Pitt Niehusmann

Background: Comprehensive genomic profiling (CGP) identifies molecular alterations to support diagnosis and guide therapy in patients with cancer, yet real-world evidence on its clinical impact remains limited. We evaluated the clinical utility of equitable and population-based CGP implementation within a publicly funded healthcare system, aiming to identify actionable alterations and support treatment recommendations in patients with advanced cancer. Methods: IMPRESS-Norway is a nationwide precision medicine trial enrolling patients with treatment-refractory advanced malignancies across oncology centres. Tumour tissue was analysed using the TruSight Oncology 500 assay (TSO500, Illumina) at four regional laboratories within the Infrastructure for Precision Diagnostics (InPreD), a national programme for implementing advanced diagnostics. Results were reviewed by the national Molecular Tumour Board (MTB) to identify actionable alterations and provide biomarker-guided treatment recommendations. Findings: From April 2021 to August 2024, 1,964 patients referred for molecular profiling consented to IMPRESS-Norway, of whom 1,835 were analysed with TSO500 and evaluated by the MTB. Of these, 769 (42%) were identified with at least one actionable alteration, and 545 (30%) received a therapy recommendation through IMPRESS-Norway (24%), other clinical trials (3%), standard-of-care (2%), or off-label programmes (0·6%). The most common actionable alterations involved PIK3CA, BRAF, ERBB2, NRAS and high tumour mutational burden. Median turnaround time from requisition to MTB recommendation was 37 days (IQR 30-47). Interpretation: Nationwide implementation of CGP within a publicly funded healthcare system is feasible and supports equal access to molecular diagnostics, enabling targeted therapies and clinical trial enrolment for a substantial proportion of patients with advanced cancer. Ongoing collection of comprehensive, structured, and standardised real-world data provides evidence for clinical utility, supports translational research, and facilitates National evaluation of cost-effectiveness of CGP in routine practice.

Background: Classification of central nervous system (CNS) tumors has become increasingly complex over the past decade, raising concerns about the availability, feasibility and sustainability of comprehensive molecular diagnostics. We have evaluated nanopore whole genome sequencing (nWGS) as a single workflow to replace multiple diagnostic assays. Methods: We performed nWGS on DNA extracted from 90 adult CNS tumor samples (58 retrospective, 32 prospective) and compared the results to findings from standard of care (SoC) diagnostic work-up. Analysis was done through an automated workflow that consolidated diagnostically and therapeutically relevant genomic alterations, including copy-number variation, structural, and single-nucleotide variants, chromosomal aberrations, gene fusions and methylation-based classification. Results: Nanopore WGS enabled final diagnostic classification in all samples with >15% tumor cell content, requiring ∼3 hours of hands-on library preparation, parallel sample processing, and sequencing times within 72 hours. Methylation-based classification was available within 1 hour and was concordant with the integrated final diagnosis in 89% of cases (80/90). All diagnostically relevant copy-number variations, single-nucleotide variants, and gene fusions were concordant with standard-of-care testing, and MGMT promoter methylation status matched in 94% of cases. In addition, nWGS identified prognostic and potentially actionable variants that were not reported or covered by SoC. Conclusions: Nanopore WGS delivers comprehensive genetic and epigenetic results with a fast turn-around compared to standard methods. This enables efficient, accurate, and scalable molecular diagnostics of CNS tumors using a single platform. Its broad applicability supports its implementation in routine clinical practice and may be extended to other cancer types requiring complex genomic profiling.

Background and purpose: Molecular profiling guides cancer treatment, by identifying actionable genomic alterations. The IMPRESS-Norway trial (NCT04817956) is a nation-wide precision medicine trial evaluating the efficacy of approved cancer drugs on a novel indication in patients with advanced cancers harbouring potentially actionable alterations. Trametinib, a selective MEK1/2 inhibitor targeting the Mitogen-Activated Protein Kinase (MAPK) signalling pathway, is approved for BRAF V600 mutant melanoma but may also show activity in tumours with other alterations. This sub-study aimed to assess the efficacy of trametinib monotherapy across tumour types with alterations activating the MAPK signalling pathway.Patient/material and methods: In the IMPRESS-Norway trial patients are screened with the TruSight Oncology 500 panel or circulating tumour DNA profiling. Eligible patients are offered biomarker matched targeted therapies. In this subgroup analysis, we identified patients treated with trametinib monotherapy. Primary endpoints were disease control rate (DCR) after 16 weeks and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS).Results: DCR after 16 weeks of treatment was 39% in 52 response evaluable patients, with four patients (8%) experiencing partial response, and 16 (31%) stable disease. Responses were seen in tumours harbouring BRAF fusions, GNA11, GNAQ, KRAS, NF1, and NRAS alterations, most frequently in low-grade serous ovarian cancer, central nervous system tumours, and uveal melanoma. Forty-eight percent of patients experienced treatment-related adverse events, including two treatment related deaths. Median PFS and OS were 4 and 9 months, respectively. Interpretation: Trametinib monotherapy achieved a 39% DCR in patients lacking standard options, supporting further studies to confirm efficacy and identify predictive biomarkers for treatment response.

Purpose: Surveillance of patient outcomes with real-world data is essential to uncover regional disparities in clinical practice or quality of care. This study explored survival differences among glioblastoma patients in Norway and investigated the role of demographic and treatment factors. Methods: We analyzed real-world data from the Norwegian Cancer Registry on 1158 adults with histologically confirmed glioblastoma during 2019–2023. Surgical treatment rates per 100,000 inhabitants per region (South-East, West, Mid, North) were compared using adjusted Poisson models. Full treatment included surgical resection, radiotherapy (≥ 55 Gy for ≤ 70 years; ≥30 Gy for > 70 years), and temozolomide. Standardized survival was estimated with flexible parametric models, standardized for age, sex, year, and distances to treatment facilities. Results: Patients from the North were older and lived further from treatment centers. For patients aged 18–70, treatment and survival did not significantly differ across regions; national median standardized survival was 14.4 months (95%CI:13.6–15.2). For elderly patients (71–89 years), the North demonstrated a higher surgical treatment rate (rate ratio = 1.32; 95%CI = 0.99–1.77), but lesser use of postoperative radiotherapy and temozolomide. Median standardized survival for elderly patients in the North was 4.5 months (95%CI: 3.5–5.7) versus 7.7 (6.9–8.6) months nationally. Early mortality was particularly high for elderly patients in the North, yet those surviving beyond six months matched other regions’ survival probability. Conclusion: Lower glioblastoma survival in the North was associated with higher early mortality among elderly patients, likely due to selecting frailer patients for surgery, who less often subsequently received anti-neoplastic treatment.

Background and purpose: In Norway, comprehensive molecular tumour profiling is implemented as part of the public healthcare system. A substantial number of tumours harbour potentially targetable molecular alterations. Therapy outcomes may improve if targeted treatments are matched with actionable genomic alterations. In the IMPRESS-Norway trial (NCT04817956), patients are treated with drugs outside the labelled indication based on their tumours molecular profile. Patients and methods: IMPRESS-Norway is a national, prospective, non-randomised, precision cancer medicine trial, offering treatment to patients with advanced-stage disease, progressing on standard treatment. Comprehensive next-generation sequencing, TruSight Oncology 500, is used for screening. Patients with tumours harbouring molecular alterations with matched targeted therapies available in IMPRESS-Norway, are offered treatment. Currently, 24 drugs are available in the study. Primary study endpoints are percentage of patients offered treatment in the trial, and disease control rate (DCR) defined as complete or partial response or stable disease in evaluable patients at 16 weeks (W16) of treatment. Secondary endpoint presented is DCR in all treated patients. Results: Between April 2021 and October 2023, 1,167 patients were screened, and an actionable mutation with matching drug was identified for 358 patients. By the data cut off 186 patients have initiated treatment, 170 had a minimum follow-up time of 16 weeks, and 145 also had evaluable disease. In patients with evaluable disease, the DCR was 40% (58/145). Secondary endpoint analysis of DCR in all treated patients, showed DCR of 34% (58/170). Interpretation: Precision cancer medicine demonstrates encouraging clinical effect in a subset of patients included in the IMPRESS-Norway trial.

Aims: Anaplastic ganglioglioma is a rare tumour, and diagnosis has been based on histological criteria. The 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS WHO) does not list anaplastic ganglioglioma as a distinct diagnosis due to lack of molecular data in previous publications. We retrospectively compiled a cohort of 54 histologically diagnosed anaplastic gangliogliomas to explore whether the molecular profiles of these tumours represent a separate type or resolve into other entities.Methods: Samples were subjected to histological review, desoxyribonucleic acid (DNA) methylation profiling and next‐generation sequencing. Morphological and molecular data were summarised to an integrated diagnosis.Results: The majority of tumours designated as anaplastic gangliogliomas resolved into other CNS WHO diagnoses, most commonly pleomorphic xanthoastrocytoma (16/54), glioblastoma, isocitrate dehydrogenase protein (IDH) wild type and diffuse paediatric‐type high‐grade glioma, H3 wild type and IDH wild type (11 and 2/54), followed by low‐grade glial or glioneuronal tumours including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumour and diffuse leptomeningeal glioneuronal tumour (5/54), IDH mutant astrocytoma (4/54) and others (6/54). A subset of tumours (10/54) was not assignable to a CNS WHO diagnosis, and common molecular profiles pointing to a separate entity were not evident.Conclusions: In summary, we show that tumours histologically diagnosed as anaplastic ganglioglioma comprise a wide spectrum of CNS WHO tumour types with different prognostic and therapeutic implications. We therefore suggest assigning this designation with caution and recommend comprehensive molecular workup.

Background: An unexplained regional difference in survival was observed in previous publications on outcome for children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor (CNS‐PNET) in Norway. We aimed now to reevaluate and perform a retrospective molecular‐based risk stratification of all embryonal brain tumors (excluding atypical teratoid rhabdoid tumors [ATRT]) in pediatric patients, who underwent surgery and treatment at Oslo University Hospital between 2005 and 2017.Procedure: Specimens from all patients p = 0.036). Five patients in our cohort had tumors that are considered as new entities in the 2021 classification of tumors of the central nervous system. Five tumors were re‐classified as nonembryonal tumors after review.Conclusion: Molecular‐based risk stratification of standard‐risk non‐WNT/non‐SHH medulloblastoma enabled superior identification of medulloblastomas with dismal prognosis. Our cohort demonstrated a significantly increased fraction of standard‐risk non‐WNT/non‐SHH medulloblastoma with molecular high‐risk profile compared to other studies, which might have contributed to previously reported unfavorable outcome data.

ZUSAMMENFASSUNG: Die Schläfenlappenepilepsie stellt die häufigste fokale Epilepsieform dar. Trotz etablierter Pathologiemuster ergaben sich zuletzt grundlegende Innovationen im Hinblick sowohl auf erworbene Epilepsien mit hippocampalem Ursprung als auch bei fokalen kortikalen Dysplasien und epilepsieassoziierten, oft glioneuronalen Tumoren. Besondere Erwähnung finden Verbesserungen des molekulargenetischen Verständnisses der Erkrankungen.

Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored common drug targets in paired primary vs. recurrent GBM tissue samples. Paired surgical tissue samples were derived from a homogeneously treated cohort of 34 GBM patients. All patients received radiotherapy and temozolomide chemotherapy. Verification of common drug targets included immunohistological analysis of PDGFR-β, FGFR-2, FGFR-3, and mTOR-pathway component (phospho-mTORSer2448) as well as molecular, MLPA-based analysis of specific copy number aberrations at the gene loci of ALK, PDGFRA, VEGFR2/KDR, EGFR, MET, and FGFR1. Paired tumor tissue exhibited significant changes of expression in 9 of the 10 investigated druggable targets (90%). Only one target (FGFR1) was found “unchanged”, since dissimilar expression was observed in only one of the 34 paired tumor tissue samples. All other targets were variably expressed with an 18–56% discordance rate between primary and recurrent tissue. The high incidence of dissimilar target expression status in clinical samples from primary vs. recurrent GBM suggests clinically relevant heterogeneity along the course of disease. Molecular target expression, as determined at primary diagnosis, may not necessarily present rational treatment clues for the clinical care of recurrent GBM. Further studies need to analyze the therapeutic impact of longitudinal heterogeneity in GBM.