolic tumor burden as determined by 2-deoxy-2-fluoro-D-glucose (18F-FDG) positron emission tomography (PET). Methods and materials: Forty-five patients with advanced non-small cell lung cancer were included in a phase 2 clinical trial and randomized between fractionated thoracic radiation therapy alone or concurrent with an epidermal growth factor receptor inhibitor. Blood was sampled at 4 different time points: prior to treatment, midtherapy, at the end of therapy, and 6 to 8 weeks after the start of treatment. The serum concentrations of 48 cytokines and 9 matrix metalloproteinases were measured with multiplex immunoassays. A subset of patients was examined by 18F-FDG PET/computed tomography before, during, and after radiation therapy. The maximum standardized uptake values (SUVmax) of the primary lung tumor, whole-body metabolic tumor volume, and total lesion glycolysis were calculated, and correlations between the PET parameters and cytokines were investigated. Results: The SUVmax decreased from baseline through midtherapy to posttherapy 18F-FDG PET/computed tomography (P = .018). The serum levels of C-C motif chemokine ligand (CCL) 23, CCL24, C-X3-C motif chemokine ligand 1, and interleukin-8 (C-X-C motif ligand [CXCL]8) were significantly correlated to SUVmax, metabolic tumor volume, and total lesion glycolysis before, during, and after radiation therapy. CXCL2 (P = .030) and CXCL6 (P = .010) decreased after the start of therapy and changed significantly across the sample time points. Serum concentrations of CCL15 (P = .031), CXCL2 (P = .028), and interleukin-6 (P = .007) were positively correlated to the irradiated volume during the second week of treatment. Conclusions: Cytokine serum levels vary and correlate with metabolic tumor burden in patients with advanced non-small cell lung cancer undergoing palliative thoracic radiation therapy.

• Lund-Iversen, Marius; Scott, Helge; Strøm, Erik Heyerdahl; Theiss, Noah; Brustugun, Odd Terje & Grønberg, Bjørn Henning (2018). Expression of estrogen receptor-α and survival in advanced-stage non-small cell lung cancer. Anticancer Research. ISSN 0250-7005. 38(4), s. 2261–2269. doi: 10.21873/anticanres.12470. Fulltekst i vitenarkiv Vis sammendrag

  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.

• George, Julie; Walter, Vonn; Peifer, Martin; Alexandrov, Ludmil B.; Seidel, Danila & Leenders, Frauke [Vis alle 62 forfattere av denne artikkelen] (2018). Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nature Communications. 9:1048, s. 1–13. doi: 10.1038/s41467-018-03099-x. Fulltekst i vitenarkiv Vis sammendrag

  Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

• Berg, Janna; Halvorsen, Ann Rita; Bengtson, May-Bente; Tasken, Kristin Austlid; Mælandsmo, Gunhild Mari & Yndestad, Arne [Vis alle 11 forfattere av denne artikkelen] (2018). Levels and prognostic impact of circulating markers of inflammation, endothelial activation and extracellular matrix remodelling in patients with lung cancer and chronic obstructive pulmonary disease. BMC Cancer. 18(1). doi: 10.1186/s12885-018-4659-0. Fulltekst i vitenarkiv Vis sammendrag

  Background The development of both chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is influenced by smoking related chronic pulmonary inflammation caused by an excessive innate immune response to smoke exposure. In addition, the smoking induced formation of covalent bonds between the carcinogens and DNA and the accumulation of permanent somatic mutations in critical genes are important in the carcinogenic processes, and can also induce inflammatory responses. How chronic inflammation is mirrored by serum markers in COPD and LC and if these markers reflect prognosis in patients with LC is, however, largely unknown. Methods Serum levels of 18 markers reflecting inflammation, endothelial activation and extracellular matrix remodelling were analysed in 207 patients with non-small lung carcinoma (NSCLC) before surgery and 42 COPD patients. 56% of the LC patients also suffered from COPD. The serum samples were analysed by enzyme immunoassays. Results Serum levels of OPG, PTX3, AXL, ALCAM, sCD163, CD147, CatS and DLL1 were significantly higher in patients with COPD as compared to patients with LC. High sTNFR1 levels were associated with improved progression free survival (PFS) and overall survival (OS) in LC patients with (PFS hazard ratio (HR) 0.49, OS HR 0.33) and without COPD (OS HR 0.30). High levels of OPG were associated with improved PFS (HR 0.17) and OS (HR 0.14) for LC with COPD. CRP was significantly associated with overall survival regardless of COPD status. Conclusion Several markers reflecting inflammation, endothelial activation and extracellular matrix remodelling are elevated in serum from patients with COPD compared to LC patients. Presence of COPD might influence the levels of circulating biomarkers. Some of these markers are also associated with prognosis.

• Brustugun, Odd Terje; Grønberg, Bjørn Henning; Fjellbirkeland, Lars; Helbekkmo, Nina; Aanerud, Marianne & Grimsrud, Tom Kristian [Vis alle 11 forfattere av denne artikkelen] (2018). Substantial nation-wide improvement in lung cancer relative survival in Norway from 2000 to 2016. Lung Cancer. ISSN 0169-5002. 122, s. 138–145. doi: 10.1016/j.lungcan.2018.06.003. Fulltekst i vitenarkiv Vis sammendrag

  Introduction There have been significant changes in both diagnostic procedures and therapy for lung cancer since the beginning of the millennium. National incidence and survival data from 2000 through 2016 are studied. Methods National data on cancer incidence and vital status are virtually complete. Changes in incidence and survival are described by absolute numbers, percentages, and calculation of relative survival (period analysis). Results A total of 44,825 individuals were diagnosed with lung cancer in Norway in the study period. The number of incident cases increased with 49% whereas the prevalence increased with 136% from 2000 to 2016. Age-standardised rates rose markedly for women and levelled off for men. In 2016, adenocarcinoma accounted for about 50% of all lung cancers, slightly more for women than for men. The entity “NSCLC not otherwise specified” declined from 24% to 13%, and the fraction of patients with metastatic disease decreased from 54% to 46% during the period, for both sexes combined. The overall median survival time doubled for women and men, reaching 14.3 months and 11.4 months, respectively. For patients with metastatic disease, median survival time showed a small increase but remained less than 6 months. The overall 5-year relative survival increased from 16% to 26% in women and from 16% to 22% in men. The corresponding improvements for the subgroup of non-surgically treated cases with localised disease, were up from 25% to more than 40% in females, and from 10% to almost 40% in males. Conclusion There have been notable changes in incidence patterns and a remarkable improvement in survival for lung cancer over the last 17 years, most markedly for patients without distant metastases at the time of diagnosis. Hopefully, survival will improve even more when immunotherapy is implemented.

• Halvorsen, Ann Rita; Sandhu, Vandana; Sprauten, Mette; Flote, Vidar Gordon; Kure, Elin Wenche Hegland & Brustugun, Odd Terje [Vis alle 7 forfattere av denne artikkelen] (2018). Circulating microRNAs associated with prolonged overall survival in lung cancer patients treated with nivolumab. Acta Oncologica. ISSN 0284-186X. 57(9), s. 1225–1231. doi: 10.1080/0284186X.2018.1465585. Fulltekst i vitenarkiv Vis sammendrag

  Background: The introduction of immune check-point inhibition in non-small cell lung cancer (NSCLC) therapy represents improved prospects for the patients. The response rates to check-point inhibitors are approximately 20% in unselected NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with higher response rates. However, patients with low PD-L1 levels may also have durable responses, and improved strategies for patient stratification are needed. Material and methods: In this study, we investigated circulating microRNAs aiming to identify circulating predictive biomarkers associated with increased overall survival after immune check-point treatment. Using next generation sequencing, we performed microRNA profiling in serum from NSCLC patients (n = 20) treated with nivolumab. Serum samples from 31 patients were used for validation using qPCR assays. Serum samples were collected prior to immune therapy initiation. Results: Based on multivariate regression analysis, we identified a signature of seven microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p, miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) > 6 months in discovery cohort (p = .0003). We further validated this in another similar set of samples (n = 31) and the model was significantly associated with overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of 71% and 90%, respectively. Conclusions: In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.

• Bugge, Anders; Lund, May-Brith; Valberg, Morten; Brustugun, Odd Terje; Solberg, Steinar & Kongerud, Johny (2018). Cause-specific death after surgical resection for early-stage non-small-cell lung cancer. European Journal of Cardio-Thoracic Surgery. ISSN 1010-7940. 53(1), s. 221–227. doi: 10.1093/ejcts/ezx274. Fulltekst i vitenarkiv
• Valan, Christine Damgaard; Slagsvold, Jens Erik; Halvorsen, Tarje Onsøien; Herje, Martin; Bremnes, Roy M. & Brunsvig, Paal Fr. [Vis alle 11 forfattere av denne artikkelen] (2018). Survival in Limited Disease Small Cell Lung Cancer According to N3 Lymph Node Involvement. Anticancer Research. ISSN 0250-7005. 38(2), s. 871–876. doi: 10.21873/anticanres.12296. Fulltekst i vitenarkiv Vis sammendrag

  We compared survival between subcategories of N3 disease in limited disease small cell lung cancer patients who received concurrent chemoradiotherapy (n=144). N3 disease was a negative prognostic factor, but there were no significant differences between the N3 subcategories. All patients had longer survival than in studies of extensive disease, suggesting that all N3 patients should be treated as limited disease.

• Stankovic, Branislava; Bjørhovde, Heidi Anine Korsmo; Skarshaug, Renate; Aamodt, Henrik; Frafjord, Astri & Müller, Elisabeth [Vis alle 14 forfattere av denne artikkelen] (2018). Immune Cell Composition in Human Non-small Cell Lung Cancer. Frontiers in Immunology. 9. doi: 10.3389/fimmu.2018.03101. Fulltekst i vitenarkiv Vis sammendrag

  Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the world. Immunological analysis of the tumor microenvironment (immunoscore) shows great promise for improved prognosis and prediction of response to immunotherapy. However, the exact immune cell composition in NSCLC remains unclear. Here, we used flow cytometry to characterize the immune infiltrate in NSCLC tumors, non-cancerous lung tissue, regional lymph node, and blood. The cellular identity of >95% of all CD45+ immune cells was determined. Thirteen distinct immune cell types were identified in NSCLC tumors. T cells dominated the lung cancer landscape (on average 47% of all CD45+ immune cells). CD4+ T cells were the most abundant T cell population (26%), closely followed by CD8+ T cells (22%). Double negative CD4−CD8− T cells represented a small fraction (1.4%). CD19+ B cells were the second most common immune cell type in NSCLC tumors (16%), and four different B cell sub-populations were identified. Macrophages and natural killer (NK) cells composed 4.7 and 4.5% of the immune cell infiltrate, respectively. Three types of dendritic cells (DCs) were identified (plasmacytoid DCs, CD1c+ DCs, and CD141+ DCs) which together represented 2.1% of all immune cells. Among granulocytes, neutrophils were frequent (8.6%) with a high patient-to- patient variability, while mast cells (1.4%), basophils (0.4%), and eosinophils (0.3%) were less common. Across the cohort of patients, only B cells showed a significantly higher representation in NSCLC tumors compared to the distal lung. In contrast, the percentages of macrophages and NK cells were lower in tumors than in non-cancerous lung tissue. Furthermore, the fraction of macrophages with high HLA-DR expression levels was higher in NSCLC tumors relative to distal lung tissue. To make the method readily accessible, antibody panels and flow cytometry gating strategy used to identify the various immune cells are described in detail. This work should represent a useful resource for the immunomonitoring of patients with NSCLC.

• Helland, Åslaug; Brustugun, Odd Terje; Nakken, Sigve; Halvorsen, Ann Rita; Dønnem, Tom & Bremnes, Roy M. [Vis alle 15 forfattere av denne artikkelen] (2017). High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival. International Journal of Cancer. ISSN 0020-7136. 141(1), s. 184–190. doi: 10.1002/ijc.30726. Fulltekst i vitenarkiv Vis sammendrag

  Lung cancer is the leading cause of cancer related death, and the past years’ improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse‐free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and untranslated regions of all known kinases, kinase receptors and selected cancer‐related genes (612 genes in total). CD8 staining was determined using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA‐repair genes and the total number of mutations in that tumour (p < 0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations.

• Mcgowan, Marc Kevin; Kleinberg, Lilach; Halvorsen, Ann Rita; Helland, Åslaug & Brustugun, Odd Terje (2017). NSCLC depend upon YAP expression and nuclear localization after acquiring resistance to EGFR inhibitors. Genes & cancer. ISSN 1947-6019. 8(3-4), s. 497–504. doi: 10.18632/genesandcancer.136. Fulltekst i vitenarkiv Vis sammendrag

  Yes-associated protein (YAP) is a downstream target of the Hippo pathway and has been found to be oncogenic driving many cancers into developing metastatic phenotypes leading to poor survival outcomes. This study investigated if YAP expression is associated with drug resistance in two non-small cell lung cancer (NSCLC) lines (HCC827 and H1975) generated to become resistant to the EGFR tyrosine kinase inhibitors (EGFR TKI) erlotinib, gefitinib or the T790M-specific osimertinib. We found that acquired EGFR TKI resistance was associated with YAP over-expression (osimertinib-resistant cells) or YAP amplification (erlotinib- and gefitinib-resistant cells) along with EMT phenotypic changes. YAP was localized in the nucleus, indicative of active protein. siRNA-mediated silencing of YAP resulted in re-sensitizing the drug-resistant cells to EGFR TKI compared to the negative siRNA controls (p = <0.05). These results suggest YAP is a potential mechanism of EGFR-TKI resistance in NSCLC and may presents itself as a viable therapeutic target.

• Brustugun, Odd Terje; Sprauten, Mette & Helland, Åslaug (2017). Real-world data on nivolumab treatment of non-small cell lung cancer. Acta Oncologica. ISSN 0284-186X. 56(3), s. 438–440. doi: 10.1080/0284186X.2016.1253865. Fulltekst i vitenarkiv
• Pedersen, Jesper Holst; Sørensen, Jens Benn; Saghir, Zaigham; Fløtten, Øystein; Brustugun, Odd Terje & Ashraf, Haseem [Vis alle 15 forfattere av denne artikkelen] (2017). Implementation of lung cancer CT screening in the Nordic countries. Acta Oncologica. ISSN 0284-186X. 56(10), s. 1249–1257. doi: 10.1080/0284186X.2017.1329592. Fulltekst i vitenarkiv
• Meyer, Mathias; Vliegenthart, Rozemarijn; Henzler, Thomas; Buergy, Daniel; Giordano, Frank A. & Kostrzewa, Michael [Vis alle 29 forfattere av denne artikkelen] (2017). Management of progressive pulmonary nodules found during and outside of CT lung cancer screening studies. Journal of Thoracic Oncology. ISSN 1556-0864. 12(12), s. 1755–1765. doi: 10.1016/j.jtho.2017.09.1956. Fulltekst i vitenarkiv
• Nyman, Jan; Hallqvist, Andreas; Lund, Jo-Åsmund; Brustugun, Odd Terje; Bergman, Bengt & Bergström, Per [Vis alle 10 forfattere av denne artikkelen] (2016). SPACE – A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC. Radiotherapy and Oncology. ISSN 0167-8140. 121(1), s. 1–8. doi: 10.1016/j.radonc.2016.08.015. Fulltekst i vitenarkiv
• Nilssen, Yngvar; Strand, Trond-Eirik; Fjellbirkeland, Lars; Bartnes, Kristian; Brustugun, Odd Terje & O'Connell, Dianne L [Vis alle 8 forfattere av denne artikkelen] (2016). Lung cancer treatment is influenced by income, education, age and place of residence in a country with universal health coverage. International Journal of Cancer. ISSN 0020-7136. 138(6), s. 1350–1360. doi: 10.1002/ijc.29875. Fulltekst i vitenarkiv
• Dønnem, Tom; Kilvær, Thomas Karsten; Andersen, Sigve; Richardsen, Elin; Paulsen, Erna-Elise & Hald, Sigurd [Vis alle 21 forfattere av denne artikkelen] (2016). Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Annals of Oncology. ISSN 0923-7534. 27(2), s. 225–232. doi: 10.1093/annonc/mdv560. Fulltekst i vitenarkiv
• Halvorsen, Tarje Onsøien; Sundstrøm, Stein Harald; Fløtten, Øystein; Brustugun, Odd Terje; Brunsvig, Paal Fr. & Aasebø, Ulf [Vis alle 9 forfattere av denne artikkelen] (2016). Comorbidity and outcomes of concurrent chemo- and radiotherapy in limited disease small cell lung cancer. Acta Oncologica. ISSN 0284-186X. 55(11), s. 1349–1354. doi: 10.1080/0284186X.2016.1201216. Fulltekst i vitenarkiv Vis sammendrag

  Background: Many patients with limited disease small cell lung cancer (LD SCLC) suffer from comorbidity. Not all patients with comorbidity are offered standard treatment, though there is little evidence for such a policy. The aim of this study was to investigate whether patients with comorbidity had inferior outcomes in a LD SCLC cohort. Material and methods: We analyzed patients from a randomized study comparing two three-week schedules of thoracic radiotherapy (TRT) plus standard chemotherapy in LD SCLC. Patients were to receive four courses of cisplatin/etoposide and TRT of 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily). Responders received prophylactic cranial irradiation (PCI). Comorbidity was assessed using the Charlson Comorbidity Index (CCI), which rates conditions with increased one-year mortality. Results: In total 157 patients were enrolled between May 2005 and January 2011. Median age was 63 years, 52% were men, 16% had performance status 2, and 72% stage III disease. Forty percent had no comorbidity; 34% had CCI-score 1; 15% CCI 2; and 11% CCI 3–5. There were no significant differences in completion rates of chemotherapy, TRT or PCI across CCI-scores; or any significant differences in the frequency of grade 3–5 toxicity (p = 0.49), treatment-related deaths (p = 0.36), response rates (p = 0.20), progression-free survival (p = 0.18) or overall survival (p = 0.09) between the CCI categories. Conclusion: Patients with comorbidity completed and tolerated chemo-radiotherapy as well as other patients. There were no significant differences in response rates, progression-free survival or overall survival – suggesting that comorbidity alone is not a reason to withhold standard therapy in LD SCLC.

• Joly-Battaglini, Albane; Hammarström, Clara Louise; Stankovic, Branislava; Aamodt, Henrik; Stjärne, Johan Folke Håkan & Brustugun, Odd Terje [Vis alle 9 forfattere av denne artikkelen] (2016). Rituximab efficiently depletes B cells in lung tumors and normal lung tissue. F1000. 5. doi: 10.12688/f1000research.7599.1. Fulltekst i vitenarkiv
• Mcgowan, Marc Kevin; Hoven, Aleksandra Silye; Lund-Iversen, Marius; Solberg, Steinar; Helland, Åslaug & Hirsch, Fred R [Vis alle 7 forfattere av denne artikkelen] (2016). PIK3CA mutations as prognostic factor in squamous cell lung carcinoma. Lung Cancer. ISSN 0169-5002. 103, s. 52–57. doi: 10.1016/j.lungcan.2016.11.018. Fulltekst i vitenarkiv

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• Brustugun, Odd Terje; Bråthen, Siri; Stensland, Elin Marie; Gløersen, Anne Siri; Madebo, Tesfaye & Heinrich, Daniel [Vis alle 10 forfattere av denne artikkelen] (2026). UV1 vaccine with standard of care PD-1 checkpoint inhibitor as first-line treatment for non-small cell lung cancer (NSCLC): A randomized phase II trial - 115P. doi: https:/cslide.ctimeetingtech.com/coasis_21526/attendee/confcal_1/presentation/list?q=115P&r=pt%7E3. Fulltekst i vitenarkiv Vis sammendrag

  Background While immunotherapy has improved outcomes in NSCLC, its efficacy is limited in many patients, warranting exploration of combination strategies such as the telomerase-targeting UV1 vaccine to enhance immune response and overcome resistance to checkpoint inhibitors. Conclusions UV1 in combination with SoC was well tolerated but did not significantly improve PFS or DoR. Although OS was not significantly longer in UV1-treated patients, a numerical OS advantage was seen, warranting further investigation and longer follow-up. Clinical trial identification EudraCT 2021-005729-25; NCT05344209.https://clinicaltrials.gov/study/NCT05344209

• Krager, Eirik; Nilssen, Yngvar & Brustugun, Odd Terje (2026). Correlation of geographic and temporal variations in diagnostic imaging and diagnosis of early-stage lung cancer - 366P. doi: https:/cslide.ctimeetingtech.com/coasis_21526/attendee/confcal_1/presentation/list?q=366P. Fulltekst i vitenarkiv Vis sammendrag

  Background CT-based screening reduces lung cancer mortality in high-risk groups, but Norway lacks formal programs. This study examines whether geographic and temporal variations in outpatient CT thorax scan rates correlate with early-stage lung cancer incidence or resection rates, potentially indicating opportunistic screening value. Conclusions High CT usage shows geographic/smoking-linked variation but no link to early-stage lung cancer detection or resections. Rising scans parallel early detections without causation, questioning opportunistic screening efficacy outside targeted programs.

• Brustugun, Odd Terje; Grønberg, Bjørn Henning; Aanerud, Marianne; Paulsen, Erna-Elise & Fjellbirkeland, Lars (2025). Lung Cancer in Norway. Journal of Thoracic Oncology. ISSN 1556-0864. 20(7), s. 839–846. doi: 10.1016/j.jtho.2025.03.046. Fulltekst i vitenarkiv
• Nyen, Johanne Elise; Booth, Anja Ødegård; Husby, Øyvind; Bugge, Christoffer; Engebretsen, Ingrid & Oteiza, Francisco [Vis alle 10 forfattere av denne artikkelen] (2025). Corrigendum: Targeted treatment and survival in advanced non-squamous non-small cell lung cancer patients – a nationwide and longitudinal study (Frontiers in Oncology, (2025), 15, (1506041), 10.3389/fonc.2025.1506041). Frontiers in Oncology. 15. doi: 10.3389/fonc.2025.1595028. Fulltekst i vitenarkiv
• Brustugun, Odd Terje (2023). Håp når håpløsheten truer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(5). doi: 10.4045/tidsskr.23.0095. Fulltekst i vitenarkiv
• Grønberg, Bjørn Henning; Killingberg, Kristin Toftaker; Fløtten, Øystein; Bjaanæs, Maria Moksnes; Madebo, Tesfaye & Schytte, Tine [Vis alle 19 forfattere av denne artikkelen] (2023). Final survival data from a randomized phase II trial comparing high-dose with standard-dose twice-daily (BID) thoracic radiotherapy (TRT) in limited stage small-cell lung cancer (LS SCLC). Journal of Clinical Oncology. ISSN 0732-183X. 41(16). doi: 10.1200/JCO.2023.41.16_suppl.8512. Fulltekst i vitenarkiv
• Tasken, Kjetil; Russnes, Hege Elisabeth Giercksky; Aas, Eline; Bjørge, Line; Blix, Egil Støre & Ahlquist, Terje C. [Vis alle 116 forfattere av denne artikkelen] (2022). A national precision cancer medicine implementation initiative for Norway. Nature Medicine. ISSN 1078-8956. 28(5), s. 885–887. doi: 10.1038/s41591-022-01777-4. Fulltekst i vitenarkiv
• Brustugun, Odd Terje (2022). Slik kan man få tilgang til legemidler uten vedtak i Beslutningsforum. 142(2). doi: 10.4045/tidsskr.21.0886. Fulltekst i vitenarkiv
• Brustugun, Odd Terje (2021). Kreft og koronarisiko. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(2). doi: 10.4045/tidsskr.20.1044. Fulltekst i vitenarkiv
• Brustugun, Odd Terje; Sørhaug, Sveinung; Grønberg, Bjørn Henning; Aanerud, Marianne; Al-Zubaydi, Mohammed Modar & Fjellbirkeland, Lars [Vis alle 13 forfattere av denne artikkelen] (2020). Lungekreft: Forbedret prognose gir kapasitetsutfordringer. 140(5). doi: 10.4045/tidsskr.20.0014. Fulltekst i vitenarkiv
• Sørensen, J.B.; Ekman, S.; Brustugun, Odd Terje; Horvat, P.; Patel, D. & Rosenlund, M. [Vis alle 13 forfattere av denne artikkelen] (2019). Evolution of overall survival (OS) in patients (pts) with incident NSCLC in Denmark and Sweden: A SCAN-LEAF study analysis from the I-O Optimise initiative. Annals of Oncology. ISSN 0923-7534. 30, s. ii16–ii17. doi: 10.1093/annonc/mdz070.004. Fulltekst i vitenarkiv
• Ekman, S.; Sørensen, J.B.; Brustugun, Odd Terje; Horvat, P.; Patel, D. & Rosenlund, M. [Vis alle 13 forfattere av denne artikkelen] (2019). Treatment (Tx) patterns and overall survival (OS) in patients (pts) with NSCLC in Sweden: A SCAN-LEAF study analysis from the I-O Optimise initiative. Annals of Oncology. ISSN 0923-7534. 30, s. ii17–ii17. doi: 10.1093/annonc/mdz070.005. Fulltekst i vitenarkiv
• Berg, Janna; Lindberg, Morten; Bengtson, May-Bente; Brustugun, Odd Terje & Helland, Åslaug (2019). The Neutrophil and Platelet to Lymphocyte Ratios and Glasgow Prognostic Score as a Predictor for Relapse After Stereotactic Radiation for Lung Cancer. Journal of Thoracic Oncology. ISSN 1556-0864. 14, s. S1101–S1101. doi: 10.1016/j.jtho.2019.08.2457. Fulltekst i vitenarkiv
• Brustugun, Odd Terje (2019). A NOTCH added to metabolomics. British Journal of Cancer. ISSN 0007-0920. 121, s. 3–4. doi: 10.1038/s41416-019-0463-0. Fulltekst i vitenarkiv
• Knudtsen, Ingerid Søberg Skjei; Eide, Hanne Astrid; Løndalen, Ayca; Abravan, Azadeh; Bogsrud, Trond & Sprauten, Mette [Vis alle 9 forfattere av denne artikkelen] (2017). 18FDG-PET/CT for assessing short-term therapy response of advanced non-small cell lung cancer patients. Fulltekst i vitenarkiv

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