Publications by authors named "Åslaug Helland"

125 Publications

Intracranial effect of osimertinib in relapsed -mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study.

Acta Oncol 2021 Sep 6:1-7. Epub 2021 Sep 6.

Section of Oncology, Vestre Viken Hospital Trust, Drammen, Norway.

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 ( < 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.
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http://dx.doi.org/10.1080/0284186X.2021.1973092DOI Listing
September 2021

MRI pulse sequence integration for deep-learning-based brain metastases segmentation.

Med Phys 2021 Aug 18. Epub 2021 Aug 18.

Department of Biomedical Data Science, Stanford University, Stanford, California, USA.

Purpose: Magnetic resonance (MR) imaging is an essential diagnostic tool in clinical medicine. Recently, a variety of deep-learning methods have been applied to segmentation tasks in medical images, with promising results for computer-aided diagnosis. For MR images, effectively integrating different pulse sequences is important to optimize performance. However, the best way to integrate different pulse sequences remains unclear. In addition, networks trained with a certain subset of pulse sequences as input are unable to perform when given a subset of those pulse sequences. In this study, we evaluate multiple architectural features and characterize their effects in the task of metastasis segmentation while creating a method to robustly train a network to be able to work given any strict subset of the pulse sequences available during training.

Methods: We use a 2.5D DeepLabv3 segmentation network to segment metastases lesions on brain MR's with four pulse sequence inputs. To study how we can best integrate MR pulse sequences for this task, we consider (1) different pulse sequence integration schemas, combining our features at early, middle, and late points within a deep network, (2) different modes of weight sharing for parallel network branches, and (3) a novel integration level dropout layer, which will allow the networks to be robust to performing inference on input with only a subset of pulse sequences available at the training.

Results: We find that levels of integration and modes of weight sharing that favor low variance work best in our regime of small amounts of training data (n = 100). By adding an input-level dropout layer, we could preserve the overall performance of these networks while allowing for inference on inputs with missing pulse sequences. We illustrate not only the generalizability of the network but also the utility of this robustness when applying the trained model to data from a different center, which does not use the same pulse sequences. Finally, we apply network visualization methods to better understand which input features are most important for network performance.

Conclusions: Together, these results provide a framework for building networks with enhanced robustness to missing data while maintaining comparable performance in medical imaging applications.
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http://dx.doi.org/10.1002/mp.15136DOI Listing
August 2021

Dynamic changes in the T cell receptor repertoire during treatment with radiotherapy combined with an immune checkpoint inhibitor.

Mol Oncol 2021 Aug 17. Epub 2021 Aug 17.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norway.

Previous studies have indicated a synergistic effect between radiotherapy and immunotherapy. A better understanding of how this combination affects the immune system can help to clarify its role in the treatment of metastatic cancer. We performed T cell receptor (TCR) sequencing on 46 sequentially collected samples from 15 patients with stage IV non-small cell lung cancer, receiving stereotactic body radiotherapy combined with a programmed cell death ligand-1 (PD-L1) inhibitor. TCR repertoire diversity was assessed using Rényi diversity curves and the Shannon diversity index. TCR clones were tracked over time. We found decreasing or stable diversity in the best responders, and an increase in diversity at progression in patients with an initial response. Expansion of TCR clones was more often seen in responders. Several patients also developed new clones of high abundance. This seemed to be more related to radiotherapy than to immune checkpoint blockade. In summary, we observed similar dynamics in the TCR repertoire as have been described with immunotherapy alone. In addition, the occurrence of new unique clones of high abundance after radiotherapy may indicate that radiotherapy functions as a personalized cancer vaccine.
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http://dx.doi.org/10.1002/1878-0261.13082DOI Listing
August 2021

Lung Function After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer, Changes and Predictive Markers.

Front Oncol 2021 24;11:674731. Epub 2021 May 24.

Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Introduction: The present study explores changes in pulmonary function, symptoms and radiological signs of pneumonitis after curatively intended stereotactic body radiation therapy (SBRT).

Methods: All inoperable, early-stage non-small cell lung cancer patients treated with stereotactic body radiation therapy (SBRT) from 2014-2017 were included in this single-centre study. They were followed regularly for 12 months after treatment. The patients were classified into three groups based on radiology and symptomatology: no radiation pneumonitis, asymptomatic and symptomatic radiation pneumonitis.

Results: Forty-four patients with stage IA-IIB disease were treated with 45-56 Gy in 3-8 fractions. The median age was 75 years, 43% of the patients were female; 60% of the patients had a COPD in GOLD grade of 2-4, and 95.5% were active or former smokers. Symptomatic radiation pneumonitis occurred in 18% of the patients and asymptomatic pneumonitis as defined by radiology, in 39%. The mean of forced expiratory volume in 1 second (FEV1) and diffusion capacity for carbon monoxide (DLCO) decreases for all patients during the first years were higher than one would expect from physiologic ageing. FEV1 and DLCO in percent decrease 7-8% at 1-1.5 months in the symptomatic radiation pneumonitis group. CT scan findings consistent with radiation pneumonitis occurred after a median of 2.9 months in the symptomatic and 5.4 months in the asymptomatic radiation pneumonitis groups. In the group with symptomatic radiation pneumonitis, symptoms, as measured by the Clinical COPD questionnaire score, significantly increased at 3 and 6 months. Significant higher maximum doses to the critical lung volumes DC1000cm (1000 cm of lung receiving a given dose or less) and DC 1500cm (1500 cm of lung receiving a given dose or less) were observed in patients who developed radiation pneumonitis.

Conclusion: Early decrease in measured FEV1 and DLCO occurred before imaging changes and symptoms and might indicate the development of symptomatic radiation pneumonitis. The dose to critical lung volumes of DC1000 cm and DC1500 cm may predict the risk for the development of symptomatic radiation pneumonitis.
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http://dx.doi.org/10.3389/fonc.2021.674731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181743PMC
May 2021

NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma.

J Transl Med 2021 05 31;19(1):232. Epub 2021 May 31.

Department of Oncology, Oslo University Hospital, Oslo, Norway.

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients.

Methods: NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy.

Discussion: Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy.

Trial Registration: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1 .
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http://dx.doi.org/10.1186/s12967-021-02905-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165504PMC
May 2021

Real-world treatment outcomes with brigatinib in patients with pretreated ALK+ metastatic non-small cell lung cancer.

Lung Cancer 2021 07 24;157:9-16. Epub 2021 May 24.

Oncology Department, University of Turin, AOU San Luigi, 10043, Orbassano, Turin, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.017DOI Listing
July 2021

Age-related treatment patterns for stage I NSCLC in three European countries.

J Geriatr Oncol 2021 May 13. Epub 2021 May 13.

Department of Registration, Cancer Registry of Norway, Oslo, Norway.

Introduction: Surgery is the preferred treatment for patients with early-stage non-small cell lung cancer (NSCLC) while stereotactic body radiation therapy (SBRT) may be applied in patients with major comorbidity or high age. We evaluated the association between age and treatment utilization for early-stage NSCLC in patients diagnosed in 2015-2016 in three European countries.

Patients And Methods: Information was retrieved from population-based registries in England, Norway and the Netherlands. Treatment patterns and two-year overall survival rates for 105,124 patients with clinical stage I were analysed by age-group.

Results: Surgical resection rates were higher in Norway (55%) and England (53%) than in the Netherlands (47%), and decreased with increasing age. SBRT use was highest in the Netherlands (41%), followed by Norway (29%) and England (12%). In the Netherlands, SBRT was the prevailing treatment in patients aged 70 years or older. In octogenarians, the proportion not receiving curative intent treatment was 53% in England, versus 35% in Norway and 22% in the Netherlands. Two-year survival rates were better for surgery than for SBRT and slightly better in Norway.

Conclusion: In patients aged 70 years or older, the proportion not receiving any curative treatment remains substantial, and differs significantly between countries. Measures to address these disparities are needed.
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http://dx.doi.org/10.1016/j.jgo.2021.05.005DOI Listing
May 2021

COVID-19 in Cancer Patients, Risk Factors for Disease and Adverse Outcome, a Population-Based Study From Norway.

Front Oncol 2021 25;11:652535. Epub 2021 Mar 25.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Cancer has been suggested as a risk factor for severe outcome of SARS-CoV-2 infection. In this population-based study we aimed to identify factors associated with higher risk of COVID-19 and adverse outcome.

Methods: Data on all confirmed SARS-CoV-2 positive patients in the period January 1 to May 31, 2020 were extracted from the Norwegian Surveillance System for Communicable Diseases. Data on cancer and treatment was available from the Cancer Registry of Norway, the Norwegian Patient Registry and the Norwegian Prescription Database. Deaths due to COVID-19 were extracted from the Cause of Death Registry. From the Norwegian Intensive Care and Pandemic Registry we retrieved data on admittance to hospital and intensive care. We determined rates of COVID-19 disease in cancer patients and the rest of the population. We also ran multivariate analyses adjusting for age and gender.

Results: A total of 8 410 patients were diagnosed with SARS-CoV-2 infection in Norway during the study period, of which 547 (6.5%) were cancer patients. Overall, we found similar age adjusted rates of COVID-19 in the population with cancer as in the population without cancer. Unadjusted analysis showed that patients having undergone major surgery within the past 3 months had an increased risk of COVID-19 while we did not find increased Odds Ratio (OR) related to other oncological treatment modalities. No patients treated with stem cell or bone marrow transplant were diagnosed with COVID-19. The fatality rate of COVID-19 among cancer patients was 0.10. This was similar to non-cancer patients, when adjusting for age and sex with OR (95% CI) for death= 0.99 (0.68-1.42). Patients with distant metastases had significantly increased OR of death due to COVID-19 disease of 9.31 (95% CI 2.60-33.34). For the combined outcome death and/or admittance to hospital due to COVID-19, we found significant two-fold increased risk estimates for patients diagnosed with cancer less than one 1 year ago (OR 2.08, 95% CI 1.14-3.80), for those treated with anti-cancer drugs during the past 3 months (OR 1.80, 95% CI 1.07-3.01) and for patients undergoing major surgery during the past 3 months (OR 2.19, 95% CI 1.40-3.44).
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http://dx.doi.org/10.3389/fonc.2021.652535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027113PMC
March 2021

Rovalpituzumab Tesirine as a Maintenance Therapy After First-Line Platinum-Based Chemotherapy in Patients With Extensive-Stage-SCLC: Results From the Phase 3 MERU Study.

J Thorac Oncol 2021 09 3;16(9):1570-1581. Epub 2021 Apr 3.

Department of Oncology, Sheba Medical Center, Ramat Gan, Israel; Sackler Medical School, Tel-Aviv University, Tel-Aviv, Israel.

Introduction: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy.

Methods: MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors.

Results: Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p < 0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%).

Conclusions: Because of the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early. As a result, the Central Radiographic Assessment Committee evaluation of PFS was not performed. The frequency of grade greater than or equal to 3 and drug-related toxicities were higher with Rova-T versus placebo. Rova-T was associated with unique toxicities, such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the population with extensive-stage-SCLC.
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http://dx.doi.org/10.1016/j.jtho.2021.03.012DOI Listing
September 2021

Handling missing MRI sequences in deep learning segmentation of brain metastases: a multicenter study.

NPJ Digit Med 2021 Feb 22;4(1):33. Epub 2021 Feb 22.

Department of Radiology, Stanford University, Stanford, USA.

The purpose of this study was to assess the clinical value of a deep learning (DL) model for automatic detection and segmentation of brain metastases, in which a neural network is trained on four distinct MRI sequences using an input-level dropout layer, thus simulating the scenario of missing MRI sequences by training on the full set and all possible subsets of the input data. This retrospective, multicenter study, evaluated 165 patients with brain metastases. The proposed input-level dropout (ILD) model was trained on multisequence MRI from 100 patients and validated/tested on 10/55 patients, in which the test set was missing one of the four MRI sequences used for training. The segmentation results were compared with the performance of a state-of-the-art DeepLab V3 model. The MR sequences in the training set included pre-gadolinium and post-gadolinium (Gd) T1-weighted 3D fast spin echo, post-Gd T1-weighted inversion recovery (IR) prepped fast spoiled gradient echo, and 3D fluid attenuated inversion recovery (FLAIR), whereas the test set did not include the IR prepped image-series. The ground truth segmentations were established by experienced neuroradiologists. The results were evaluated using precision, recall, Intersection over union (IoU)-score and Dice score, and receiver operating characteristics (ROC) curve statistics, while the Wilcoxon rank sum test was used to compare the performance of the two neural networks. The area under the ROC curve (AUC), averaged across all test cases, was 0.989 ± 0.029 for the ILD-model and 0.989 ± 0.023 for the DeepLab V3 model (p = 0.62). The ILD-model showed a significantly higher Dice score (0.795 ± 0.104 vs. 0.774 ± 0.104, p = 0.017), and IoU-score (0.561 ± 0.225 vs. 0.492 ± 0.186, p < 0.001) compared to the DeepLab V3 model, and a significantly lower average false positive rate of 3.6/patient vs. 7.0/patient (p < 0.001) using a 10 mm lesion-size limit. The ILD-model, trained on all possible combinations of four MRI sequences, may facilitate accurate detection and segmentation of brain metastases on a multicenter basis, even when the test cohort is missing input MRI sequences.
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http://dx.doi.org/10.1038/s41746-021-00398-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900111PMC
February 2021

Epigenetic-smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients.

Mol Oncol 2020 11 3;14(11):2759-2774. Epub 2020 Sep 3.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 × 10), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking (37.49 vs 54.79, P = 1.03 × 10) and included a higher proportion of current smokers than LUAD patients (28.24% vs 34.09%, P = 0.037). cg05293407 was significantly associated with overall survival only in NSCLC patients with medium-high pack-year of smoking (HR = 1.58, 95% CI: 1.26-1.96, P = 5.25 × 10). We conclude that cg05293407 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.
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http://dx.doi.org/10.1002/1878-0261.12785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607178PMC
November 2020

Immune checkpoint blockade in the treatment of advanced non-small cell lung cancer - predictors of response and impact of previous radiotherapy.

Acta Oncol 2021 Feb 24;60(2):149-156. Epub 2020 Dec 24.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.

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.
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http://dx.doi.org/10.1080/0284186X.2020.1854851DOI Listing
February 2021

Protein Kinase C Isozymes Associated With Relapse Free Survival in Non-Small Cell Lung Cancer Patients.

Front Oncol 2020 25;10:590755. Epub 2020 Nov 25.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.

Introduction: 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 , , and -mutations.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.3389/fonc.2020.590755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725872PMC
November 2020

Noise dependency in vascular parameters from combined gradient-echo and spin-echo DSC MRI.

Phys Med Biol 2020 11 17;65(22):225020. Epub 2020 Nov 17.

Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway. Department of Physics, University of Oslo, Oslo, Norway.

Dynamic susceptibility contrast (DSC) imaging is a widely used technique for assessment of cerebral blood volume (CBV). With combined gradient-echo and spin-echo DSC techniques, measures of the underlying vessel size and vessel architecture can be obtained from the vessel size index (VSI) and vortex area, respectively. However, how noise, and specifically the contrast-to-noise ratio (CNR), affect the estimations of these parameters has largely been overlooked. In order to address this issue, we have performed simulations to generate DSC signals with varying levels of CNR, defined by the peak of relaxation rate curve divided by the standard deviation of the baseline. Moreover, DSC data from 59 brain cancer patients were acquired at two different 3 T-scanners (N = 29 and N = 30, respectively), where CNR and relative parameter maps were obtained. Our simulations showed that the measured parameters were affected by CNR in different ways, where low CNR led to overestimations of CBV and underestimations of VSI and vortex area. In addition, a higher noise-sensitivity was found in vortex area than in CBV and VSI. Results from clinical data were consistent with simulations, and indicated that CNR < 4 gives highly unreliable measurements. Moreover, we have shown that the distribution of values in the tumour regions could change considerably when voxels with CNR below a given cut off are excluded when generating the relative parameter maps. The widespread use of CBV and attractive potential of VSI and vortex area, makes the noise-sensitivity of these parameters found in our study relevant for further use and development of the DSC imaging technique. Our results suggest that the CNR has considerable impact on the measured parameters, with the potential to affect the clinical interpretation of DSC-MRI, and should therefore be taken into account in the clinical decision-making process.
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http://dx.doi.org/10.1088/1361-6560/abb71aDOI Listing
November 2020

Responses in the diffusivity and vascular function of the irradiated normal brain are seen up until 18 months following SRS of brain metastases.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa028. Epub 2020 Feb 28.

Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway.

Background: MRI may provide insights into longitudinal responses in the diffusivity and vascular function of the irradiated normal-appearing brain following stereotactic radiosurgery (SRS) of brain metastases.

Methods: Forty patients with brain metastases from non-small cell lung cancer ( = 26) and malignant melanoma ( = 14) received SRS (15-25 Gy). Longitudinal MRI was performed pre-SRS and at 3, 6, 9, 12, and 18 months post-SRS. Measures of tissue diffusivity and vascularity were assessed by diffusion-weighted and perfusion MRI, respectively. All maps were normalized to white matter receiving less than 1 Gy. Longitudinal responses were assessed in normal-appearing brain, excluding tumor and edema, in the LowDose (1-10 Gy) and HighDose (>10 Gy) regions. The Eastern Cooperative Oncology Group (ECOG) performance status was recorded pre-SRS.

Results: Following SRS, the diffusivity in the LowDose region increased continuously for 1 year (105.1% ± 6.2%; < .001), before reversing toward pre-SRS levels at 18 months. Transient reductions in microvascular cerebral blood volume ( < .05), blood flow ( < .05), and vessel densities ( < .05) were observed in LowDose at 6-9 months post-SRS. Correspondingly, vessel calibers in LowDose transiently increased at 3-9 months ( < .01). The responses in HighDose displayed similar trends as in LowDose, but with larger interpatient variations. Vascular responses followed pre-SRS ECOG status.

Conclusions: Our results imply that even low doses of radiation to normal-appearing brain following cerebral SRS induce increased diffusivity and reduced vascular function for up until 18 months. In particular, the vascular responses indicate the reduced ability of the normal-appearing brain tissue to form new capillaries. Assessing the potential long-term neurologic effects of SRS on the normal-appearing brain is warranted.
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http://dx.doi.org/10.1093/noajnl/vdaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212876PMC
February 2020

Epigenome-wide gene-age interaction analysis reveals reversed effects of DNA methylation on survival between young and elderly early-stage NSCLC patients.

Aging (Albany NY) 2020 06 8;12(11):10642-10662. Epub 2020 Jun 8.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

DNA methylation changes during aging, but it remains unclear whether the effect of DNA methylation on lung cancer survival varies with age. Such an effect could decrease prediction accuracy and treatment efficacy. We performed a methylation-age interaction analysis using 1,230 early-stage lung adenocarcinoma patients from five cohorts. A Cox proportional hazards model was used to investigate lung adenocarcinoma and squamous cell carcinoma patients for methylation-age interactions, which were further confirmed in a validation phase. We identified one adenocarcinoma-specific CpG probe, cg14326354, with effects significantly modified by age ( = 0.989; 95% CI: 0.986-0.994; = 9.18×10-7). The effect of low methylation was reversed for young and elderly patients categorized by the boundary of 95% CI standard ( = 2.44; 95% CI: 1.26-4.72; = 8.34×10-3; = 0.58; 95% CI: 0.42-0.82; = 1.67×10-3). Moreover, there was an antagonistic interaction between low cg14326354 methylation and elderly age ( = 0.21; 95% CI: 0.11-0.40; = 2.20×10-6). In summary, low methylation of cg14326354PRODH might benefit survival of elderly lung adenocarcinoma patients, providing new insight to age-specific prediction and potential drug targeting.
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http://dx.doi.org/10.18632/aging.103284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346054PMC
June 2020

Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy.

Int J Cancer 2020 11 17;147(10):2957-2966. Epub 2020 Jun 17.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

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.
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http://dx.doi.org/10.1002/ijc.33121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540694PMC
November 2020

The immune microenvironment in typical carcinoid lung tumour, a brief report of four cases.

Scand J Immunol 2020 Aug 9;92(2):e12893. Epub 2020 Jun 9.

Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway.

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.
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http://dx.doi.org/10.1111/sji.12893DOI Listing
August 2020

Antibody combinations for optimized staining of macrophages in human lung tumours.

Scand J Immunol 2020 Jul 10;92(1):e12889. Epub 2020 May 10.

Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway.

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.
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http://dx.doi.org/10.1111/sji.12889DOI Listing
July 2020

Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study).

Lung Cancer 2020 05 12;143:27-35. Epub 2020 Mar 12.

Vestre Viken Hospital Trust, Drammen, Norway; Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

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.

Clinical Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02504346).
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http://dx.doi.org/10.1016/j.lungcan.2020.03.009DOI Listing
May 2020

Radiotherapy-related lymphopenia in patients with advanced non-small cell lung cancer receiving palliative radiotherapy.

Clin Transl Radiat Oncol 2020 May 19;22:15-21. Epub 2020 Feb 19.

Department of Medical Physics, Oslo University Hospital, Oslo, Norway.

Background: Lymphopenia during radiotherapy (RT) may have an adverse effect on treatment outcome. The aim of this study is to investigate associations between lymphopenia and RT parameters in patients with advanced lung cancer. Moreover, to investigate the prognostic role of lymphopenia, blood protein levels, and treatment and patient-related factors.

Material And Methods: Sixty-two advanced stage non-small cell lung cancer (NSCLC) patients were retrospectively analyzed. Blood counts were available prior to, during, and after RT (3Gyx10). For each patient, a thoracic volume of interest (VOI) -including thoracic soft tissue and trabecular bone- was obtained by applying a CT window of -500 to 1200 HU in the planning CT. Dose parameters from thoracic VOI and other regions including lungs and vertebrae were calculated. Association between risk of lymphopenia ≥ G3 (lymphocytes at nadir according to CTCAE v4.0) and therapeutic parameters was investigated using Logistic regression. Relationships between overall survival (OS) and RT dose parameters, baseline blood counts and protein levels, and clinical factors were evaluated using Log-rank and Cox models.

Result: Mean thoracic RT dose (odds ratio [OR] 1.67; p = 0.04), baseline lymphocytes (OR 0.65; p = 0.01), and corticosteroids use (OR 6.07; p = 0.02) were significantly associated with increased risk of lymphopenia ≥ G3 in multivariable analysis. Worse OS was associated with high mean thoracic RT dose, high CRP/Albumin, large tumor volume and corticosteroids use (p < 0.05, univariate analysis), but not with lymphopenia ≥ G3. CRP/Albumin ratio > 0.12 (hazard ratio [HR] 2.28, p = 0.03) and corticosteroid use (HR 2.52, p = 0.01) were independently associated with worse OS.

Conclusion: High thoracic RT dose gave a higher risk of lymphopenia ≥ G3; hence limiting dose volume to the thorax may be valuable in preventing severe lymphopenia for patients receiving palliative fractionated RT. Still, lymphopenia ≥ G3 was not associated with worse OS. however, high baseline CRP/Albumin was associated with poorer OS and may carry important information as a prognostic factor of OS in advanced NSCLC receiving palliative RT.
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http://dx.doi.org/10.1016/j.ctro.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063172PMC
May 2020

Independent Validation of Early-Stage Non-Small Cell Lung Cancer Prognostic Scores Incorporating Epigenetic and Transcriptional Biomarkers With Gene-Gene Interactions and Main Effects.

Chest 2020 08 28;158(2):808-819. Epub 2020 Feb 28.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA; Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Background: DNA methylation and gene expression are promising biomarkers of various cancers, including non-small cell lung cancer (NSCLC). Besides the main effects of biomarkers, the progression of complex diseases is also influenced by gene-gene (G×G) interactions.

Research Question: Would screening the functional capacity of biomarkers on the basis of main effects or interactions, using multiomics data, improve the accuracy of cancer prognosis?

Study Design And Methods: Biomarker screening and model validation were used to construct and validate a prognostic prediction model. NSCLC prognosis-associated biomarkers were identified on the basis of either their main effects or interactions with two types of omics data. A prognostic score incorporating epigenetic and transcriptional biomarkers, as well as clinical information, was independently validated.

Results: Twenty-six pairs of biomarkers with G×G interactions and two biomarkers with main effects were significantly associated with NSCLC survival. Compared with a model using clinical information only, the accuracy of the epigenetic and transcriptional biomarker-based prognostic model, measured by area under the receiver operating characteristic curve (AUC), increased by 35.38% (95% CI, 27.09%-42.17%; P = 5.10 × 10) and 34.85% (95% CI, 26.33%-41.87%; P = 2.52 × 10) for 3- and 5-year survival, respectively, which exhibited a superior predictive ability for NSCLC survival (AUC, 0.88 [95% CI, 0.83-0.93]; and AUC, 0.89 [95% CI, 0.83-0.93]) in an independent Cancer Genome Atlas population. G×G interactions contributed a 65.2% and 91.3% increase in prediction accuracy for 3- and 5-year survival, respectively.

Interpretation: The integration of epigenetic and transcriptional biomarkers with main effects and G×G interactions significantly improves the accuracy of prognostic prediction of early-stage NSCLC survival.
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http://dx.doi.org/10.1016/j.chest.2020.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417380PMC
August 2020

A 10-year prediagnostic follow-up study shows that serum RNA signals are highly dynamic in lung carcinogenesis.

Mol Oncol 2020 02 10;14(2):235-247. Epub 2020 Jan 10.

Department of Research, Cancer Registry of Norway, Oslo, Norway.

The majority of lung cancer (LC) patients are diagnosed at a late stage, and survival is poor. Circulating RNA molecules are known to have a role in cancer; however, their involvement before diagnosis remains an open question. In this study, we investigated circulating RNA dynamics in prediagnostic LC samples, focusing on smokers, to identify if and when disease-related signals can be detected in serum. We sequenced small RNAs in 542 serum LC samples donated up to 10 years before diagnosis and 519 matched cancer-free controls coming from 905 individuals in the Janus Serum Bank. This sample size provided sufficient statistical power to independently analyze time to diagnosis, stage, and histology. The results showed dynamic changes in differentially expressed circulating RNAs specific to LC histology and stage. The greatest number of differentially expressed RNAs was identified around 7 years before diagnosis for early-stage LC and 1-4 years prior to diagnosis for locally advanced and advanced-stage LC, regardless of LC histology. Furthermore, NSCLC and SCLC histologies have distinct prediagnostic signals. The majority of differentially expressed RNAs were associated with cancer-related pathways. The dynamic RNA signals pinpointed different phases of tumor development over time. Stage-specific RNA profiles may be associated with tumor aggressiveness. Our results improve the molecular understanding of carcinogenesis. They indicate substantial opportunity for screening and improved treatment and will guide further research on early detection of LC. However, the dynamic nature of the RNA signals also suggests challenges for prediagnostic biomarker discovery.
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http://dx.doi.org/10.1002/1878-0261.12620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998662PMC
February 2020

PathTracer: High-sensitivity detection of differential pathway activity in tumours.

Sci Rep 2019 11 8;9(1):16332. Epub 2019 Nov 8.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Gene expression profiling of tumours is an important source of information for cancer patient stratification. Detecting subtle alterations of gene expression remains a challenge, however. Here, we propose a novel tool for high-sensitivity detection of differential pathway activity in tumours. For a pathway defined by a collection of genes, the samples are projected onto a low-dimensional manifold in the subspace spanned by those genes. For each sample, a score is next found by calculating the distance between each projected sample and the projection of a subgroup of reference samples. Depending on the aim of the analysis and the available data, the reference samples may represent e.g. normal tissue or tumour samples with a particular genotype or phenotype. The proposed tool, PathTracer, is demonstrated on gene expression data from 1952 invasive breast cancer samples, 10 DCIS, 9 benign samples and 144 tumour adjacent normal breast tissue samples. PathTracer scores are shown to predict survival, clinical subtypes, cellular proliferation and genomic instability. Furthermore, predictions are shown to outperform those obtained with other comparable methods.
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http://dx.doi.org/10.1038/s41598-019-52529-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841931PMC
November 2019

Identification of microRNAs involved in pathways which characterize the expression subtypes of NSCLC.

Mol Oncol 2019 12 22;13(12):2604-2615. Epub 2019 Sep 22.

Department of Cancer Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo, Norway.

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.
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http://dx.doi.org/10.1002/1878-0261.12571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887593PMC
December 2019

Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma.

Aging (Albany NY) 2019 08 21;11(16):6312-6335. Epub 2019 Aug 21.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups ( = 0.01 and = 2.71×10). Further, potential functional DNA methylation-gene expression-overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk.
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http://dx.doi.org/10.18632/aging.102189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738411PMC
August 2019

Increase in curative treatment and survival of lung cancer in Norway 2001-2016.

Eur J Epidemiol 2019 Oct 16;34(10):951-955. Epub 2019 Jul 16.

Department of Pulmology, Rikshospitalet, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway.

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.
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http://dx.doi.org/10.1007/s10654-019-00536-zDOI Listing
October 2019

SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis.

Mol Oncol 2019 05 17;13(5):1235-1248. Epub 2019 Apr 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Smoking cessation prolongs survival and decreases mortality of patients with non-small-cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome-wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two-stage study design to identify DNA methylation-smoking cessation interactions that affect overall survival for early-stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology-stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation-smoking cessation interaction terms. Interactions with false discovery rate-q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology-specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510 ) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)  = 1.12; 95% confidence interval (CI): 1.07-1.16; P = 4.30 × 10 ]. Further, the effect of smoking cessation on early-stage LUAD survival varied across patients with different methylation levels of cg02268510 . Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34-0.82; P = 4.61 × 10 ) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86-1.70; P = 0.266) of cg02268510 . Moreover, there was an antagonistic interaction between elevated methylation of cg02268510 and smoking cessation (HR  = 2.1835; 95% CI: 1.27-3.74; P = 4.46 × 10 ). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510 . The results have implications for not only smoking cessation after diagnosis, but also possible methylation-specific drug targeting.
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http://dx.doi.org/10.1002/1878-0261.12482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487703PMC
May 2019
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