Publications by authors named "Harry J M Groen"

230 Publications

Community-based lung cancer screening by low-dose computed tomography in China: First round results and a meta-analysis.

Eur J Radiol 2021 Nov 1;144:109988. Epub 2021 Oct 1.

Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Department of Radiology, Tianjin, People's Republic of China. Electronic address:

Objective: To evaluate the efficiency of low-dose computed tomography (LDCT) screening for lung cancer in China by analyzing the baseline results of a community-based screening study accompanied with a meta-analysis.

Methods: A first round of community-based lung cancer screening with LDCT was conducted in Tianjin, China, and a systematic literature search was performed to identify LDCT screening and registry-based clinical studies for lung cancer in China. Baseline results in the community-based screening study were described by participant risk level and the lung cancer detection rate was compared with the pooled rate among the screening studies. The percentage of patients per stage was compared between the community-based study and screening and clinical studies.

Results: In the community-based study, 5523 participants (43.6% men) underwent LDCT. The lung cancer detection rate was 0.5% (high-risk, 1.2%; low-risk, 0.4%), with stage I disease present in 70.0% (high-risk, 50.0%; low-risk, 83.3%), and the adenocarcinoma present in 84.4% (high-risk, 61.5%; low-risk, 100%). Among all screen-detected lung cancer, women accounted for 8.3% and 66.7% in the high- and low-risk group, respectively. In the screening studies from mainland China, the lung cancer detection rate 0.6% (95 %CI: 0.3%-0.9%) for high-risk populations. The proportions with carcinoma in situ and stage I disease in the screening and clinical studies were 76.4% (95 %CI: 66.3%-85.3%) and 15.2% (95 %CI: 11.8%-18.9%), respectively.

Conclusions: The stage shift of lung cancer due to screening suggests a potential effectiveness of LDCT screening in China. Nearly 70% of screen-detected lung cancers in low-risk populations are identified in women.
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http://dx.doi.org/10.1016/j.ejrad.2021.109988DOI Listing
November 2021

Association of different fractionation schedules for prophylactic cranial irradiation with toxicity and brain metastases-free survival in stage III non-small cell lung cancer: A pooled analysis of individual patient data from three randomized trials.

Radiother Oncol 2021 Oct 4;164:163-166. Epub 2021 Oct 4.

Department of Radiation Oncology (Maastro Clinic), Maastricht University Medical Centre (MUMC), The Netherlands.

We assessed the impact of different PCI fractionation schedules (30 Gy in 10 versus 15 fractions) on brain metastases-free survival (BMFS) and toxicity in stage III NSCLC. Our results suggest that 30 Gy in 10 fractions is associated with increased toxicity, while no conclusive evidence of improving BMFS was seen with this schedule.
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http://dx.doi.org/10.1016/j.radonc.2021.09.029DOI Listing
October 2021

Efficacy and Safety of Rociletinib Versus Chemotherapy in Patients With -Mutated NSCLC: The Results of TIGER-3, a Phase 3 Randomized Study.

JTO Clin Res Rep 2021 Feb 26;2(2):100114. Epub 2020 Oct 26.

Division of Oncology, Department of Medicine, Stanford University, Stanford, California.

Introduction: The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets T790M and common -activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs.

Methods: Patients with advanced or metastatic -mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel).

Results: Enrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6-5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8-8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4-2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28-1.07,  = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively).

Conclusions: Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced -mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474221PMC
February 2021

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis.

J Thorac Oncol 2021 Aug 26. Epub 2021 Aug 26.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address:

Introduction: Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data.

Methods: Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety.

Results: At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5-78.5) and 16.3 (range: 0.4-80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median progression-free survival (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median overall survival (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation.

Conclusions: Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment.
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http://dx.doi.org/10.1016/j.jtho.2021.08.011DOI Listing
August 2021

Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors.

Mol Oncol 2021 Nov 25;15(11):2910-2922. Epub 2021 Sep 25.

Department of Pathology, University of Groningen, University Medical Center Groningen, The Netherlands.

Immunotherapy for metastasized non-small-cell lung cancer (NSCLC) can show long-lasting clinical responses. Selection of patients based on programmed death-ligand 1 (PD-L1) expression shows limited predictive value for durable clinical benefit (DCB). We investigated whether early treatment effects as measured by a change in circulating tumor DNA (ctDNA) level is a proxy of early tumor response to immunotherapy according to response evaluation criteria in solid tumors v1.1 criteria, progression-free survival (PFS), DCB, and overall survival (OS). To this aim, blood tubes were collected from advanced-stage lung adenocarcinoma patients (n = 100) receiving immune checkpoint inhibitors (ICI) at baseline (t ) and prior to first treatment evaluation (4-6 weeks; t ). Nontargetable (driver) mutations detected in the pretreatment tumor biopsy were used to quantify tumor-specific ctDNA levels using droplet digital PCR. We found that changes in ctDNA levels were strongly associated with tumor response. A > 30% decrease in ctDNA at t correlated with a longer PFS and OS. In total, 80% of patients with a DCB of ≥ 26 weeks displayed a > 30% decrease in ctDNA levels. For patients with a PD-L1 tumor proportion score of ≥ 1%, decreasing ctDNA levels were associated with a higher frequency a DCB (80%) and a prolonged median PFS (85 weeks) and OS (101 weeks) compared with patients with no decrease in ctDNA (34%; 11 and 39 weeks, respectively). This study shows that monitoring of ctDNA dynamics is an easy-to-use and promising tool for assessing PFS, DCB, and OS for ICI-treated NSCLC patients.
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http://dx.doi.org/10.1002/1878-0261.13090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564646PMC
November 2021

A contrast-enhanced-CT-based classification tree model for classifying malignancy of solid lung tumors in a Chinese clinical population.

J Thorac Dis 2021 Jul;13(7):4407-4417

Department of Radiology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre of Cancer, Tianjin, China.

Background: To develop and validate a contrast-enhanced CT based classification tree model for classifying solid lung tumors in clinical patients into malignant or benign.

Methods: Between January 2015 and October 2017, 827 pathologically confirmed solid lung tumors (487 malignant, 340 benign; median size, 27.0 mm, IQR 18.0-39.0 mm) from 827 patients from a dedicated Chinese cancer hospital were identified. Nodules were divided randomly into two groups, a training group (575 cases) and a testing group (252 cases). CT characteristics were collected by two radiologists, and analyzed using a classification and regression tree (CART) model. For validation, we used the decision analysis threshold to evaluate the classification performance of the CART model and radiologist's diagnosis (benign; malignant) in the testing group.

Results: Three out of 19 characteristics [margin (smooth; slightly lobulated/lobulated/spiculated), and shape (round/oval; irregular), subjective enhancement (no/uniform enhancement; heterogeneous enhancement)] were automatically generated by the CART model for classifying solid lung tumors. The sensitivity, specificity, PPV, NPV, and diagnostic accuracy of the CART model is 98.5%, 58.1%, 80.6%, 98.6%, 79.8%, and 90.4%, 54.7%, 82.4% 98.5%, 74.2% for the radiologist's diagnosis by using three-threshold decision analysis.

Conclusions: Tumor margin and shape, and subjective tumor enhancement were the most important CT characteristics in the CART model for classifying solid lung tumors as malignant. The CART model had higher discriminatory power than radiologist's diagnosis. The CART model could help radiologists making recommendations regarding follow-up or surgery in clinical patients with a solid lung tumor.
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http://dx.doi.org/10.21037/jtd-21-588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339765PMC
July 2021

Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma.

Lung Cancer 2021 10 4;160:44-49. Epub 2021 Aug 4.

Department of Pulmonary Diseases, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, the Netherlands. Electronic address:

Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC).

Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m intravenously on day 1 plus erlotinib 150 mg/day orally on day 2-16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity.

Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5-7.1) versus 1.9 months (95% CI 1.4-3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16-5.43). Corresponding median OS was 10.6 months (95% CI: 7.0-8.6) versus 4.7 months (95% CI: 3.2-8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46-9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia.

Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice.
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http://dx.doi.org/10.1016/j.lungcan.2021.08.002DOI Listing
October 2021

Actionability of on-target ALK Resistance Mutations in Patients With Non-Small Cell Lung Cancer: Local Experience and Review of the Literature.

Clin Lung Cancer 2021 Jul 3. Epub 2021 Jul 3.

Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Introduction: Non-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) gene fusions respond well to ALK inhibitors but commonly develop on-target resistance mutations. The objective of this study is to collect clinical evidence for subsequent treatment with ALK inhibitors.

Patients And Methods: Local experience with on-target ALK resistance mutations and review of the literature identified 387 patients with ALK inhibitor resistance mutations. Clinical benefit of mutation-inhibitor combinations was assessed based on reported response, progression-free survival and duration of treatment. Furthermore, this clinical evidence was compared to previously reported in vitro sensitivity of mutations to the inhibitors.

Results: Of the pooled population of 387 patients in this analysis, 239 (62%) received at least 1 additional line of ALK inhibition after developing on-target resistance to ALK inhibitor therapy. Clinical benefit was reported for 177 (68%) patients, but differed for each mutation-inhibitor combination. Agreement between in vitro predicted sensitivity of 6 published models and observed clinical benefit ranged from 64% to 87%. The observed clinical evidence for highest probability of response in the context of specific on-target ALK inhibitor resistance mutations is presented.

Conclusion: Molecular diagnostics performed on tissue samples that are refractive to ALK inhibitor therapy can reveal new options for targeted therapy for NSCLC patients. Our comprehensive overview of clinical evidence of drug actionability of ALK on-target resistance mechanisms may serve as a practical guide to select the most optimal drug for individual patients.
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http://dx.doi.org/10.1016/j.cllc.2021.06.011DOI Listing
July 2021

A Nationwide Study on the Impact of Routine Testing for Mutations in Advanced NSCLC Reveals Distinct Survival Patterns Based on Mutation Subclasses.

Cancers (Basel) 2021 Jul 20;13(14). Epub 2021 Jul 20.

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.

mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of testing, test results and survival of -mutant NSCLC patients in the Netherlands, with the overall objective to characterize the landscape of clinically actionable mutations and determine the role and clinical relevance of uncommon and composite mutations. Non-squamous NSCLC patients diagnosed in 2013, 2015 and 2017 were identified in the Netherlands Cancer Registry (NCR) and matched to the Dutch Pathology Registry (PALGA). Overall, 10,254 patients were included. Between 2013-2017, the uptake of testing gradually increased from 72.7% to 80.9% ( < 0.001). Multi-gene testing via next-generation sequencing (increased from 7.8% to 78.7% ( < 0.001), but did not affect the number of detected mutations ( = 925; 11.7%; 95% confidence interval (CI), 11.0-12.4) nor the distribution of variants. For patients treated with first-line EGFR inhibitors ( = 651), exon 19 deletions were associated with longer OS than L858R (HR 1.58; 95% CI, 1.30-1.92; < 0.001) or uncommon, actionable variants (HR 2.13; 95% CI, 1.60-2.84; < 0.001). Interestingly, OS for patients with L858R was similar to those with uncommon, actionable variants (HR 1.31; 95% CI, 0.98-1.75; = 0.069). Our analysis indicates that grouping exon 19 deletions and L858R into one class of 'common' mutations in a clinical trial may mask the true activity of an EGFR inhibitor towards specific mutations.
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http://dx.doi.org/10.3390/cancers13143641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307492PMC
July 2021

EPAC-lung: European pooled analysis of the prognostic value of circulating tumour cells in small cell lung cancer.

Transl Lung Cancer Res 2021 Apr;10(4):1653-1665

Service de Biostatistique et d'Épidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Background: Circulating tumour cell (CTC) number is an independent prognostic factor in patients with small cell lung cancer (SCLC) but there is no consensus on the CTC threshold for prognostic significance. We undertook a pooled analysis of individual patient data to clinically validate CTC enumeration and threshold for prognostication.

Methods: Four European cancer centres, experienced in CellSearch CTC enumeration for SCLC provided pseudo anonymised data for patients who had undergone pre-treatment CTC count. Data was collated, and Cox regression models, stratified by centre, explored the relationship between CTC count and survival. The added value of incorporating CTCs into clinico-pathological models was investigated using likelihood ratio tests.

Results: A total of 367 patient records were evaluated. A one-unit increase in log-transformed CTC counts corresponded to an estimated hazard ratio (HR) of 1.24 (95% CI: 1.19-1.29, P<0.0001) for progression free survival (PFS) and 1.23 (95% CI: 1.18-1.28, P<0.0001) for overall survival (OS). CTC count of ≥15 or ≥50 was significantly associated with an increased risk of progression (CTC ≥15: HR 3.20, 95% CI: 2.50-4.09, P<0.001; CTC ≥50: HR 2.56, 95% CI: 2.01-3.25, P<0.001) and an increased risk of death (CTC ≥15: HR 2.90, 95% CI: 2.28-3.70, P<0.001; CTC ≥50: HR 2.47, 95% CI: 1.95-3.13, P<0.001). There was no significant inter-centre heterogeneity observed. Addition of CTC count to clinico-pathological models as a continuous log-transformed variable, offers further prognostic value (both likelihood ratio P<0.001 for OS and PFS).

Conclusions: Higher pre-treatment CTC counts are a negative independent prognostic factor in SCLC when considered as a continuous variable or dichotomised counts of ≥15 or ≥50. Incorporating CTC counts, as a continuous variable, improves clinic-pathological prognostic models.
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http://dx.doi.org/10.21037/tlcr-20-1061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107738PMC
April 2021

Development and Evaluation of a Real-World Outcomes-Based Tool to Support Informed Clinical Decision Making in the Palliative Treatment of Patients With Metastatic NSCLC.

JCO Clin Cancer Inform 2021 05;5:570-578

Department of Clinical Pharmacy, St Antonius Hospital, Utrecht/Nieuwegein, the Netherlands.

Purpose: To develop and evaluate a tool for patients with stage IV non-small-cell lung cancer and their thoracic oncologists (TOs) that provides insight into real-world effectiveness of systemic treatments to support informed clinical decision making in the palliative setting.

Methods: A participatory design approach was used to acquire insights from patients and TOs into preferences regarding the content and design of the web-based tool. Implementation was investigated by means of an adoption and usage rate. The appreciation of the tool was evaluated through a telephone survey with patients and a questionnaire for TOs.

Results: From clinical data of 2,989 patients with stage IV non-small-cell lung cancer diagnosed in one of the Santeon hospitals, an interface was developed to show treatments plus both real-world outcomes and clinical trial results after selecting patient characteristics (patients like me). This prototype of the tool was finalized after discussion in a focus group with four TOs and semi-structured interviews with six patients. The tool was implemented and used by TOs in three of six Santeon hospitals (50% adoption rate). The tool was used in 48 patients (29% usage rate), of which 17 participated in the telephone survey. Ten TOs responded to the questionnaire. The responses varied from positive reactions on the clear overview of treatment outcomes to statements that the tool rarely changed treatment decisions. Overall, the majority of patients and TOs scored the tool as of added value (71% and 83%, respectively).

Conclusion: Our real-world data tool in metastatic lung cancer was appreciated in clinical practice by both patients and TOs. However, the efficacy of the implementation can be improved.
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http://dx.doi.org/10.1200/CCI.20.00160DOI Listing
May 2021

Veliparib in Combination with Carboplatin and Etoposide in Patients with Treatment-Naïve Extensive-Stage Small Cell Lung Cancer: A Phase 2 Randomized Study.

Clin Cancer Res 2021 Jul 4;27(14):3884-3895. Epub 2021 May 4.

Juravinski Cancer Center, McMaster University, Hamilton, Ontario, Canada.

Purpose: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC).

Patients And Methods: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4-6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control.

Results: Overall ( = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50-0.88; = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36-0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09-1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic.

Conclusions: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4259DOI Listing
July 2021

Simultaneous Identification of and Mutations in Patients with Non-Small Cell Lung Cancer by Machine Learning-Derived Three-Dimensional Radiomics.

Cancers (Basel) 2021 Apr 10;13(8). Epub 2021 Apr 10.

Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Haining Rd.100, Shanghai 200080, China.

Purpose: To develop a machine learning-derived radiomics approach to simultaneously discriminate epidermal growth factor receptor (), Kirsten rat sarcoma viral oncogene (), Erb-B2 receptor tyrosine kinase 2 (), and tumor protein 53 () genetic mutations in patients with non-small cell lung cancer (NSCLC).

Methods: This study included consecutive patients from April 2018 to June 2020 who had histologically confirmed NSCLC, and underwent pre-surgical contrast-enhanced CT and post-surgical next-generation sequencing (NGS) tests to determine the presence of , , , and mutations. A dedicated radiomics analysis package extracted 1672 radiomic features in three dimensions. Discriminative models were established using the least absolute shrinkage and selection operator to determine the presence of , , , and mutations, based on radiomic features and relevant clinical factors.

Results: In 134 patients (63.6 ± 8.9 years), the 20 most relevant radiomic features (13 for ) to mutations were selected to construct models. The areas under the curve (AUCs) of the combined model (radiomic features and relevant clinical factors) for discriminating and mutations were 0.78 (95% CI: 0.70-0.86), 0.81 (0.69-0.93), 0.87 (0.78-0.95), and 0.84 (0.78-0.91), respectively. In particular, the specificity to exclude mutations was 0.96 (0.87-0.99). The sensitivity to determine , , and mutations ranged from 0.82 (0.69-90) to 0.92 (0.62-0.99).

Conclusions: Machine learning-derived 3D radiomics can simultaneously discriminate the presence of , , , and mutations in patients with NSCLC. This noninvasive and low-cost approach may be helpful in screening patients before invasive sampling and NGS testing.
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http://dx.doi.org/10.3390/cancers13081814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070114PMC
April 2021

Seasonal prevalence and characteristics of low-dose CT detected lung nodules in a general Dutch population.

Sci Rep 2021 04 28;11(1):9139. Epub 2021 Apr 28.

Department of Radiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

We investigated whether presence and characteristics of lung nodules in the general population using low-dose computed tomography (LDCT) varied by season. Imaging in Lifelines (ImaLife) study participants who underwent chest LDCT-scanning between October 2018 and October 2019 were included in this sub-study. Hay fever season (summer) was defined as 1st April to 30th September and Influenza season (winter) as 1st October to 31st March. All lung nodules with volume of ≥ 30 mm (approximately 3 mm in diameter) were registered. In total, 2496 lung nodules were found in 1312 (38%) of the 3456 included participants (nodules per participant ranging from 1 to 21, median 1). In summer, 711 (54%) participants had 1 or more lung nodule(s) compared to 601 (46%) participants in winter (p = 0.002). Of the spherical, perifissural and left-upper-lobe nodules, relatively more were detected in winter, whereas of the polygonal-, irregular-shaped and centrally-calcified nodules, relatively more were detected in summer. Various seasonal diseases with inflammation as underlying pathophysiology may influence presence and characteristics of lung nodules. Further investigation into underlying pathophysiology using short-term LDCT follow-up could help optimize the management strategy for CT-detected lung nodules in clinical practice.
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http://dx.doi.org/10.1038/s41598-021-88328-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080793PMC
April 2021

Real-world outcomes versus clinical trial results of immunotherapy in stage IV non-small cell lung cancer (NSCLC) in the Netherlands.

Sci Rep 2021 03 18;11(1):6306. Epub 2021 Mar 18.

Department of Clinical Pharmacy, St. Antonius Hospital, Utrecht, Nieuwegein, The Netherlands.

This study aims to assess how clinical outcomes of immunotherapy in real-world (effectiveness) correspond to outcomes in clinical trials (efficacy) and to look into factors that might explain an efficacy-effectiveness (EE) gap. All patients diagnosed with stage IV non-small cell lung cancer (NSCLC) in 2015-2018 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. Progression-free survival (PFS) and overall survival (OS) from first-line (1L) pembrolizumab and second-line (2L) nivolumab were compared with clinical trial data by calculating hazard ratios (HRs). From 1950 diagnosed patients, 1005 (52%) started with any 1L treatment, of which 83 received pembrolizumab. Nivolumab was started as 2L treatment in 141 patients. For both settings, PFS times were comparable between real-world and trials (HR 1.08 (95% CI 0.75-1.55), and HR 0.91 (95% CI 0.74-1.14), respectively). OS was significantly shorter in real-world for 1L pembrolizumab (HR 1.55; 95% CI 1.07-2.25). Receiving subsequent lines of treatment was less frequent in real-world compared to trials. There is no EE gap for PFS from immunotherapy in patients with stage IV NSCLC. However, there is a gap in OS for 1L pembrolizumab. Fewer patients proceeding to a subsequent line of treatment in real-world could partly explain this.
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http://dx.doi.org/10.1038/s41598-021-85696-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973789PMC
March 2021

Clinical Value of EGFR Copy Number Gain Determined by Amplicon-Based Targeted Next Generation Sequencing in Patients with EGFR-Mutated NSCLC.

Target Oncol 2021 03 19;16(2):215-226. Epub 2021 Feb 19.

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, HPC: EA10, Room F0-15, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Background: The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated.

Objective: We aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value.

Patients And Methods: Next generation sequencing data were obtained for 1566 patients with non-small cell lung cancer. EGFR copy number gain was defined based on an increase in EGFR read counts relative to internal reference amplicons and normal controls in combination with a modified z-score ≥ 3.5. Clinical follow-up data were available for 60 patients treated with first-line EGFR-tyrosine kinase inhibitors.

Results: Specificity and sensitivity of next generation sequencing-based EGFR copy number estimations were above 90%. EGFR copy number gain was observed in 27.9% of EGFR mutant cases and in 7.4% of EGFR wild-type cases. EGFR gain was not associated with progression-free survival but showed a significant effect on overall survival with an adjusted hazard ratio of 3.14 (95% confidence interval 1.46-6.78, p = 0.003). Besides EGFR copy number gain, osimertinib in second or subsequent lines of treatment and the presence of T790M at relapse revealed significant effects in a multivariate analysis with adjusted hazard ratio of 0.43 (95% confidence interval 0.20-0.91, p = 0.028) and 0.24 (95% confidence interval 0.1-0.59, p = 0.001), respectively.

Conclusions: Pre-treatment EGFR copy number gain determined by amplicon-based next generation sequencing data predicts worse overall survival in EGFR-mutated patients treated with first-line EGFR-tyrosine kinase inhibitors. T790M at relapse and subsequent treatment with osimertinib predict longer overall survival.
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http://dx.doi.org/10.1007/s11523-021-00798-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935828PMC
March 2021

Individual patient data meta-analysis of prophylactic cranial irradiation in locally advanced non-small cell lung cancer.

Radiother Oncol 2021 05 13;158:40-47. Epub 2021 Feb 13.

Department of Radiation Oncology (Maastro Clinic), Maastricht University Medical Center(+), GROW Research Institute, Maastricht, The Netherlands.

Background: Prophylactic cranial irradiation (PCI) was compared to observation in several randomized trials (RCTs), and a reduction greater than 50% was shown regarding the incidence of brain metastases (BM). However, none of these studies showed an improvement of overall survival (OS), possibly related to relatively small sample sizes and short follow-up. The aim of this meta-analysis was therefore to assess the impact of PCI on long term OS for stage III non-small cell lung cancer (NSCLC) compared to observation based on the pooled updated individual patient RCT data.

Methods: Seven RCTs were eligible, and data from the four most recent trials (924 patients) could be retrieved. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Inter-trial heterogeneity was studied using the I test. In addition, the 5-year absolute survival difference between arms was calculated for all endpoints. The pre-specified toxicities were reported descriptively.

Results: The median follow-up was 97 months (74-108). Compared to observation, no statistically significant impact of PCI on OS was observed (HR 0.90 [0.76-1.07] p = 0.23, 5-year absolute difference 1.8% [-5.2-8.8]). PCI significantly prolonged progression-free survival (HR 0.77 [0.66-0.91] p = 0.002) and BM-free survival (HR 0.82 [0.69-0.97] p = 0.02). The number of patients with high-grade (≥3) toxicity was 6.4% (21/330) for PCI.

Conclusion: No OS benefit by PCI was observed, but PCI prolonged the progression-free survival and BM-free survival at an increased risk of late memory impairment and fatigue.
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http://dx.doi.org/10.1016/j.radonc.2021.02.002DOI Listing
May 2021

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial.

Lancet Respir Med 2021 06 27;9(6):585-592. Epub 2021 Jan 27.

Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. Electronic address:

Background: Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy.

Methods: We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847.

Findings: Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6-8·7]) than in the supportive care group (3·2 months [2·8-4·1]; hazard ratio [HR] 0·48 [95% CI 0·33-0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33-0·72]; p=0·0002). Grade 3-4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection.

Interpretation: Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma.

Funding: Dutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.
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http://dx.doi.org/10.1016/S2213-2600(20)30362-3DOI Listing
June 2021

F-FDG PET/CT Scans Can Identify Sub-Groups of NSCLC Patients with High Glucose Uptake in the Majority of Their Tumor Lesions.

J Cancer 2021 1;12(2):562-570. Epub 2021 Jan 1.

University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands. Department of Medical Oncology.

Reprogrammed glucose metabolism is a hallmark of cancer making it an attractive therapeutic target, especially in cancers with high glucose uptake such as non-small cell lung cancer (NSCLC). Tools to select patients with high glucose uptake in the majority of tumor lesions are essential in the development of anti-cancer drugs targeting glucose metabolism. Type 2 diabetes mellitus (T2DM) patients may have tumors highly dependent on glucose uptake. Surprisingly, this has not been systematically studied. Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose (F-FDG) positron emission tomography (PET)/computed tomography (CT) scans. Routine primary diagnostic F-FDG PET/CT scans of consecutive NSCLC patients were included. Mean standardized uptake value (SUVmean) of F-FDG was determined for all evaluable tumor lesions and corrected for serum glucose levels according to the European Association of Nuclear Medicine Research Ltd guidelines. Patient characteristics potentially determining degree of tumor lesion glucose uptake in the majority of tumor lesions per patient were investigated. The cohort consisted of 102 patients, 28 with T2DM and 74 without T2DM. The median SUVmean per patient ranged from 0.8 to 35.2 (median 4.2). T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, < 0.001 and SUVmean 5.4 vs 3.7, = 0.009, respectively). However, in multivariable analysis, high tumor lesion glucose uptake was only independently determined by number of tumor lesions ≥1 mL per patient (odds ratio 0.8, 95% confidence interval 0.7-0.9). F-FDG PET/CT scans can identify sub-groups of NSCLC patients with high glucose uptake in the majority of their tumor lesions. T2DM patients had higher tumor lesion glucose uptake than non-diabetic patients. However, this was not independent of other factors such as the histological subtype and number of tumor lesions per patient.
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http://dx.doi.org/10.7150/jca.45899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738988PMC
January 2021

Systematic evaluation of the efficacy-effectiveness gap of systemic treatments in extensive disease small cell lung cancer.

Pharmacoepidemiol Drug Saf 2021 04 18;30(4):445-450. Epub 2020 Dec 18.

Department of Clinical Pharmacy, St. Antonius Hospital, Utrecht, The Netherlands.

Purpose: The aim of this study is to assess how clinical outcomes in real-world (effectiveness) correspond to the outcomes in clinical trials (efficacy) of systemic treatments for extensive disease small cell lung cancer (ED SCLC).

Methods: All patients diagnosed with ED SCLC between 2008 and 2014 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. For every patient, an efficacy-effectiveness factor (EE factor) was calculated by dividing individual patients' overall survival (OS) by the pooled median OS assessed from clinical trials with the respective treatment.

Results: From 792 diagnosed patients, 568 (72%) started with first-line treatment. Overall, the median EE factor was 0.79 (P < .001 from 1.00). Poor performance status (ECOG≥2) and a higher age at diagnosis (age ≥ 65 years) were independent predictors for a lower EE factor. The EE gap was 43% in patients with both age ≥ 65 years and ECOG ≥2 (EE factor 0.57). The mean age and the proportion of patients with ECOG≥2 in real-world were different from those in clinical trials (mean age of 66 versus 62 years, and ECOG≥2 25% versus 17%; both P < .001).

Conclusion: OS of patients with ED SCLC treated with systemic therapy in real-world practice is 21% shorter than for patients included in trials. Age at diagnosis and performance status partly explain this gap.
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http://dx.doi.org/10.1002/pds.5179DOI Listing
April 2021

Multicenter Comparison of Molecular Tumor Boards in The Netherlands: Definition, Composition, Methods, and Targeted Therapy Recommendations.

Oncologist 2021 08 10;26(8):e1347-e1358. Epub 2020 Nov 10.

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands.

Materials And Methods: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy.

Results: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type-specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%).

Conclusion: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a "Dutch MTB model" for an optimal, collaborative, and nationally aligned MTB workflow.

Implications For Practice: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing.
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http://dx.doi.org/10.1002/onco.13580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342588PMC
August 2021

Mass Spectrometry as a Highly Sensitive Method for Specific Circulating Tumor DNA Analysis in NSCLC: A Comparison Study.

Cancers (Basel) 2020 Oct 16;12(10). Epub 2020 Oct 16.

Laboratoire de Cellules Rares Circulantes, University Medical Center of Montpellier, 641, Avenue du Doyen Gaston GIRAUD, 34093 Montpellier, France.

Plasma-based tumor mutational profiling is arising as a reliable approach to detect primary and therapy-induced resistance mutations required for accurate treatment decision making. Here, we compared the FDA-approved Cobas EGFR Mutation Test v2 with the UltraSEEK™ Lung Panel on the MassARRAY System on detection of mutations, accompanied with preanalytical sample assessment using the novel Liquid IQ Panel. 137 cancer patient-derived cell-free plasma samples were analyzed with the Cobas and UltraSEEK™ tests. Liquid IQ analysis was initially validated ( = 84) and used to determine ccfDNA input for all samples. Subsequently, Liquid IQ results were applied to harmonize ccfDNA input for the Cobas and UltraSEEK™ tests for 63 NSCLC patients. The overall concordance between the Cobas and UltraSEEK™ tests was 86%. The Cobas test detected more exon19 deletions and L858R mutations, while the UltraSEEK™ test detected more T790M mutations. A 100% concordance in both the clinical ( = 137) and harmonized ( = 63) cohorts was observed when >10 ng of ccfDNA was used as determined by the Liquid IQ Panel. The Cobas and UltraSEEK™ tests showed similar sensitivity in mutation detection, particularly when ccfDNA input was sufficient. It is recommended to preanalytically determine the ccfDNA concentration accurately to ensure sufficient input for reliable interpretation and treatment decision making.
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http://dx.doi.org/10.3390/cancers12103002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602843PMC
October 2020

An All-In-One Transcriptome-Based Assay to Identify Therapy-Guiding Genomic Aberrations in Nonsmall Cell Lung Cancer Patients.

Cancers (Basel) 2020 Oct 1;12(10). Epub 2020 Oct 1.

Department of Genetics, University Medical Centre Groningen, University of Groningen, 9700RB Groningen, The Netherlands.

The number of genomic aberrations known to be relevant in making therapeutic decisions for non-small cell lung cancer patients has increased in the past decade. Multiple molecular tests are required to reliably establish the presence of these aberrations, which is challenging because available tissue specimens are generally small. To optimize diagnostic testing, we developed a transcriptome-based next-generation sequencing (NGS) assay based on single primed enrichment technology. We interrogated 11 cell lines, two patient-derived frozen biopsies, nine pleural effusion, and 29 formalin-fixed paraffin-embedded (FFPE) samples. All clinical samples were selected based on previously identified mutations at the DNA level in or at the DNA level, or fusion genes at the chromosome level, or by aberrant protein expression of , , and . A successful analysis is dependent on the number of unique reads and the RNA quality, as indicated by the DV200 value. In 27 out of 51 samples with >50 K unique reads and a DV200 >30, all 19 single nucleotide variants (SNVs)/small insertions and deletions (INDELs), three exon 14 skipping events, and 13 fusion gene transcripts were detected at the RNA level, giving a test accuracy of 100%. In summary, this lung-cancer-specific all-in-one transcriptome-based assay for the simultaneous detection of mutations and fusion genes is highly sensitive.
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http://dx.doi.org/10.3390/cancers12102843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650834PMC
October 2020

Comparison of three commercial decision support platforms for matching of next-generation sequencing results with therapies in patients with cancer.

ESMO Open 2020 09;5(5):e000872

Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria. Electronic address:

Objective: Precision oncology depends on translating molecular data into therapy recommendations. However, with the growing complexity of next-generation sequencing-based tests, clinical interpretation of somatic genomic mutations has evolved into a formidable task. Here, we compared the performance of three commercial clinical decision support tools, that is, NAVIFY Mutation Profiler (NAVIFY; Roche), QIAGEN Clinical Insight (QCI) Interpret (QIAGEN) and CureMatch Bionov (CureMatch).

Methods: In order to obtain the current status of the respective tumour genome, we analysed cell-free DNA from patients with metastatic breast, colorectal or non-small cell lung cancer. We evaluated somatic copy number alterations and in parallel applied a 77-gene panel (AVENIO ctDNA Expanded Panel). We then assessed the concordance of tier classification approaches between NAVIFY and QCI and compared the strategies to determine actionability among all three platforms. Finally, we quantified the alignment of treatment suggestions across all decision tools.

Results: Each platform varied in its mode of variant classification and strategy for identifying druggable targets and clinical trials, which resulted in major discrepancies. Even the frequency of concordant actionable events for tier I-A or tier I-B classifications was only 4.3%, 9.5% and 28.4% when comparing NAVIFY with QCI, NAVIFY with CureMatch and CureMatch with QCI, respectively, and the obtained treatment recommendations differed drastically.

Conclusions: Treatment decisions based on molecular markers appear at present to be arbitrary and dependent on the chosen strategy. As a consequence, tumours with identical molecular profiles would be differently treated, which challenges the promising concepts of genome-informed medicine.
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http://dx.doi.org/10.1136/esmoopen-2020-000872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513637PMC
September 2020

Microsieves for the detection of circulating tumor cells in leukapheresis product in non-small cell lung cancer patients.

Transl Lung Cancer Res 2020 Aug;9(4):1093-1100

Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Circulating tumor cells (CTC) in non-small cell lung cancer (NSCLC) patients are a prognostic and possible therapeutic marker, but have a low frequency of appearance. Diagnostic leukapheresis (DLA) concentrates CTC and mononuclear cells from the blood. We evaluated a protocol using two VyCAP microsieves to filter DLA product of NSCLC patients and enumerate CTC, compared with CellSearch as a gold standard.

Methods: DLA was performed in NSCLC patients before starting treatment. DLA product equaling 2×10 leukocytes was diluted to 9 mL with CellSearch dilution buffer in a Transfix CTC tube. Within 72 hours the sample was filtered with a 7 µm pore microsieve and subsequently over a 5µm pore microsieve. CTC were defined as nucleated cells which stained for cytokeratin, but lacked CD45 and CD16. CellSearch detected CTC in the same volume of DLA.

Results: Of 29 patients a median of 1.4 mL DLA product (range, 0.5-4.1) was filtered (2% of total product) successfully in 93% and 45% of patients using 7 and 5 µm pores, respectively. Two DLA products were unevaluable for CTC detection. Clogging of the 5 µm but not 7 µm microsieves was positively correlated with fixation time (ρ=0.51, P<0.01). VyCAP detected CTC in 44% (12/27) of DLA products. Median CTC count per mL DLA was 0 [interquartile range (IQR): 0-1]. CellSearch detected CTC in 63% of DLA products (median =0.9 CTC per mL DLA, IQR: 0-2.1). CTC counts detected by CellSearch were significantly higher compared with VyCAP (P=0.05).

Conclusions: VyCAP microsieves can identify CTC in DLA product, but workflows need to be optimized.
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http://dx.doi.org/10.21037/tlcr-19-413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481649PMC
August 2020

Capmatinib in Exon 14-Mutated or -Amplified Non-Small-Cell Lung Cancer.

N Engl J Med 2020 09;383(10):944-957

From the Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne and University of Cologne, Cologne (J.W.), Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Heidelberg (M.T.), the Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen (T.R.O.), and Hämato-Onkologie Hamburg, Hamburg (E.L.) - all in Germany; the National Hospital Organization Kyushu Cancer Center, Fukuoka (T.S.), Aichi Cancer Center, Nagoya (T.H.), the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (M.N.), the Department of Respiratory Medicine, Okayama University Hospital, Okayama (K.O.), and the National Kyushu Cancer Center, Fukuoka (R.T.) - all in Japan; the National Cancer Center, Gyeonggi-do (J.-Y.H.), and the Department of Internal Medicine, Seoul National University Hospital, Seoul (T.-M.K.) - both in South Korea; the Hospital Clinic of Barcelona (N.R.), Translational Genomic and Targeted Therapeutics in Solid Tumors (IDIBAPS) (N.R.), and Vall d'Hebron University Hospital-Vall d'Hebron Institute of Oncology (E.F.), Barcelona; David Geffen School of Medicine at UCLA, Los Angeles (E.B.G.); the University of Groningen and University Medical Center Groningen, Groningen (H.J.M.G.), Erasmus MC Cancer Institute, Rotterdam (M.J.), and the Netherlands Cancer Institute, Amsterdam (E.F.S.) - all in the Netherlands; the National Cancer Centre Singapore, Singapore (D.S.W.T.); St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (S.V.O.); University Hospital of Lyon-Sud, Lyon (P.-J.S.), and Novartis Pharma, Rueil-Malmaison (S.L.M.) - both in France; the Respiratory Oncology Unit, University Hospitals KU Leuven, Leuven, Belgium (J.V.); the Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna (M.H.); the Thoracic Oncology Division, European Institute of Oncology, IRCCS, Milan (F.M.); Novartis Pharmaceuticals, East Hanover, NJ (A.R., M.G.); Novartis Pharma, Basel, Switzerland (M.W.-L., M.A.); and Novartis Institutes for BioMedical Research, Cambridge (B.S., O.A.B., X.C.), and Massachusetts General Hospital, Boston (R.S.H.) - both in Massachusetts.

Background: Among patients with non-small-cell lung cancer (NSCLC), exon 14 skipping mutations occur in 3 to 4% and amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.

Methods: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with -dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and status ( exon 14 skipping mutation or amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.

Results: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.

Conclusions: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a exon 14 skipping mutation, particularly in those not treated previously. The efficacy in -amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).
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http://dx.doi.org/10.1056/NEJMoa2002787DOI Listing
September 2020

Supplementary data for a model-based health economic evaluation on lung cancer screening with low-dose computed tomography in a high-risk population.

Data Brief 2020 Aug 4;31:105999. Epub 2020 Jul 4.

University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.

This supplementary data is supportive to the research article entitled 'Cost-effectiveness of lung cancer screening with low-dose computed tomography (LDCT) in heavy smokers: A micro-simulation modelling study' (Yihui Du et al. 2020). This supplementary contains a description of the model input and the related model output data that were not included in the research article. The input data used for the tumour growth model and the self-detected tumour size model are provided. The output data of this article include the data used for cost-effectiveness analysis of lung cancer LDCT screening with the Dutch and international discount rates, the data of the sensitivity analysis, and the data of the model validation.
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http://dx.doi.org/10.1016/j.dib.2020.105999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352064PMC
August 2020

Efficacy of Ibandronate Loading Dose on Rapid Pain Relief in Patients With Non-Small Cell Lung Cancer and Cancer Induced Bone Pain: The NVALT-9 Trial.

Front Oncol 2020 24;10:890. Epub 2020 Jun 24.

Department of Pulmonary Diseases, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+ (MUMC+), Maastricht, Netherlands.

Approximately 80% of non-small cell lung cancer (NSCLC) patients with bone metastases have cancer induced bone pain (CIBP). The NVALT-9 was an open-label, single arm, phase II, multicenter study. Main inclusion criterion: bone metastasized NSCLC patients with uncontrolled CIBP [brief pain inventory [BPI] ≥ 5 over last 7 days]. Patients were treated with six milligram ibandronate intravenously (day 1-3) once a day. Main exclusion criteria: active secondary malignancy, systemic anti-tumor treatment and radiotherapy ≤4 weeks before study start, previous bisphosphonate treatment. Statistics: Simon's Optimal two-stage design with a 90% power to declare the treatment active if the pain response rate is ≥ 80% and 95% confidence to declare the treatment inactive if the pain response rate is ≤ 60%. If pain response is observed in ≤ 12 of the first 19 patients further enrollment will be stopped. Primary endpoint: bone pain response, defined as 25% decrease in worst pain score (PSc) over a 3-day period (day 5-7) compared to baseline PSc with maximum of 25% increase in mean analgesic consumption during the same period. Secondary endpoints: BPI score, quality of life, toxicity and World Health Organization Performance Score. Of the 19 enrolled patients in the first stage, 18 were evaluable for response. All completed ibandronate treatment according to protocol. In 4 (22.2%), a bone pain response was observed. According to the stopping rule, further enrollment was halted. Ibandronate loading doses lead to insufficient pain relief in NSCLC patients with CIBP.
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http://dx.doi.org/10.3389/fonc.2020.00890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326766PMC
June 2020

Molecular data show conserved DNA locations distinguishing lung cancer subtypes and regulation of immune genes.

Lung Cancer 2020 08 20;146:341-349. Epub 2020 Jun 20.

University of Groningen and University Medical Center Groningen, Departments of Pulmonary Diseases and Pathology and Medical Biology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands. Electronic address:

Introduction: Non-small-cell lung cancer exhibits a range of transcriptional and epigenetic patterns that not only define distinct phenotypes, but may also govern immune related genes, which have a major impact on survival.

Methods: We used open-source RNA expression and DNA methylation data of the Cancer Genome Atlas with matched non-cancerous tissue to evaluate whether these pretreatment molecular patterns also influenced genes related to the immune system and overall survival.

Results: The distinction between lung adenocarcinoma and squamous cell carcinoma are determined by 1083 conserved methylation loci and RNA expression of 203 genes which differ for >80 % of patients between the two subtypes. Using the RNA expression profiles of 6 genes, more than 95 % of patients could be correctly classified as having either adeno or squamous cell lung cancer. Comparing tumor tissue with matched normal tissue, no differences in RNA expression were found for costimulatory and co-inhibitory genes, nor genes involved in cytokine release. However, genes involved in antigen presentation had a lower expression and a wider distribution in tumor tissue.

Discussion: Only a small number of genes, influenced by DNA methylation, determine the lung cancer subtype. The antigen presentation of cancer cells is dysfunctional, while other T cell immune functions appear to remain intact.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.008DOI Listing
August 2020

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non-small-cell Lung Cancer.

Clin Lung Cancer 2020 11 22;21(6):e647-e653. Epub 2020 May 22.

Department of Respiratory Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands.

Background: Only a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival.

Patients And Methods: Information about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals.

Results: A total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis.

Conclusion: Dutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib.
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http://dx.doi.org/10.1016/j.cllc.2020.05.019DOI Listing
November 2020
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