Hege Elisabeth Giercksky Russnes

• Schuster, Cornelia; Oppedal, Irja Alida; Vinnem, Liv Iren; Abrahamsson, Eirin Lunden; Barrett, Torill & Steinskog, Eli Sihn Samdal [Show all 8 contributors for this article] (2026). Targeted ALK inhibition achieving tumour control in metastatic melanoma: a case report. Acta Oncologica. ISSN 0284-186X. 65, p. 814–817. doi: 10.2340/1651-226X.2026.46424.
• Nakken, Sigve; Edsjö, Anders; Lehtiö, Janne; Nygaard, Vigdis; Roepman, Paul & Rosenquist, Richard [Show all 69 contributors for this article] (2026). Towards an ecosystem of clinical decision support tools for precision cancer medicine. NPJ precision oncology. doi: 10.1038/s41698-026-01551-6. Full text in Research Archive Show summary

  Molecular tumor boards are supported by clinical decision support system (CDSS) tools for the interpretation of complex molecular data towards personalized treatments. Current CDSS tools are genomics-focused and characterized by tight couplings between data ingestion, guideline-based reasoning logic and curated knowledgebases. Next-generation CDSS solutions should integrate multimodal data and learn from outcomes in an interoperable ecosystem, leveraging explainable, trustworthy output from AI models through rigorous clinical validation processes.

• Nygaard, Vigdis; Zhao, S.; Tamborero, D.; Rosenquist, R.; Stenzinger, A. & Roepman, P. [Show all 23 contributors for this article] (2026). Assessing clinical decision support system tools in precision oncology: piloting ring testing. ESMO Real World Data and Digital Oncology. 13. doi: 10.1016/j.esmorw.2026.100731. Full text in Research Archive
• Westphalen, C. B.; Bielo, L. Boscolo; Aftimos, P.; Beltran, H.; Benary, M. & Chakravarty, D. [Show all 29 contributors for this article] (2025). ESMO Precision Oncology Working Group recommendations on the structure and quality indicators for molecular tumour boards in clinical practice. Annals of Oncology. ISSN 0923-7534. 36(6), p. 614–625. doi: 10.1016/j.annonc.2025.02.009. Full text in Research Archive Show summary

  Background With an increased uptake of genomic profiling in clinical practice and the evolving complexity of diagnostic modalities, vast amounts of complex data need to be properly interpreted and integrated into an individualised care plan. To address these challenges, molecular tumour boards (MTBs) have been widely established. As of today, no international recommendations regulating the composition and workflows of MTBs have been defined. Methods ESMO’s Precision Oncology Working Group (POWG) established an international expert panel in precision oncology and defined core areas of interest. After several consultations and through an expert consensus process, the group reached a consensus level for each recommendation. Results The group defined five components in the MTB process that are critical to its function and clinical use: (i) the primary task of MTBs consists in providing genomic-informed clinical recommendations, particularly for cases exhibiting complex genomic alterations; (ii) to achieve this, MTBs should encompass interdisciplinary expertise, with key roles for oncologists with genomic expertise, pathologists with molecular training and clinical geneticists; (iii) MTBs’ recommendations should be documented in a structured report that includes genomic-informed treatment strategies, management plans for potential tumour-detected germline alterations and guidance for additional genomic testing; (iv) structured follow-up processes should be implemented for monitoring the clinical effectiveness of MTBs recommendations and (v) finally, the panel proposed quality indicators for operating MTBs, including turnaround times for cases discussion and the proportion of cases for which actionable recommendations and clinical trial enrolments were successfully implemented. Conclusions These ESMO’s POWG recommendations can serve as a guidance and help to define quality standards for MTBs to allow for harmonisation and to further expedite the integration of precision oncology into clinical practice.

• Mohammad, S.F. Haj; Pol, H. van der; Vrdoljak, E.; Lassen, U.; Ojamaa, K. & Jalkanen, K. [Show all 19 contributors for this article] (2025). A comprehensive assessment of the existing landscape of personalized cancer medicine in the European Union, on behalf of the PCM4EU consortium. ESMO Open. 10(11), p. 105872–105872. doi: 10.1016/j.esmoop.2025.105872. Full text in Research Archive
• Fjørtoft, Marit Otterlei; Garred, Øystein; Lingjærde, Ole Christian; Johannesen, Karin Teien; Ottestad, Lars & Bergheim, Inger Riise [Show all 29 contributors for this article] (2025). Single-cell analysis reveals tumour size as a key driver of immune cell profile alterations in primary breast tumours and corresponding lymph nodes. BJC Reports. 3(1). doi: 10.1038/s44276-025-00152-3. Full text in Research Archive Show summary

  At diagnosis, 30–40% of women with breast cancer have metastases in sentinel (SN) or axillary lymph nodes (ALN). Nodal status is a strong prognostic factor and guides treatment decisions. Immune checkpoint inhibition has shown some efficacy, which can increase in the neoadjuvant setting. A better understanding of how tumour cells in primary tumours and metastatic lymph nodes shape the local immune microenvironment may provide clues for more individualized therapeutic interventions. Methods We conducted deep immunophenotypic analysis of 29 primary breast tumours and 36 lymph nodes from 38 patients with primary operable breast cancer. Results The immune profile of the primary tumour was not predictive of the lymph node immune profile or metastatic status. Primary tumours showed prominent CD8 T cell exhaustion and activated regulatory T cells, and the frequencies of these subsets were associated with tumour size. The immune cell profile in lymph nodes were different from the profile in primary tumours, except for the ALN+ nodes, which displayed a T-cell profile more similar to primary tumours. The frequencies of the T cell subsets in lymph nodeswere associated with metastatic size. Tumour cells from smaller metastases exhibited a distinct phenotype compared to those from larger tumour deposits, and the size of the tumour cell deposit impacted the local immune cell composition. Conclusion The tumour size of primary tumours and metastatic size in lymph nodes are the main drivers of changes in immune cell composition

• Hermansen, Johanne Uthus; Athanasiadis, Paschalis; Yanping, Yin; Rise, Anne-sofie Forfot; Arribas, Alberto J. & Cascione, Luciano [Show all 13 contributors for this article] (2025). Proteasome inhibition overcomes resistance to targeted therapies in B-cell malignancy models and in an index patient. Cell Death & Disease. 16(1), p. 1–14. doi: 10.1038/s41419-025-07884-7. Full text in Research Archive Show summary

  Treatment of B-cell malignancies with the PI3K inhibitor (PI3Ki) idelalisib often results in high toxicity and resistance, with limited treatment alternatives for relapsed/refractory patients since idelalisib is recommended as a later or last line therapy. To investigate resistance mechanisms and identify alternative treatments, we studied functional phenotypes of idelalisib-resistant B-cell malignancy models. The idelalisib-resistant KARPAS1718 model remained sensitive to Bcl-2 inhibitors (Bcl-2i), whereas the resistant VL51 model showed reduced sensitivity compared to parental cells. Sensitivity correlated with phosphorylation and expression of the Bcl-2 family members Bcl-2 and Bim. Target addiction scoring revealed high dependence on the proteasome, and proteasome inhibitors (PI) were effective across models and in primary chronic lymphocytic leukemia (CLL) cells, independently of their PI3Ki- or Bcl-2i-sensitivities. PI treatment consistently upregulated Bim and Mcl-1, while Bcl-2 increased in KARPAS1718 and CLL cells. Bcl-2i plus PI combinations led to an additive effect in these models. A multi-refractory CLL patient in the IMPRESS-Norway trial (NCT04817956) treated with Bcl-2i plus PI showed initial clinical improvement but relapsed within four months. Treatment induced Bim and Mcl-1 upregulation and reduced cytotoxic CD8 + T-cell and CD56 dim NK-cell populations. Our findings suggest that PIs may overcome resistance to targeted therapies, and warrant further studies to optimize clinical responses.

• Henkel, Pia S.; Aas, Eline; Russnes, Hege Elisabeth Giercksky; Dyvik, Ingrid; Fagereng, Gro Live & Helland, Åslaug [Show all 9 contributors for this article] (2025). Microcosting Study of Genomic Profiling for Precision Cancer Medicine. Application from the National Infrastructure for Precision Diagnostics in Norway. Journal of Molecular Diagnostics. ISSN 1525-1578. 27(10), p. 945–953. doi: 10.1016/j.jmoldx.2025.06.006. Full text in Research Archive Show summary

  Detailed cost analyses of genomic profiling for precision cancer medicine can inform strategic planning and cost-effectiveness analysis. A flexible costing framework was developed in this study to conduct microcosting of genomic profiling in precision cancer medicine using the broad gene panel TruSight Oncology 500 and accounting for its integration into the molecular tumor board within the national Infrastructure for Precision Diagnostics in Norway. The framework enables calculation of costs per sample, by workflow steps and cost categories. Site visits and discussions with staff at Oslo University Hospital informed the diagnostic workflow, validation of the framework, and resource use inputs. Sensitivity analysis addressed alternative resource use estimates, higher batch sizes, and investment costs for automation of the library preparation step. Total costs per sample were $2944 USD, ranging from $2366 to $4307 when considering uncertainties in estimates. Consumables and personnel were the most resource-intensive cost categories across analyses. Automating the resource-intensive library preparation step enabled a higher weekly batch size with slightly lower costs per sample ($2881) despite the additional equipment costs. The dynamic costing framework highlights how the choice of equipment and batch sizes affects sample costs and personnel needs for genomic profiling. Consumables and personnel offer the largest potential for costs savings, but potential personnel bottlenecks need to be considered when further upscaling capacity.

• Røssevold, Andreas Hagen; Tekpli, Xavier; Lingjærde, Ole Christian; Russnes, Hege Elisabeth Giercksky; Vallon-Christersson, Johan & Borgen, Elin [Show all 12 contributors for this article] (2025). High tumor expression of CTLA4 identifies lymph node-negative basal-like breast cancer patients with excellent prognosis. Communications Medicine. 5(1), p. 1–13. doi: 10.1038/s43856-025-00865-z. Full text in Research Archive Show summary

  Background Tumor immune cell infiltration is a favorable prognostic factor in triple-negative breast cancer. Most triple-negative tumors belong to the aggressive basal-like subtype. We hypothesized that immune gene expression may identify low-risk patients for whom adjuvant chemotherapy can be de-escalated. Methods The expression of 753 immune-related genes was analyzed in tumor biopsies from 45 patients with basal-like disease and no lymph node metastases (Oslo1 cohort) and evaluated for prognostic value. Findings were validated in two independent cohorts. Oslo1 biopsies were also analyzed for tumor-infiltrating lymphocytes (TIL) and tertiary lymphoid structures (TLS). Results Here we show that a high expression of CTLA4 (above 63rd percentile) is associated with an excellent prognosis in the Oslo1 cohort. None of the patients in the CTLA4high group suffered disease recurrence (median follow-up 7.4 years) or breast cancer-related death (median follow-up 17.7 years). Analysis of the SCAN-B (n = 233; 97% without distant recurrence in CTLA4high group) and METABRIC cohorts (n = 155; 93% disease-specific survival in CTLA4high group) validates this finding, which also applies to patients who did not receive chemotherapy. CTLA4 expression correlates with TIL score and TLS levels (Oslo1 cohort), but no TILlow/CTLA4high patients died from breast cancer, suggesting that the CTLA4 readout identifies low-risk patients not captured by TIL assessment. Conclusions A high primary tumor expression of CTLA4 identifies patients with an excellent prognosis, for whom standard chemotherapy may be de-escalated or omitted.

• Asphaug, Lars; Akslen, Lars Andreas; Blix, Egil Støre; Boge, Beate; Borgen, Elin Faye & Brekke, Marianne B. [Show all 28 contributors for this article] (2025). Cost-Effectiveness of Prosigna for Adjuvant Treatment Decisions in Early Breast Cancer: Healthcare Sector and Societal Perspectives. Clinical Breast Cancer. ISSN 1526-8209. 25(6), p. e721–e730. doi: 10.1016/j.clbc.2025.04.011. Full text in Research Archive Show summary

  Background Gene expression profiling tests such as the Prosigna-assay are used to aid adjuvant treatment decisions in hormone receptor positive (HR+) HER2 negative (HER2-) early breast cancer (EBC). In this economic evaluation, the cost-effectiveness of Prosigna against immunohistochemical (IHC) markers including Ki-67, was evaluated from the Norwegian healthcare- and societal perspective. Materials and methods The impact of Prosigna on the treatment decision was assessed in the prospective, observational EMIT-1 trial. Using individual data collected during the first 12 months post-surgery, a decision model was built to project the economic consequences of using the Prosigna compared to IHC-markers for adjuvant treatment decisions. A bottom-up costing analysis assessed the two strategies' material- and labour costs. Health benefits were measured by cost per quality-adjusted life-years (QALYs) using the EQ-5D-5L questionnaire and data on income and welfare benefits was obtained from Statistics Norway. Results Of 2,178 HR+/HER2- pN0 EBC patients in the EMIT-1 trial, 1,985 had available health economic data and 1,850 had complete income and welfare benefit records. Including all pN0 patients in the Prosigna-test strategy, the test was above the cost-effective threshold (€26,000; incremental cost-per QALY gained (ICER) €255,622) in a healthcare sector perspective. Applying a societal perspective incorporating productivity costs, Prosigna was cost saving (ICER €-435,677). Restricting Prosigna-testing to patients assessed as chemotherapy candidates/uncertain chemotherapy candidates, the strategy was cost-effective from both the healthcare and societal perspective (ICER €8,884 and €-620,170, respectively). For other subgroups (pT>1cm, ≤/>50 years), cost-effectiveness was only achievable from a societal perspective (ICER €-574,911, €-602,955 and €-336,832, respectively). Conclusions Using the Prosigna-assay for all HR+/HER2- pN0 EBC patients was not cost-effective from a healthcare perspective, but from the societal perspective it was cost-saving compared to the IHC-classification. Selecting patients who are clear/uncertain candidates for chemotherapy based on IHC-classification, Prosigna is cost-effective from both perspectives. Micro-abstract This economic evaluation assessed the cost-effectiveness of the Prosigna gene expression profiling test versus immunohistochemical (IHC) markers for adjuvant treatment decisions in hormone receptor positive (HR+) HER2 negative (HER2-) early breast cancer (EBC) from Norwegian healthcare and societal perspectives. The Prosigna test was not cost-effective from a healthcare perspective but was cost-saving from a societal perspective. When use was restricted to patients who were clear chemotherapy candidates or uncertain candidates, Prosigna was cost-effective from both perspectives.

• Wei, Qian; Foyn, Håvard; Landskron, Johannes; Wang, Shixiong; Rye, Inga Hansine & Skånland, Sigrid S [Show all 10 contributors for this article] (2025). Identification of a group of 9-amino-acridines that selectively downregulate regulatory T cell functions through FoxP3. iScience. 28(3). doi: 10.1016/j.isci.2025.111931. Full text in Research Archive Show summary

  FoxP3+ regulatory T cells (Tregs) are responsible for immune homeostasis by suppressing excessive anti-self-immunity. Tregs facilitate tumor growth by inhibiting anti-tumor immunity. Here, we explored the targeting of FoxP3 as a basis for new immunotherapies. In a high-throughput phenotypic screening of a drug repurposing library using human primary T cells, we identified quinacrine as a FoxP3 downregulator. In silico searches based on the structure of quinacrine, testing of sub-libraries of analogs in vitro, and validation identified a subset of 9-amino-acridines that selectively abrogated Treg suppressive functions. Mechanistically, these acridines interfered with the DNA-binding activity of FoxP3 and inhibited FoxP3-regulated downstream gene regulation. Release from Treg suppression by 9-amino-acridines increased anti-tumor immune responses both in cancer patient samples and in mice in a syngeneic tumor model. Our study highlights the feasibility of screening for small molecular inhibitors of FoxP3 as an approach to pursuing Treg-based immunotherapy.

• Haar, de van de; Roepman, P.; Andre, F.; Balmaña, J.; Castro, E. & Chakravarty, D. [Show all 24 contributors for this article] (2024). ESMO Recommendations on clinical reporting of genomic test results for solid cancers. Annals of Oncology. ISSN 0923-7534. 35(11), p. 954–967. doi: 10.1016/j.annonc.2024.06.018. Full text in Research Archive Show summary

  Background Genomic tumour profiling has a crucial role in the management of patients with solid cancers, as it helps selecting and prioritising therapeutic interventions based on prognostic and predictive biomarkers, as well as identifying markers of hereditary cancers. Harmonised approaches to interpret the results of genomic testing are needed to support physicians in their decision making, prevent inequalities in precision medicine and maximise patient benefit from available cancer management options. Methods The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group assembled a group of international experts to propose recommendations for preparing clinical genomic reports for solid cancers. These recommendations aim to foster best practices in integrating genomic testing within clinical settings. After review of available evidence, several rounds of surveys and focused discussions were conducted to reach consensus on the recommendation statements. Only consensus recommendations were reported. Recommendation statements were graded in two tiers based on their clinical importance: level A (required to maintain common standards in reporting) and level B (optional but necessary to achieve ideal practice). Results Genomics reports should present key information in a front page(s) followed by supplementary information in one or more appendices. Reports should be structured into sections: (i) patient and sample details; (ii) assay and data analysis characteristics; (iii) sample-specific assay performance and quality control; (iv) genomic alterations and their functional annotation; (v) clinical actionability assessment and matching to potential therapy indications; and (vi) summary of the main findings. Specific recommendations to prepare each of these sections are made. Conclusions We present a set of recommendations aimed at structuring genomics reports to enhance physician comprehension of genomic profiling results for solid cancers. Communication between ordering physicians and professionals reporting genomic data is key to minimise uncertainties and to optimise the impact of genomic tests in patient care.

• Sharma, Abhibhav; Debik, Julia; Naume, Bjørn; Ohnstad, Hege Oma; Sahlberg, Guro Kristine Kleivi & Borgen, Elin [Show all 25 contributors for this article] (2024). Comprehensive multi-omics analysis of breast cancer reveals distinct long-term prognostic subtypes. Oncogenesis. 13(1), p. 1–13. doi: 10.1038/s41389-024-00521-6. Full text in Research Archive Show summary

  Breast cancer (BC) is a leading cause of cancer-related death worldwide. The diverse nature and heterogeneous biology of BC pose challenges for survival prediction, as patients with similar diagnoses often respond differently to treatment. Clinically relevant BC intrinsic subtypes have been established through gene expression profiling and are implemented in the clinic. While these intrinsic subtypes show a significant association with clinical outcomes, their long-term survival prediction beyond 5 years often deviates from expected clinical outcomes. This study aimed to identify naturally occurring long-term prognostic subgroups of BC based on an integrated multi-omics analysis. This study incorporates a clinical cohort of 335 untreated BC patients from the Oslo2 study with long-term follow-up (>12 years). Multi-Omics Factor Analysis (MOFA+) was employed to integrate transcriptomic, proteomic, and metabolomic data obtained from the tumor tissues. Our analysis revealed three prominent multi-omics clusters of BC patients with significantly different long-term prognoses (p = 0.005). The multi-omics clusters were validated in two independent large cohorts, METABRIC and TCGA. Importantly, a lack of prognostic association to long-term follow-up above 12 years in the previously established intrinsic subtypes was shown for these cohorts. Through a systems-biology approach, we identified varying enrichment levels of cell-cycle and immune-related pathways among the prognostic clusters. Integrated multi-omics analysis of BC revealed three distinct clusters with unique clinical and biological characteristics. Notably, these multi-omics clusters displayed robust associations with long-term survival, outperforming the established intrinsic subtypes.

• Kildal, Wanja; Cyll, Karolina Urszula; Kalsnes, Joakim; Islam, Rakibul; Julbø, Frida Marie Ihle & Pradhan, Manohar [Show all 35 contributors for this article] (2024). Deep learning for automated scoring of immunohistochemically stained tumour tissue sections – Validation across tumour types based on patient outcomes. Heliyon. 10(13), p. 1–19. doi: 10.1016/j.heliyon.2024.e32529. Full text in Research Archive Show summary

  We aimed to develop deep learning (DL) models to detect protein expression in immunohistochemically (IHC) stained tissue-sections, and to compare their accuracy and performance with manually scored clinically relevant proteins in common cancer types. Five cancer patient cohorts (colon, two prostate, breast, and endometrial) were included. We developed separate DL models for scoring IHC-stained tissue-sections with nuclear, cytoplasmic, and membranous staining patterns. For training, we used images with annotations of cells with positive and negative staining from the colon cohort stained for Ki-67 and PMS2 (nuclear model), the prostate cohort 1 stained for PTEN (cytoplasmic model) and β-catenin (membranous model). The nuclear DL model was validated for MSH6 in the colon, MSH6 and PMS2 in the endometrium, Ki-67 and CyclinB1 in prostate, and oestrogen and progesterone receptors in the breast cancer cohorts. The cytoplasmic DL model was validated for PTEN and Mapre2, and the membranous DL model for CD44 and Flotillin1, all in prostate cohorts. When comparing the results of manual and DL scores in the validation sets, using manual scores as the ground truth, we observed an average correct classification rate of 91.5 % (76.9–98.5 %) for the nuclear model, 85.6 % (73.3–96.6 %) for the cytoplasmic model, and 78.4 % (75.5–84.3 %) for the membranous model. In survival analyses, manual and DL scores showed similar prognostic impact, with similar hazard ratios and p-values for all DL models. Our findings demonstrate that DL models offer a promising alternative to manual IHC scoring, providing efficiency and reproducibility across various data sources and markers.

• Tasken, Kjetil; Mohammad, Soemeya F. Haj; Fagereng, Gro Live; Falk, Ragnhild Sørum; Helland, Åslaug & Doorn-Khosrovani, Sahar van [Show all 25 contributors for this article] (2024). PCM4EU and PRIME-ROSE: Collaboration for implementation of precision cancer medicine in Europe. Acta Oncologica. ISSN 0284-186X. 63, p. 384–392. doi: 10.2340/1651-226X.2024.34791. Full text in Research Archive Show summary

  Background: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. Patients and methods: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. Results: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. Conclusion: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.

• Andresen, Nikolai Kragøe; Røssevold, Andreas Hagen; Borgen, Elin; Schirmer, Cecilie; Gilje, Bjørnar & Garred, Øystein [Show all 14 contributors for this article] (2024). Circulating tumor cells in metastatic breast cancer patients treated with immune checkpoint inhibitors – a biomarker analysis of the ALICE and ICON trials. Molecular Oncology. ISSN 1574-7891. doi: 10.1002/1878-0261.13675. Full text in Research Archive Show summary

  Immune checkpoint inhibitors (ICIs) have been introduced in breast cancer (BC) treatment and better biomarkers are needed to predict benefit. Circulating tumor cells (CTCs) are prognostic in BC, but knowledge is limited on CTCs in the context of ICI therapy. In this study, serial sampling of CTCs (CellSearch system) was evaluated in 82 patients with metastatic BC enrolled in two randomized trials investigating ICI plus chemotherapy. Programmed death-ligand 1 (PD-L1) expression on CTCs was also measured. Patients with ≥ 2 CTCs per 7.5 mL at baseline had gene expression profiles in tumor suggestive of increased T-cell activity, including increased tumor inflammation signature (TIS) in both triple-negative (P = 0.010) and hormone receptor-positive (P = 0.024) disease. Patients with luminal A BC had higher CTC levels. The association between CTC status and outcome was most apparent 4 weeks into therapy. PD-L1 expression in CTCs was observed in 6/17 CTC-positive patients and was associated with inferior survival. In conclusion, our study indicates that CTC numbers may inform on tumor immune composition, as well as prognosis. These findings suggest a potential of using CTCs as an accessible biomarker source in BC patients treated with immunotherapy.

• Ohnstad, Hege Oma; Blix, Egil Støre; Akslen, Lars Andreas; Gilje, Bjørnar; Raj, Sunil Xavier & Skjerven, Helle [Show all 45 contributors for this article] (2024). Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer—a prospective national multicentre study (EMIT-1). ESMO Open. 9(6), p. 1–12. doi: 10.1016/j.esmoop.2024.103475. Full text in Research Archive Show summary

  Background EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions. Patients and methods Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians’ treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed. Results Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94). Conclusion The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.

• Edsjö, Anders; Russnes, Hege Elisabeth Giercksky; Lehtiö, Janne; Tamborero, David; Hovig, Eivind & Stenzinger, Albrecht [Show all 65 contributors for this article] (2024). High-throughput molecular assays for inclusion in personalised oncology trials – State-of-the-art and beyond. Journal of Internal Medicine. ISSN 0954-6820. 295(6), p. 785–803. doi: 10.1111/joim.13785. Full text in Research Archive Show summary

  In the last decades, the development of high-throughput molecular assays has revolutionised cancer diagnostics, paving the way for the concept of personalised cancer medicine. This progress has been driven by the introduction of such technologies through biomarker-driven oncology trials. In this review, strengths and limitations of various state-of-the-art sequencing technologies, including gene panel sequencing (DNA and RNA), whole-exome/whole-genome sequencing and whole-transcriptome sequencing, are explored, focusing on their ability to identify clinically relevant biomarkers with diagnostic, prognostic and/or predictive impact. This includes the need to assess complex biomarkers, for example microsatellite instability, tumour mutation burden and homologous recombination deficiency, to identify patients suitable for specific therapies, including immunotherapy. Furthermore, the crucial role of biomarker analysis and multidisciplinary molecular tumour boards in selecting patients for trial inclusion is discussed in relation to various trial concepts, including drug repurposing. Recognising that today's exploratory techniques will evolve into tomorrow's routine diagnostics and clinical study inclusion assays, the importance of emerging technologies for multimodal diagnostics, such as proteomics and in vivo drug sensitivity testing, is also discussed. In addition, key regulatory aspects and the importance of patient engagement in all phases of a clinical trial are described. Finally, we propose a set of recommendations for consideration when planning a new precision cancer medicine trial.

• Andresen, Nikolai Kragøe; Røssevold, Andreas Hagen; Quaghebeur, Claire; Gilje, Bjørnar; Boge, Beate & Gombos, Andrea [Show all 17 contributors for this article] (2024). Ipilimumab and nivolumab combined with anthracycline-based chemotherapy in metastatic hormone receptor-positive breast cancer: A randomized phase 2b trial. Journal for ImmunoTherapy of Cancer (JITC). 12:e007990(1), p. 1–12. doi: 10.1136/jitc-2023-007990. Full text in Research Archive Show summary

  Background Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR+ mBC). Doxorubicin and low- dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte- associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR + mBC. Methods Patients with HR+ mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/ m 2 every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/ nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death- ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers. Results Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross- over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross- over-arm. In the PP population (N=78) median PFS in the immune- chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo- only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor. Conclusion The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses.

• Puco, Katarina; Fagereng, Gro Live; Brabrand, Sigmund; Niehusmann, Pitt; Blix, Egil Støre & Steinskog, Eli Sihn Samdal [Show all 24 contributors for this article] (2024). IMPRESS-Norway: improving public cancer care by implementing precision medicine in Norway; inclusion rates and preliminary results. Acta Oncologica. ISSN 0284-186X. 63, p. 379–384. doi: 10.2340/1651-226X.2024.28322. Full text in Research Archive
• Figlioli, Gisella; Billaud, Amandine; Ahearn, Thomas U.; Antonenkova, Natalia N.; Becher, Heiko & Beckmann, Matthias W. [Show all 114 contributors for this article] (2023). FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. European Journal of Human Genetics. ISSN 1018-4813. 31(5), p. 578–587. doi: 10.1038/s41431-022-01257-w. Full text in Research Archive Show summary

  Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07–2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08–1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs

• Stashko, Connor; Hayward, Mary-Kate; Northey, Jason J.; Pearson, Neil; Ironside, Alastair J. & Lakins, Johnathon N. [Show all 14 contributors for this article] (2023). A convolutional neural network STIFMap reveals associations between stromal stiffness and EMT in breast cancer. Nature Communications. 14:3561, p. 1–16. doi: 10.1038/s41467-023-39085-1. Full text in Research Archive Show summary

  Abstract Intratumor heterogeneity associates with poor patient outcome. Stromal stiffening also accompanies cancer. Whether cancers demonstrate stiffness heterogeneity, and if this is linked to tumor cell heterogeneity remains unclear. We developed a method to measure the stiffness heterogeneity in human breast tumors that quantifies the stromal stiffness each cell experiences and permits visual registration with biomarkers of tumor progression. We present S patially T ransformed I nferential F orce Map (STIFMap) which exploits computer vision to precisely automate atomic force microscopy (AFM) indentation combined with a trained convolutional neural network to predict stromal elasticity with micron-resolution using collagen morphological features and ground truth AFM data. We registered high-elasticity regions within human breast tumors colocalizing with markers of mechanical activation and an epithelial-to-mesenchymal transition (EMT). The findings highlight the utility of STIFMap to assess mechanical heterogeneity of human tumors across length scales from single cells to whole tissues and implicates stromal stiffness in tumor cell heterogeneity.

• Ree, Anne Hansen; Mælandsmo, Gunhild Mari; Flatmark, Kjersti; Russnes, Hege Elisabeth Giercksky; Casteneda, Monica Gomez & Aas, Eline (2022). Cost-effectiveness of molecularly matched off-label therapies for end-stage cancer – the MetAction precision medicine study. Acta Oncologica. ISSN 0284-186X. 61(8), p. 955–962. doi: 10.1080/0284186X.2022.2098053. Full text in Research Archive Show summary

  Background: Precision cancer medicine (PCM), frequently used for the expensive and often modestly efficacious off-label treatment with medications matched to the tumour genome of end-stage cancer, challenges healthcare resources. We compared the health effects, costs and cost-effectiveness of our MetAction PCM study with corresponding data from comparator populations given best supportive care (BSC) in two external randomised controlled trials.<p> <p>Methods: We designed three partitioned survival models to evaluate the healthcare costs and qualityadjusted life years (QALYs) as the main outcomes. Cost-effectiveness was calculated as the incremental cost-effectiveness ratio (ICER) of PCM relative to BSC with an annual willingness-to-pay (WTP) threshold of EUR 56,384 (NOK 605,000). One-way and probabilistic sensitivity analyses addressed uncertainty. <p>Results: We estimated total healthcare costs (relating to next-generation sequencing (NGS) equipment and personnel wages, molecularly matched medications to the patients with an actionable tumour target and follow-up of the responding patients) and the health outcomes for the MetAction patients versus costs (relating to estimated hospital admission) and outcomes for the BSC cases. The ICERs for incremental QALYs were twice or more as high as the WTP threshold and relatively insensitive to cost decrease of the NGS procedures, while reduction of medication prices would contribute significantly towards a cost-effective PCM strategy. <p>Conclusions: The models suggested that the high ICERs of PCM were driven by costs of the NGS diagnostics and molecularly matched medications, with a likelihood for the strategy to be cost-effective defying WTP constraints. Reducing drug expenses to half the list price would likely result in an ICER at the WTP threshold. This can be an incentive for a public-private partnership for sharing drug costs in PCM, exemplified by ongoing European initiatives.

• Bjørklund, Sunniva; Aure, Miriam Ragle; Häkkinen, Jari; Vallon-Christersson, Johan; Kumar, Surendra & Evensen, Katrine Bull [Show all 34 contributors for this article] (2022). Subtype and cell type specific expression of lncRNAs provide insight into breast cancer. Communications Biology. 5(1), p. 1–14. doi: 10.1038/s42003-022-03559-7. Full text in Research Archive Show summary

  Abstract Long non-coding RNAs (lncRNAs) are involved in breast cancer pathogenesis through chromatin remodeling, transcriptional and post-transcriptional gene regulation. We report robust associations between lncRNA expression and breast cancer clinicopathological features in two population-based cohorts: SCAN-B and TCGA. Using co-expression analysis of lncRNAs with protein coding genes, we discovered three distinct clusters of lncRNAs. In silico cell type deconvolution coupled with single-cell RNA-seq analyses revealed that these three clusters were driven by cell type specific expression of lncRNAs. In one cluster lncRNAs were expressed by cancer cells and were mostly associated with the estrogen signaling pathways. In the two other clusters, lncRNAs were expressed either by immune cells or fibroblasts of the tumor microenvironment. To further investigate the cis-regulatory regions driving lncRNA expression in breast cancer, we identified subtype-specific transcription factor (TF) occupancy at lncRNA promoters. We also integrated lncRNA expression with DNA methylation data to identify long-range regulatory regions for lncRNA which were validated using ChiA-Pet-Pol2 loops. lncRNAs play an important role in shaping the gene regulatory landscape in breast cancer. We provide a detailed subtype and cell type-specific expression of lncRNA, which improves the understanding of underlying transcriptional regulation in breast cancer.

• Flobak, Åsmund; Skånland, Sigrid S; Hovig, Eivind; Tasken, Kjetil & Russnes, Hege Elisabeth Giercksky (2022). Functional precision cancer medicine: drug sensitivity screening enabled by cell culture models. TIPS - Trends in Pharmacological Sciences. ISSN 0165-6147. 43(11), p. 973–985. doi: 10.1016/j.tips.2022.08.009. Full text in Research Archive Show summary

  Functional precision medicine is a new, emerging area that can guide cancer treatment by capturing information from direct perturbations of tumor-derived, living cells, such as by drug sensitivity screening. Precision cancer medicine as currently implemented in clinical practice has been driven by genomics, and current molecular tumor boards rely extensively on genomic characterization to advise on therapeutic interventions. However, genomic biomarkers can only guide treatment decisions for a fraction of the patients. In this review we provide an overview of the current state of functional precision medicine, highlight advances for drug-sensitivity screening enabled by cell culture models, and discuss how artificial intelligence (AI) can be coupled to functional precision medicine to guide patient stratification.

• Staaf, Johan; Häkkinen, Jari; Hegardt, Cecilia; Saal, Lao H.; Kimbung, Siker & Hedenfalk, Ingrid [Show all 25 contributors for this article] (2022). RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer. NPJ breast cancer. 8:94(1), p. 1–17. doi: 10.1038/s41523-022-00465-3. Full text in Research Archive Show summary

  Abstract Multigene assays for molecular subtypes and biomarkers can aid management of early invasive breast cancer. Using RNA-sequencing we aimed to develop single-sample predictor (SSP) models for clinical markers, subtypes, and risk of recurrence (ROR). A cohort of 7743 patients was divided into training and test set. We trained SSPs for subtypes and ROR assigned by nearest-centroid (NC) methods and SSPs for biomarkers from histopathology. Classifications were compared with Prosigna in two external cohorts (ABiM, n  = 100 and OSLO2-EMIT0, n  = 103). Prognostic value was assessed using distant recurrence-free interval. Agreement between SSP and NC for PAM50 (five subtypes) was high (85%, Kappa = 0.78) for Subtype (four subtypes) very high (90%, Kappa = 0.84) and for ROR risk category high (84%, Kappa = 0.75, weighted Kappa = 0.90). Prognostic value was assessed as equivalent and clinically relevant. Agreement with histopathology was very high or high for receptor status, while moderate for Ki67 status and poor for Nottingham histological grade. SSP and Prosigna concordance was high for subtype (OSLO-EMIT0 83%, Kappa = 0.73 and ABiM 80%, Kappa = 0.72) and moderate and high for ROR risk category (68 and 84%, Kappa = 0.50 and 0.70, weighted Kappa = 0.70 and 0.78). Pooled concordance for emulated treatment recommendation dichotomized for chemotherapy was high (85%, Kappa = 0.66). Retrospective evaluation suggested that SSP application could change chemotherapy recommendations for up to 17% of postmenopausal ER+/HER2-/N0 patients with balanced escalation and de-escalation. Results suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level and that SSP models can be derived to closely match clinical tests.

• Røssevold, Andreas Hagen; Andresen, Nikolai Kragøe; Bjerre, Christina Annette; Gilje, Bjørnar; Jakobsen, Erik Hugger & Raj, Sunil Xavier [Show all 17 contributors for this article] (2022). Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial. Nature Medicine. ISSN 1078-8956. p. 1–28. doi: 10.1038/s41591-022-02126-1. Full text in Research Archive Show summary

  Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1positive disease. The randomized, placebo-controlled ALICE trial (NCT03164993, 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33–0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33–0.95; P = 0.033). A numerical advantage was observed for both the PD-L1positive (n = 27; HR = 0.65; 95% CI 0.27–1.54) and PD-L1negative subgroups (n = 31; HR = 0.57, 95% CI 0.27–1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4–30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.

• Ambrosini, Margherita; Re, Marzia Del; Manca, Paolo; Hendifar, Andrew; Drilon, Alexander & Harada, Guilherme [Show all 21 contributors for this article] (2022). ALK Inhibitors in Patients with ALK Fusion-Positive GI Cancers: An International Data Set and a Molecular Case Series. JCO Precision Oncology (JCO PO). 6(1). doi: 10.1200/PO.22.00015. Full text in Research Archive Show summary

  PURPOSE In GI cancers, anaplastic lymphoma kinase (ALK) rearrangements are extremely less frequent than in non–small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce. MATERIALS AND METHODS We assembled a clinical and molecular international data set of pretreated patients with metastatic or nonresectable cancers of GI primary tumor origin with documented ALK rearrangement treated with at least one line of ALKi. Measurable disease as per RECIST 1.1 was required for response analysis. RESULTS Primary tumor sites were distributed as follows: 5 (38%) pancreas, 3 (23%) right colon, and 1 (8%) for each one of gastric, duodenal, rectal, left colon, and biliary tract sites. Seven patients (54%) were treated with alectinib, 5 (38%) with crizotinib, and 1 (8%) with entrectinib. After disease progression, five patients (38%) received a subsequent ALKi treatment line, and at the time of data cutoff date, treatment was still ongoing in two patients. Five of 12 evaluable patients (41%) achieved a partial response to first-line ALKi, five patients (41%) had stable disease, and 2 (17%) had progressive disease. No complete responses were registered. At a median follow-up of 39.6 months (interquartile range: 19.8-59.5), the median progression-free survival was 5.0 months (95% CI, 3.68 to no response) and the median overall survival was 9.3 months (95% CI, 5.46 to no response). CONCLUSION Treatment with ALKi provides remarkable responses and clinical benefit in pretreated patients with ALK fusion–positive GI malignancies. Despite the rarity, ALK rearrangements represent an important therapeutic target in individual pretreated patients with GI solid tumors. Further work providing prospective clinical validation of this target is needed.

• Lomakin, Artem; Svedlund, Jessica; Strell, Carina; Gataric, Milana; Shmatko, Artem & Rukhovich, Gleb [Show all 21 contributors for this article] (2022). Spatial genomics maps the structure, nature and evolution of cancer clones. Nature. ISSN 0028-0836. 611(7936), p. 594–602. doi: 10.1038/s41586-022-05425-2. Full text in Research Archive Show summary

  Abstract Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour 1–3 . Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive 4,5 . Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.

• Vik, Kirsti Lund; Johansson, Anna L. V.; Trewin, Cassia Bree; Russnes, Hege Elisabeth Giercksky & Ursin, Giske (2022). Incidence of breast cancer subtypes in immigrant and non-immigrant women in Norway. Breast Cancer Research. ISSN 1465-5411. 24(4). doi: 10.1186/s13058-021-01498-5. Full text in Research Archive Show summary

  Background Breast cancer incidence differs between non-immigrants and immigrants from low- and middle-income countries. This study investigates whether immigrants also have different subtype-specific incidences. Methods We used national health registries in Norway and calculated subtype-specific incidence rate ratios (IRRs) for invasive breast cancer among women aged 20–75 and 20–49 years between 2005 and 2015. Immigrant groups were classified by country of birth broadly defined based on WHO regional groupings. Subtype was defined using estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status as luminal A-like (ER+ PR+ HER2-), luminal B-like/HER2- (ER+ PR- HER2-), luminal B-like/HER2+ (ER+ PR any HER2+), HER2+ (ER-PR-HER2+) and triple-negative breast cancer (TNBC) (ER-PR-HER2-). Results Compared to non-immigrants, incidence of the luminal A-like subtype was lower in immigrants from Sub-Saharan Africa (IRR 0.43 95% CI 0.28–0.66), South East Asia (IRR 0.63 95% CI 0.51–0.79), South Asia (IRR 0.67 95% CI 0.52–0.86) and Eastern Europe (IRR 0.86 95% CI 0.76–0.99). Immigrants from South Asia had higher rates of HER2 + tumors (IRR 2.02 95% CI 1.26–3.23). The rates of TNBC tended to be similar regardless of region of birth, except that women from South East Asia had an IRR of 0.54 (95% CI 0.32–0.91). Conclusions Women from Eastern Europe, Sub-Saharan Africa and Asia had different subtype-specific incidences compared to women from high-income countries (including non-immigrants). These differences in tumor characteristics between immigrant groups should be taken into consideration when planning preventive or screening strategies.

• Dorraji, Seyed Esmaeil; Borgen, Elin; Segura-Pena, Dario; Rawat, Puneet; Smorodina, Eva & Dunn, Claire [Show all 10 contributors for this article] (2022). Development of a High-Affinity Antibody against the Tumor-Specific and Hyperactive 611-p95HER2 Isoform. Cancers. 14:4859(19), p. 1–24. doi: 10.3390/cancers14194859. Full text in Research Archive Show summary

  Simple Summary In the present study, we addressed the unmet need for a molecular antibody (mAb) with high affinity and specificity against a truncated hyperactive isoform of human epidermal growth factor receptor 2 (HER2), called 611-carboxy terminal fragment (CTF)-p95HER2. Patients with p95HER2+ breast cancer are at risk of developing metastatic breast cancer with a poor prognosis and resistance to therapies targeting full-length HER2. We have generated a mAb named Oslo-2, which react specifically with 611-CTF-p95HER2 and has a high affinity. We also characterized the antigenic determinant (epitope) on the p95HER2 protein and the antigen-binding site (paratope) on the Oslo-2 mAb. The antibody can be used to develop antibody- or cell-based therapies targeting p95HER2, as well as a diagnostic assay to identify p95HER2+ disease. Abstract The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for aggressive disease and confers resistance to therapy. Contrary to full-length HER2, 611-p95HER2 has negligible normal tissue expression. There is currently no approved diagnostic assay to identify this subgroup and no therapy targeting this mechanism of tumor escape. The purpose of this study was to develop a monoclonal antibody (mAb) against 611-CTF-p95HER2. Hybridomas were generated from rats immunized with cells expressing 611-CTF. A hybridoma producing a highly specific Ab was identified and cloned further as a mAb. This mAb, called Oslo-2, gave strong staining for 611-CTF and no binding to full-length HER2, as assessed in cell lines and tissues by flow cytometry, immunohistochemistry and immunofluorescence. No cross-reactivity against HER2 negative controls was detected. Surface plasmon resonance analysis demonstrated a high binding affinity (equilibrium dissociation constant 2 nM). The target epitope was identified at the N-terminal end, using experimental alanine scanning. Further, the mAb paratope was identified and characterized with hydrogen-deuterium-exchange, and a molecular model for the (Oslo-2 mAb:611-CTF-p95HER2) complex was generated by an experimental-information-driven docking approach. We conclude that the Oslo-2 mAb has a high affinity and is highly specific for 611-CTF-p95HER2. The Ab may be used to develop potent and safe therapies, overcoming p95HER2-mediated tumor escape, as well as for developing diagnostic assays. Keywords: HER2; p95HER2; antibody; tumor-specific; breast cancer; cancer stem cells; HDX-MS; epitope and paratope mapping; docking

• Lien, Tonje Gulbrandsen; Ohnstad, Hege Oma; Lingjærde, Ole Christian; Vallon-Christersson, Johan; Aaserud, Marit & Sveli, My Anh Tu [Show all 12 contributors for this article] (2021). Sample preparation approach influences pam50 risk of recurrence score in early breast cancer. Cancers. 13(23). doi: 10.3390/cancers13236118. Full text in Research Archive Show summary

  The PAM50 gene expression subtypes and the associated risk of recurrence (ROR) score are used to predict the risk of recurrence and the benefits of adjuvant therapy in early-stage breast cancer. The Prosigna assay includes the PAM50 subtypes along with their clinicopathological features, and is approved for treatment recommendations for adjuvant hormonal therapy and chemotherapy in hormone-receptor-positive early breast cancer. The Prosigna test utilizes RNA extracted from macrodissected tumor cells obtained from formalin-fixed, paraffin-embedded (FFPE) tissue sections. However, RNA extracted from fresh-frozen (FF) bulk tissue without macrodissection is widely used for research purposes, and yields high-quality RNA for downstream analyses. To investigate the impact of the sample preparation approach on ROR scores, we analyzed 94 breast carcinomas included in an observational study that had available gene expression data from macrodissected FFPE tissue and FF bulk tumor tissue, along with the clinically approved Prosigna scores for the node-negative, hormone-receptor-positive, HER2-negative cases (n = 54). ROR scores were calculated in R; the resulting two sets of scores from FFPE and FF samples were compared, and treatment recommendations were evaluated. Overall, ROR scores calculated based on the macrodissected FFPE tissue were consistent with the Prosigna scores. However, analyses from bulk tissue yielded a higher proportion of cases classified as normal-like; these were samples with relatively low tumor cellularity, leading to lower ROR scores. When comparing ROR scores (low, intermediate, and high), discordant cases between the two preparation approaches were revealed among the luminal tumors; the recommended treatment would have changed in a minority of cases.

• Nobre, Ana Rita; Risson, Emma; Singh, Deepak K.; Martino, Julie S. Di; Cheung, Julie F. & Wang, Jiapeng [Show all 14 contributors for this article] (2021). Bone marrow NG2+/Nestin+ mesenchymal stem cells drive DTC dormancy via TGF-β2. Nature Cancer. doi: 10.1038/s43018-021-00179-8. Full text in Research Archive
• Johansson, Anna; Trewin, Cassia Bree; Fredriksson, Irma; Reinertsen, Kristin Valborg; Russnes, Hege Elisabeth Giercksky & Ursin, Giske (2021). In modern times, how important are breast cancer stage, grade and receptor subtype for survival: a population-based cohort study. Breast Cancer Research. ISSN 1465-5411. 23(17). doi: 10.1186/s13058-021-01393-z. Full text in Research Archive Show summary

  Background In breast cancer, immunohistochemistry (IHC) subtypes, together with grade and stage, are well-known independent predictors of breast cancer death. Given the immense changes in breast cancer treatment and survival over time, we used recent population-based data to test the combined influence of IHC subtypes, grade and stage on breast cancer death. Methods We identified 24,137 women with invasive breast cancer aged 20 to 74 between 2005 and 2015 in the database of the Cancer Registry of Norway. Kaplan-Meier curves, mortality rates and adjusted hazard ratios for breast cancer death were estimated by IHC subtypes, grade, tumour size and nodal status during 13 years of follow-up. Results Within all IHC subtypes, grade, tumour size and nodal status were independent predictors of breast cancer death. When combining all prognostic factors, the risk of death was 20- to 40-fold higher in the worst groups compared to the group with the smallest size, low grade and ER+PR+HER2− status. Among node-negative ER+HER2− tumours, larger size conferred a significantly increased breast cancer mortality. ER+PR−HER2− tumours of high grade and advanced stage showed particularly high breast cancer mortality similar to TNBC. When examining early versus late mortality, grade, size and nodal status explained most of the late (> 5 years) mortality among ER+ subtypes. Conclusions There is a wide range of risks of dying from breast cancer, also across small breast tumours of low/intermediate grade, and among node-negative tumours. Thus, even with modern breast cancer treatment, stage, grade and molecular subtype (reflected by IHC subtypes) matter for prognosis.

• Aamdal, Elin; Jacobsen, Kari Dolven; Straume, Oddbjørn; Kersten, Christian; Herlofsen, Oluf & Karlsen, Jarle [Show all 19 contributors for this article] (2021). Ipilimumab in a real-world population: A prospective Phase IV trial with long-term follow-up. International Journal of Cancer. ISSN 0020-7136. 150(1), p. 100–111. doi: 10.1002/ijc.33768. Full text in Research Archive Show summary

  Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III

• Bjaanæs, Maria Moksnes; Nilsen, Gro; Halvorsen, Ann Rita; Russnes, Hege Elisabeth Giercksky; Solberg, Steinar & Jørgensen, Lars [Show all 9 contributors for this article] (2021). Whole genome copy number analyses reveal a highly aberrant genome in TP53 mutant lung adenocarcinoma tumors. BMC Cancer. 21(1). doi: 10.1186/s12885-021-08811-7. Full text in Research Archive Show summary

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

• Svendsen, Henrik Aasrum; Meling, Torstein Ragnar; Nygaard, Vigdis; Waagene, Stein; Russnes, Hege Elisabeth Giercksky & Juell, Siri [Show all 11 contributors for this article] (2021). Novel human melanoma brain metastasis models in athymic nude fox1^nu mice: Site-specific metastasis patterns reflecting their clinical origin. Cancer Medicine. 10(23), p. 8604–8613. doi: 10.1002/cam4.4334. Full text in Research Archive Show summary

  Background: Malignant melanomas frequently metastasize to the brain, but metastases in the cerebellum are underrepresented compared with metastases in the cerebrum.<p> <p>Methods: We established animal models by injecting intracardially in athymic nude fox1^nu mice two human melanoma cell lines, originating from a cerebral metastasis (HM19) and a cerebellar metastasis (HM86).<p> <p>Results: Using magnetic resonance imaging (MRI), metastases were first detected after a mean of 34.5 days. Mean survival time was 59.6 days for the mice in the HM86 group and significantly shorter (43.7 days) for HM19-injected animals (p < 0.001). In the HM86 group, the first detectable metastasis was located in the cerebellum in 15/55 (29%) mice compared with none in the HM19 group (p < 0.001). At sacrifice, cerebellar metastases were found in 34/55 (63%) HM86- injected mice compared with 1/53 (2%) in the HM19-injected (p < 0.001) mice. At that time, all mice in both groups had detectable metastases in the cerebrum. Comparing macroscopic and histologic appearances of the brain metastases with their clinical counterparts, the cell line-based tumors had kept their original morphologic characteristics.<p> <p>Conclusions: The present work demonstrates that human brain-metastatic melanoma cells injected intracardially in mice had retained inherent characteristics also in reproducing interaction with subtle microenvironmental brain tissue compartment-specific features. The models offer new possibilities for investigating tumor- and host-associated factors involved in determining tissue specificity of brain metastasis.

• Rye, Inga Hansine; Huse, Kanutte; Josefsson, Sarah Elisabet; Kildal, Wanja; Danielsen, Håvard Emil Greger & Schlichting, Ellen [Show all 28 contributors for this article] (2021). Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression. Molecular Oncology. ISSN 1574-7891. 16(1), p. 88–103. doi: 10.1002/1878-0261.13047. Full text in Research Archive Show summary

  Sentinel lymph nodes are the first nodes draining the lymph from a breast and could reveal early changes in the host immune system upon dissemination of breast cancer cells. To investigate this, we performed single-cell immune profiling of lymph nodes with and without metastatic cells. Whereas no significant changes were observed for B-cell and natural killer (NK)-cell subsets, metastatic lymph nodes had a significantly increased frequency of CD8 T cells and a skewing toward an effector/memory phenotype of CD4 and CD8 T cells, suggesting an ongoing immune response. Additionally, metastatic lymph nodes had an increased frequency of TIGIT (T-cell immunoreceptor with Ig and ITIM domains)-positive T cells with suppressed TCR signaling compared with non-metastatic nodes, indicating exhaustion of effector T cells, and an increased frequency of regulatory T cells (Tregs) with an activated phenotype. T-cell alterations correlated with the percentage of metastatic tumor cells, reflecting the presence of metastatic tumor cells driving T effector cells toward exhaustion and promoting immunosuppression by recruitment or increased differentiation toward Tregs. These results show that immune suppression occurs already in early stages of tumor progression.

• Janiszewska, Michalina; Stein, Shayna; Filho, Otto Metzger; Eng, Jennifer; Kingston, Natalie L. & Harper, Nicholas W. [Show all 23 contributors for this article] (2021). The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer. JCI Insight. 6(11), p. 1–19. doi: 10.1172/jci.insight.147617. Full text in Research Archive
• Liu, Jingjing; Smissen, Wendy J. C. Prager van der; Collee, Margriet J.; Bolla, Manjeet K.; Wang, Qin & Kristensen, Vessela N. [Show all 82 contributors for this article] (2020). Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk. Scientific Reports. 10:9688(1), p. 1–14. doi: 10.1038/s41598-020-65665-y. Full text in Research Archive Show summary

  In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR=1.035, 95% CI=0.859–1.246, P=0.718 and OR=0.798, 95% CI=0.482–1.322, P=0.381 respectively), nor in specifc high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

• Pladsen, Arne Valebjørg; Nilsen, Gro; Rueda, Oscar M.; Aure, Miriam Ragle; Borgan, Ørnulf & Liestøl, Knut [Show all 18 contributors for this article] (2020). DNA copy number motifs are strong and independent predictors of survival in breast cancer. Communications Biology. 3. doi: 10.1038/s42003-020-0884-6. Full text in Research Archive Show summary

  Somatic copy number alterations are a frequent sign of genome instability in cancer. A precise characterization of the genome architecture would reveal underlying instability mechanisms and provide an instrument for outcome prediction and treatment guidance. Here we show that the local spatial behavior of copy number profiles conveys important information about this architecture. Six filters were defined to characterize regional traits in copy number profiles, and the resulting Copy Aberration Regional Mapping Analysis (CARMA) algorithm was applied to tumors in four breast cancer cohorts (n = 2919). The derived motifs represent a layer of information that complements established molecular classifications of breast cancer. A score reflecting presence or absence of motifs provided a highly significant independent prognostic predictor. Results were consistent between cohorts. The nonsite-specific occurrence of the detected patterns suggests that CARMA captures underlying replication and repair defects and could have a future potential in treatment stratification.

• Lampignano, Rita; Neumann, Martin H.D; Weber, Sabrina; Kloten, Vera; Herdean, Andrei & Voss, Thorsten [Show all 32 contributors for this article] (2020). Multicenter Evaluation of Circulating Cell-Free DNA Extraction and Downstream Analyses for the Development of Standardized (Pre)analytical Work Flows. Clinical Chemistry. ISSN 0009-9147. 66(1), p. 146–160. doi: 10.1373/clinchem.2019.306837. Full text in Research Archive
• Kyte, Jon A; Andresen, Nikolai Kragøe; Russnes, Hege Elisabeth Giercksky; Fretland, Signe Øien; Falk, Ragnhild Sørum & Lingjærde, Ole Christian [Show all 7 contributors for this article] (2020). ICON: A randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer. Journal of Translational Medicine. 18(1). doi: 10.1186/s12967-020-02421-w. Full text in Research Archive Show summary

  Background Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as “immunogenic” chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. Methods ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression. Discussion ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198

• Ree, Anne Hansen; Nygaard, Vigdis; Pedersen, Kjetil Boye; Heinrich, Daniel; Dueland, Svein & Bergheim, Inger Riise [Show all 25 contributors for this article] (2020). Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer?the MetAction study. Acta Oncologica. ISSN 0284-186X. p. 1–10. doi: 10.1080/0284186X.2020.1742377. Full text in Research Archive Show summary

  <i>Background</i>: In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014–2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016–2019).<p><p> <i>Material and methods</i>: Metastatic tissue from 26 patients (16 colorectal cancer cases) was sequenced by the Oncomine assay. The study tumor boards interpreted called variants with respect to sensitivity or resistance to matched therapy and recommended single-agent or combination treatment if considered tolerable. The primary endpoint was the rate of progression-free survival 1.3-fold longer than for the most recent systemic therapy. The objective response rate and overall survival were secondary endpoints.<p><p> <i>Results</i>: Both common and rare actionable alterations were identified. Thirteen patients were found eligible for therapy following review of tumor sensitivity and resistance variants and patient tolerability. The interventions were inhibitors of ALK/ROS1-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling for 2–3 cases each. Among 10 patients who received treatment until radiologic evaluation, 6 (46% of the eligible cases) met the primary endpoint. Four colorectal cancer patients (15% of the total study cohort) had objective response. The only serious adverse event was a transient colitis, which appeared in 1 of the 2 patients given PD-1 inhibitor with complete response. Apart from those two, overall survival was similar for patients who did and did not receive study treatment.<p><p> <i>Conclusions</i>: The systematic MetAction approach may point forward to a refined framework for how to interpret the complexity of sensitivity <i>versus</i> resistance and patient safety that resides in tumor sequence data, for the possibly improved outcome of precision cancer medicine in future studies.

• Tekpli, Xavier; Lien, Tonje Gulbrandsen; Røssevold, Andreas Hagen; Nebdal, Daniel J.H.; Borgen, Elin & Ohnstad, Hege Oma [Show all 19 contributors for this article] (2019). An independent poor-prognosis subtype of breast cancer defined by a distinct tumor immune microenvironment. Nature Communications. 10:5499, p. 1–14. doi: 10.1038/s41467-019-13329-5. Full text in Research Archive Show summary

  How mixtures of immune cells associate with cancer cell phenotype and affect pathogenesis is still unclear. In 15 breast cancer gene expression datasets, we invariably identify three clusters of patients with gradual levels of immune infiltration. The intermediate immune infiltration cluster (Cluster B) is associated with a worse prognosis independently of known clinicopathological features. Furthermore, immune clusters are associated with response to neoadjuvant chemotherapy. In silico dissection of the immune contexture of the clusters identified Cluster A as immune cold, Cluster C as immune hot while Cluster B has a pro-tumorigenic immune infiltration. Through phenotypical analysis, we find epithelial mesenchymal transition and proliferation associated with the immune clusters and mutually exclusive in breast cancers. Here, we describe immune clusters which improve the prognostic accuracy of immune contexture in breast cancer. Our discovery of a novel independent prognostic factor in breast cancer highlights a correlation between tumor phenotype and immune contexture.

• Taylor-King, Jake P; Baratchart, Etienne; Dhawan, Andrew; Coker, Elizabeth A; Rye, Inga Hansine & Russnes, Hege Elisabeth Giercksky [Show all 9 contributors for this article] (2019). Simulated ablation for detection of cells impacting paracrine signalling in histology analysis. Mathematical Medicine and Biology. ISSN 1477-8599. 36(1), p. 93–112. doi: 10.1093/imammb/dqx022. Full text in Research Archive
• Johansson, Henrik J.; Socciarelli, Fabio; Vacanti, Nathaniel M.; Haugen, Mads Haugland; Zhu, Yafeng & Siavelis, Ioannis [Show all 36 contributors for this article] (2019). Breast cancer quantitative proteome and proteogenomic landscape. Nature Communications. 10:1600, p. 1–14. doi: 10.1038/s41467-019-09018-y. Full text in Research Archive Show summary

  In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.

• Kraby, Maria Ryssdal; Opdahl, Signe; Russnes, Hege Elisabeth Giercksky & Bofin, Anna M. (2019). Microvessel density in breast cancer: The impact of field area on prognostic informativeness. Journal of Clinical Pathology. ISSN 0021-9746. p. 304–310. doi: 10.1136/jclinpath-2018-205536. Full text in Research Archive
• Lilleborge, Marie; Falk, Ragnhild Sørum; Russnes, Hege Elisabeth Giercksky; Sauer, Torill; Ursin, Giske & Hofvind, Solveig (2019). Risk of breast cancer by prior screening results among women participating in BreastScreen Norway. Cancer. ISSN 0008-543X. 125(19), p. 3330–3337. doi: 10.1002/cncr.32330. Full text in Research Archive Show summary

  Background: This registry‐based cohort study followed women who participated in the organized breast cancer screening program in Norway, BreastScreen Norway, in 1995‐2016. Incidence rates and incidence rate ratios were used to estimate absolute and relative risks of breast cancer associated with PSRs. Histopathological characteristics of subsequent breast cancers were presented by PSRs. Results: This study included 762,643 women with up to 21 years of follow‐up. In comparison with negatively screened women, increased incidence rate ratios of 1.8, 2.0, 2.9, and 3.8 were observed after negative additional imaging, for benign biopsy, for hyperplasia with atypia, and for carcinoma in situ, respectively. Subsequent breast cancers did not differ in tumor diameter or histological grade, whereas the proportion of lymph node–positive breast cancers decreased as the presumed malignancy potential of PSRs increased. Conclusions: The risk of subsequent breast cancer increased with the presumed malignancy potential of PSRs, whereas the tumor characteristics of subsequent cancers did not differ except for the lymph node status. Women with screen‐detected benign lesions or hyperplasia with atypia might benefit from more frequent screening.

• Ree, Anne Hansen; Nygaard, Vigdis; Russnes, Hege Elisabeth Giercksky; Heinrich, Daniel; Nygaard, Vegard & Johansen, Christin [Show all 13 contributors for this article] (2019). Responsiveness to PD-1 Blockade in End-Stage Colon Cancer with Gene Locus 9p24.1 Copy-Number Gain. Cancer immunology research. ISSN 2326-6066. 7(5), p. 701–706. doi: 10.1158/2326-6066.CIR-18-0777. Full text in Research Archive Show summary

  Most patients whose large bowel cancer has spread to other organs do not respond to immune therapy. We detected a rare gene mutation, termed 9p24.1 copy-number gain (CNG), in an otherwise incurable colorectal cancer that provoked an immune therapy response. We identified this gene mutation by gene-panel sequencing of DNA from a liver metastasis biopsy from a patient who had disease refractory to standard therapies. Following immune checkpoint blockade (ICB) with pembrolizumab (anti–PD-1), the patient experienced conversion of the tumor phenotype from one with epithelial features to that of an inflamed microenvironment, detected by high-resolution RNA sequencing. Circulating tumor DNA disappeared over the first weeks of therapy. As assessed by standard radiographic measurement, the patient had a partial response that was durable. This patient's response may support the use of histology-agnostic ICB in solid tumors that carry the rare 9p24.1 CNG.

• Glodzik, Dominic; Purdie, C; Rye, Inga Hansine; Simpson, PT; Staaf, J & Span, P.N [Show all 8 contributors for this article] (2018). Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers. Annals of Oncology. ISSN 0923-7534. 29(11), p. 2223–2231. doi: 10.1093/annonc/mdy404. Full text in Research Archive
• Ellingjord-Dale, Merete; Vos, Linda; Vik, Kirsti Lund; Hjartåker, Anette; Russnes, Hege Elisabeth Giercksky & Treti, Steinar [Show all 9 contributors for this article] (2018). Number of Risky Lifestyle Behaviors and Breast Cancer Risk. JNCI Cancer Spectrum. 2(3). doi: 10.1093/jncics/pky030. Full text in Research Archive Show summary

  Lifestyle factors are associated with overall breast cancer risk, but less is known about their associations, alone or jointly, with risk of specific breast cancer subtypes. We conducted a case–control subjects study nested within a cohort of women who participated in the Norwegian Breast Cancer Screening Program during 2006–2014 to examine associations between risky lifestyle factors and breast cancer risk. In all, 4402 breast cancer cases subjects with information on risk factors and hormone receptor status were identified. Conditional logistic regression was used to estimate odds ratios (ORs), with 95% confidence intervals (CIs), in relation to five risky lifestyle factors: body mass index (BMI) of 25 kg/m² or greater, three or more glasses of alcoholic beverages per week, ever smoking, fewer than four hours of physical activity per week, and ever use of menopausal hormone therapy. Analyses were adjusted for education, age at menarche, number of pregnancies, and menopausal status. All statistical tests were two-sided. Compared with women with no risky lifestyle behaviors, those with five had 85% (OR = 1.85, 95% CI = 1.42 to 2.42, Ptrend &lt; .0001) increased risk of breast cancer overall. This association was limited to luminal A–like (OR = 2.20, 95% CI = 1.55 to 3.12, Ptrend &lt; .0001) and luminal B–like human epidermal growth factor receptor 2 (HER2)–positive (OR = 1.66, 95% CI = 0.61 to 4.54, Ptrend &lt; .004) subtypes. Number of risky lifestyle factors was not associated with increased risk of luminal B–like HER2-negative, HER2-positive, or triple-negative subtypes (Ptrend &gt; .18 for all). Number of risky lifestyle factors was positively associated with increased risk for luminal A–like and luminal B–like HER2-positive breast cancer.

• Alves, Cleidson P.; Dey-Guha, Ipsita; Kabraji, Sheheryar; Yeh, Albert C; Talele, Nilesh P & Solé, Xavier [Show all 14 contributors for this article] (2018). AKT1low Quiescent Cancer Cells Promote Solid Tumor Growth. Molecular Cancer Therapeutics. ISSN 1535-7163. 17(1), p. 254–263. doi: 10.1158/1535-7163.MCT-16-0868. Full text in Research Archive
• Rye, Inga Hansine; Trinh, Anne; Sætersdal, Anna Barbro; Nebdal, Daniel J.H.; Lingjærde, Ole Christian & Almendro, Vanessa [Show all 11 contributors for this article] (2018). Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors. Molecular Oncology. ISSN 1574-7891. p. 1–18. doi: 10.1002/1878-0261.12375. Full text in Research Archive Show summary

  Targeted therapy for patients with HER2‐positive (HER2+) breast cancer has improved overall survival, but many patients still suffer relapse and death from the disease. Intratumor heterogeneity of both estrogen receptor (ER) and HER2 expression has been proposed to play a key role in treatment failure, but little work has been done to comprehensively study this heterogeneity at the single‐cell level. In this study, we explored the clinical impact of intratumor heterogeneity of ER protein expression, HER2 protein expression, and HER2 gene copy number alterations. Using combined immunofluorescence and in situ hybridization on tissue sections followed by a validated computational approach, we analyzed more than 13 000 single tumor cells across 37 HER2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER2‐targeted treatment, enabling us to study tumor evolution as well. We found that intratumor heterogeneity for HER2 copy number varied substantially between patient samples. Highly heterogeneous tumors were associated with significantly shorter disease‐free survival and fewer long‐term survivors. Patients for which HER2 characteristics did not change during treatment had a significantly worse outcome. This work shows the impact of intratumor heterogeneity in molecular diagnostics for treatment selection in HER2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies.

• Glodzik, Dominik; Morganella, Sandro; Davies, Helen; Simpson, Peter T.; Li, Yilong & Zou, Xueqing [Show all 30 contributors for this article] (2017). A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nature Genetics. ISSN 1061-4036. 49(3), p. 341–348. doi: 10.1038/ng.3771. Full text in Research Archive
• Ohnstad, Hege Oma; Borgen, Elin; Falk, Ragnhild Sørum; Lien, Tonje Gulbrandsen; Aaserud, Marit & Sveli, My Anh Tu [Show all 14 contributors for this article] (2017). Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up. Breast Cancer Research. ISSN 1465-5411. 19(120). doi: 10.1186/s13058-017-0911-9. Full text in Research Archive Show summary

  Background The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) pN0 patients not treated with chemotherapy. Methods Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995–1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS). Results Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2− patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2− patients) yielded strong prognostic information. Among the HR+/HER2− pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2− pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2− population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%). Conclusions The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy.

• Davies, Helen; Morganella, Sandro; Purdie, Colin A.; Jang, Se Jin; Borgen, Elin & Russnes, Hege Elisabeth Giercksky [Show all 16 contributors for this article] (2017). Whole-genome sequencing reveals breast cancers with mismatch repair deficiency. Cancer Research. ISSN 0008-5472. 77(18), p. 4755–4762. doi: 10.1158/0008-5472.CAN-17-1083. Full text in Research Archive
• Russnes, Hege Elisabeth Giercksky; Lingjærde, Ole Christian; Børresen-Dale, Anne-Lise & Caldas, Carlos (2017). Breast cancer molecular stratification– from intrinsic subtypes to integrative clusters. American Journal of Pathology. ISSN 0002-9440. doi: 10.1016/j.ajpath.2017.04.022. Full text in Research Archive
• Ree, Anne Hansen; Russnes, Hege Elisabeth Giercksky; Heinrich, Daniel; Dueland, Svein; Pedersen, Kjetil Boye & Nygaard, Vigdis [Show all 34 contributors for this article] (2017). Implementing precision cancer medicine in the public health services of Norway: the diagnostic infrastructure and a cost estimate. ESMO Open. 2(2), p. 1–10. doi: 10.1136/esmoopen-2017-000158. Full text in Research Archive Show summary

  Objective Through the conduct of an individual-based intervention study, the main purpose of this project was to build and evaluate the required infrastructure that may enable routine practice of precision cancer medicine in the public health services of Norway, including modelling of costs. Methods An eligible patient had end-stage metastatic disease from a solid tumour. Metastatic tissue was analysed by DNA sequencing, using a 50-gene panel and a study-generated pipeline for analysis of sequence data, supplemented with fluorescence in situ hybridisation to cover relevant biomarkers. Cost estimations compared best supportive care, biomarker-agnostic treatment with a molecularly targeted agent and biomarker-based treatment with such a drug. These included costs for medication, outpatient clinic visits, admission from adverse events and the biomarker-based procedures. Results The diagnostic procedures, which comprised sampling of metastatic tissue, mutation analysis and data interpretation at the Molecular Tumor Board before integration with clinical data at the Clinical Tumor Board, were completed in median 18 (8-39) days for the 22 study patients. The 23 invasive procedures (12 from liver, 6 from lung, 5 from other sites) caused a single adverse event (pneumothorax). Per patient, 0–5 mutations were detected in metastatic tumours; however, no actionable target case was identified for the current single-agent therapy approach. Based on the cost modelling, the biomarker-based approach was 2.5-fold more costly than best supportive care and 2.5-fold less costly than the biomarker-agnostic option. Conclusions The first project phase established a comprehensive diagnostic infrastructure for precision cancer medicine, which enabled expedite and safe mutation profiling of metastatic tumours and data interpretation at multidisciplinary tumour boards for patients with end-stage cancer. Furthermore, it prepared for protocol amendments, recently approved by the designated authorities for the second study phase, allowing more comprehensive mutation analysis and opportunities to define therapy targets.

• Alcazar, Carlos Rodrigo Gil Del; Huh, Sung Jin; Ekram, Muhammad B.; Trinh, Anne; Liu, Lin L. & Beca, Francisco [Show all 30 contributors for this article] (2017). Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discovery. ISSN 2159-8274. 7(10), p. 1098–1115. doi: 10.1158/2159-8290.CD-17-0222. Full text in Research Archive
• Ellingjord-Dale, Merete; Vos, Linda; Vik, Kirsti Lund; Hjartåker, Anette; Russnes, Hege Elisabeth Giercksky & Tretli, Steinar [Show all 9 contributors for this article] (2017). Alcohol, physical activity, smoking and breast cancer subtypes in a large nested case-control study from the Norwegian Breast Cancer Screening Program. Cancer Epidemiology, Biomarkers and Prevention. ISSN 1055-9965. 26(12), p. 1736–1744. doi: 10.1158/1055-9965.EPI-17-0611. Full text in Research Archive
• Cheng, Jiqiu; Demeulemeester, Jonas; Wedge, David C.; Vollan, Hans Kristian Moen; Pitt, Jason & Russnes, Hege Elisabeth Giercksky [Show all 18 contributors for this article] (2017). Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors. Nature Communications. 8:1221, p. 1–14. doi: 10.1038/s41467-017-01355-0. Full text in Research Archive Show summary

  Homozygous deletions are rare in cancers and often target tumour suppressor genes. Here, we build a compendium of 2218 primary tumours across 12 human cancer types and systematically screen for homozygous deletions, aiming to identify rare tumour suppressors. Our analysis defines 96 genomic regions recurrently targeted by homozygous deletions. These recurrent homozygous deletions occur either over tumour suppressors or over fragile sites, regions of increased genomic instability. We construct a statistical model that separates fragile sites from regions showing signatures of positive selection for homozygous deletions and identify candidate tumour suppressors within those regions. We find 16 established tumour suppressors and propose 27 candidate tumour suppressors. Several of these genes (including MGMT, RAD17, and USP44) show prior evidence of a tumour suppressive function. Other candidate tumour suppressors, such as MAFTRR, KIAA1551, and IGF2BP2, are novel. Our study demonstrates how rare tumour suppressors can be identified through copy number meta-analysis.

• Risberg, Bente; Vålerhaugen, Helen & Russnes, Hege Elisabeth Giercksky (2016). Cellefritt tumor-DNA i blod, et nytt verktøy for diagnostikk og monitorering av kreftpasienter? Bioingeniøren. ISSN 0801-6828. 51(1), p. 14–20. Full text in Research Archive
• Sas-Chen, Aldema; Aure, Miriam Ragle; Leibovich, Limor; Carvalho, Silvia; Enuka, Yehoshua & Körner, Cindy [Show all 38 contributors for this article] (2016). LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer. EMBO Molecular Medicine. ISSN 1757-4676. 8(9), p. 1052–1064. doi: 10.15252/emmm.201606198. Full text in Research Archive Show summary

  Long noncoding RNAs (lncRNAs) are emerging as regulators of gene expression in pathogenesis, including cancer. Recently, lncRNAs have been implicated in progression of specific subtypes of breast cancer. One aggressive, basal‐like subtype associates with increased EGFR signaling, while another, the HER2‐enriched subtype, engages a kin of EGFR. Based on the premise that EGFR‐regulated lncRNAs might control the aggressiveness of basal‐like tumors, we identified multiple EGFR‐inducible lncRNAs in basal‐like normal cells and overlaid them with the transcriptomes of over 3,000 breast cancer patients. This led to the identification of 11 prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal‐like and in HER2‐positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. We also find that LIMT inhibits extracellular matrix invasion of mammary cells in vitro and tumor metastasis in vivo. In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers.

• Rye, Inga Hansine; Lundin, Pär; Månér, Susanne; Fjelldal, Renathe; Naume, Bjørn & Wigler, Michael [Show all 10 contributors for this article] (2015). Quantitative multigene FISH on breast carcinomas identifies der(1;16)(q10;p10) as an early event in luminal A tumors. Genes, Chromosomes and Cancer. ISSN 1045-2257. 54(4), p. 235–248. doi: 10.1002/gcc.22237. Full text in Research Archive
• Silwal-Pandit, Laxmi; Russnes, Hege Elisabeth Giercksky; Borgen, Elin; Vang, Veronica Okkenhaug; Vollan, Hans Kristian Moen & Schlichting, Ellen [Show all 11 contributors for this article] (2015). The sub-cellular localization of WRAP53 has prognostic impact in breast cancer. PLOS ONE. 10:e0139965(10). doi: 10.1371/journal.pone.0139965. Full text in Research Archive Show summary

  WRAP53 protein controls intracellular trafficking of DNA repair proteins, the telomerase enzyme, and splicing factors. Functional loss of the protein has been linked to carcinogenesis, premature aging and neurodegeneration. The aim of this study was to investigate the prognostic significance of WRAP53 protein expression in breast cancer. A tissue microarray was constructed from primary breast tumors and immunostained by a polyclonal WRAP53 antibody to assess the protein expression pattern. Two different patient cohorts with long term follow-up were studied; a test- and a validation set of 154 and 668 breast tumor samples respectively. Breast cancer patients with tumor cells lacking the expression of WRAP53 in the nucleus had a significantly poorer outcome compared to patients with tumor cells expressing this protein in the nuclei (HR = 1.95, 95%CI = 1.09–3.51, p = 0.025). Nuclear localization of WRAP53 was further shown to be an independent marker of prognosis in multivariate analysis (HR = 2.57, 95%CI = 1.27–5.19, p = 0.008), and also significantly associated with better outcome in patients with TP53 mutation. Here we show that the sub-cellular localization of the WRAP53 protein has a significant impact on breast cancer survival, and thus has a potential as a clinical marker in diagnostics and treatment.

• Potapenko, Ivan Olegovich; Luders, Torben; Russnes, Hege Elisabeth Giercksky; Helland, Åslaug; Sørlie, Therese & Kristensen, Vessela N. [Show all 10 contributors for this article] (2015). Glycan-related gene expression signatures in breast cancer subtypes; relation to survival. Molecular Oncology. ISSN 1574-7891. 9(4), p. 861–876. doi: 10.1016/j.molonc.2014.12.013. Full text in Research Archive
• Yamamoto, Shoji; Wu, Zhenhua; Russnes, Hege Elisabeth Giercksky; Takagi, Shinji; Peluffo, Guillermo & Vaske, Charles [Show all 22 contributors for this article] (2014). JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell. ISSN 1535-6108. 25(6), p. 762–777. doi: 10.1016/j.ccr.2014.04.024. Full text in Research Archive
• Russnes, Hege Elisabeth Giercksky; Lønning, Per Eystein; Børresen-Dale, Anne-Lise & Lingjærde, Ole Christian (2014). The multitude of molecular analyses in cancer: the opening of Pandora’s box. Genome Biology. ISSN 1465-6906. 15:447. doi: 10.1186/s13059-014-0447-6. Full text in Research Archive Show summary

  The availability of large amounts of molecular data of unprecedented depth and width has instigated new paths of interdisciplinary activity in cancer research. Translation of such information to allow its optimal use in cancer therapy will require molecular biologists to embrace statistical and computational concepts and models. Progress in science has been and should be driven by our innate curiosity. This is the human quality that led Pandora to open the forbidden box, and like her, we do not know the nature or consequences of the output resulting from our actions. Throughout history, ground-breaking scientific achievements have been closely linked to advances in technology. The microscope and the telescope are examples of inventions that profoundly increased the amount of observable features that further led to paradigmatic shifts in our understanding of life and the Universe. In cell biology, the microscope revealed details of different types of tissue and their cellular composition; it revealed cells, their structures and their ability to divide, develop and die. Further, the molecular compositions of individual cell types were revealed gradually by generations of scientists. For each level of insight gained, new mathematical and statistical descriptive and analytical tools were needed (Figure 1a). The integration of knowledge of ever-increasing depth and width in order to develop useful therapies that can prevent and cure diseases such as cancer will continue to require the joint effort of scientists in biology, medicine, statistics, mathematics and computation. Here, we discuss some major challenges that lie ahead of us and why we believe that a deeper integration of biology and medicine with mathematics and statistics is required to gain the most from the diverse and extensive body of data now being generated. We also argue that to take full advantage of current technological opportunities, we must explore biomarkers using clinical studies that are optimally designed for this purpose. The need for a tight interdisciplinary collaboration has never been stronger.

• Sternemalm, Anders Johan Wilhelm; Russnes, Hege Elisabeth Giercksky; Zhao, X; Risberg, Bjørn Åke; Nord, Silje H. & Caldas, C [Show all 9 contributors for this article] (2014). Nuclear CSPP1 expression defined subtypes of basal-like breast cancer. British Journal of Cancer. ISSN 0007-0920. 111(2), p. 326–338. doi: 10.1038/bjc.2014.297. Full text in Research Archive
• Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy & Ametller, Elisabet [Show all 21 contributors for this article] (2014). Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell reports. 6(3), p. 514–527. doi: 10.1016/j.celrep.2013.12.041. Full text in Research Archive
• Zhao, Xi; Rødland, Einar Andreas; Sørlie, Therese; Vollan, Hans Kristian Moen; Russnes, Hege Elisabeth Giercksky & Kristensen, Vessela N. [Show all 8 contributors for this article] (2014). Systematic assessment of prognostic gene signatures for breast cancer shows distinct influence of time and ER status. BMC Cancer. 14(211). doi: 10.1186/1471-2407-14-211. Full text in Research Archive
• Kristensen, Vessela N.; Lingjærde, Ole Christian; Russnes, Hege Elisabeth Giercksky; Vollan, Hans Kristian Moen; Frigessi, Arnoldo & Børresen-Dale, Anne-Lise (2014). Principles and methods of integrative genomic analyses in cancer. Nature Reviews Cancer. ISSN 1474-175X. 14(5), p. 299–313. doi: 10.1038/nrc3721. Full text in Research Archive
• Trinh, Anne; Rye, Inga Hansine; Almendro, Vanessa; Helland, Åslaug; Russnes, Hege Elisabeth Giercksky & Markowetz, Florian (2014). GoIFISH: a system for the quantification of single cell heterogeneity from IFISH images. Genome Biology. ISSN 1465-6906. 15(8). doi: 10.1186/s13059-014-0442-y. Full text in Research Archive
• Synnestvedt, Marit; Borgen, Elin; Russnes, Hege Elisabeth Giercksky; Kumar, Neena Theresa; Schlichting, Ellen & Giercksky, Karl-Erik [Show all 9 contributors for this article] (2013). Combined analysis of vascular invasion, grade, HER2 and Ki67 expression identifies early breast cancer patients with questionable benefit of systemic adjuvant therapy. Acta Oncologica. ISSN 0284-186X. 52(1), p. 91–101. doi: 10.3109/0284186X.2012.713508. Full text in Research Archive
• Garcia-Recio, Susana; Fuster, Gemma; Fernandez-Nogueira, Patricia; Pastor-Arroyo, Eva M.; Park, So Yeon & Mayordomo, Cristina [Show all 15 contributors for this article] (2013). Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer. Cancer Research. ISSN 0008-5472. 73(21), p. 6424–6434. doi: 10.1158/0008-5472.CAN-12-4573. Full text in Research Archive
• Margolin, Adam A.; Bilal, Erhan; Huang, Erich; Norman, Thea C.; Ottestad, Lars & Mecham, Brigham H. [Show all 30 contributors for this article] (2013). Systematic Analysis of Challenge-Driven Improvements in Molecular Prognostic Models for Breast Cancer. Science Translational Medicine. ISSN 1946-6234. 5(181). doi: 10.1126/scitranslmed.3006112. Full text in Research Archive
• Bilal, Erhan; Vassallo, Kristen; Toppmeyer, Deborah; Barnard, Nicola; Rye, Inga Hansine & Almendro, Vanessa [Show all 11 contributors for this article] (2012). Amplified Loci on Chromosomes 8 and 17 Predict Early Relapse in ER-Positive Breast Cancers. PLOS ONE. 7(6). doi: 10.1371/journal.pone.0038575. Full text in Research Archive
• Enerly, Espen; Steinfeld, Israel; Kleivi, Kristine; Leivonen, Suvi-Katri; Aure, Miriam Ragle & Russnes, Hege Elisabeth Giercksky [Show all 17 contributors for this article] (2011). miRNA-mRNA Integrated Analysis Reveals Roles for miRNAs in Primary Breast Tumors. PLOS ONE. 6(2). doi: 10.1371/journal.pone.0016915. Full text in Research Archive
• Molloy, Timothy J.; Bosma, Astrid J.; Baumbusch, Lars Oliver; Synnestvedt, Marit; Borgen, Elin & Russnes, Hege Elisabeth Giercksky [Show all 9 contributors for this article] (2011). The prognostic significance of tumour cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients. Breast Cancer Research. ISSN 1465-5411. 13(3). doi: 10.1186/bcr2898. Full text in Research Archive

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• Skaara, Turid Rygh; Puco, Katarina; Dyvik, Ingrid; Slørdahl, Kathinka Schmidt; Falk, Ragnhild Sørum & Brabrand, Sigmund [Show all 32 contributors for this article] (2026). Alteration-matched therapy in advanced lung cancer: results from the IMPRESS-Norway study. Full text in Research Archive
• Bjørgo, Elisa; Ånensen, Nina; Fagereng, Gro Live; Russnes, Hege Elisabeth Giercksky; Smeland, Sigbjørn & Tasken, Kjetil [Show all 7 contributors for this article] (2026). Merging clinical research and standard healthcare – Nordic Precision Cancer Medicine Symposium 2025. Acta Oncologica. ISSN 0284-186X. 65, p. 185–185. doi: 10.2340/1651-226x.2026.45168. Full text in Research Archive
• Brabrand, Sigmund; Steinskog, Eli Sihn Samdal; Blix, Egil Støre; Flobak, Åsmund; Puco, Katarina & Fagereng, Gro Live [Show all 20 contributors for this article] (2025). 3137O IMPRESS-Norway: A nationwide precision-oncology study for off-label targeted therapies - Results from the first 1,740 patients. doi: 10.1016/j.annonc.2025.08.1609. Full text in Research Archive
• Fagereng, Gro Live; Russnes, Hege Elisabeth Giercksky; Tasken, Kjetil; Smeland, Sigbjørn & Helland, Åslaug (2024). Presisjonsmedisin innen kreft. [Journal]. Aftenposten (Persontilpasset Behandling – Addendum to AP). Full text in Research Archive
• Dyvik, Ingrid; Fagereng, Gro Live; Lien, Tonje; Nygaard, Vigdis; Silwal-Pandit, Laxmi & Noon, J Christopher [Show all 20 contributors for this article] (2024). Comprehensive genomic profiling of circulating tumor DNA for treatment recommendation: A sub-project of the IMPRESS-Norway trial. Full text in Research Archive
• Helland, Åslaug; Steinskog, Eli Sihn Samdal; Blix, Egil Støre; Flobak, Åsmund; Brabrand, Sigmund & Puco, Katarina [Show all 20 contributors for this article] (2024). Hever kvaliteten på behandling av kreft. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 144(1), p. 52–53. doi: 10.4045/tidsskr.23.0740. Full text in Research Archive Show summary

  Alle norske sykehus med kreftavdeling deltar i en nasjonal kreftbehandlingsstudie. Den er aktuell for pasienter med avansert kreftsykdom etter standard behandling.

• Bjørgo, elisa; Fagereng, Gro Live; Russnes, Hege Elisabeth Giercksky; Smeland, Sigbjørn; Tasken, Kjetil & Helland, Åslaug (2024). Acta Oncologica Nordic Precision Cancer Medicine Symposium 2023 – merging clinical research and standard healthcare. Acta Oncologica. ISSN 0284-186X. 63, p. 487–490. doi: 10.2340/1651-226X.2024.24954. Full text in Research Archive
• Torkildsen, Cecilie Fredvik; Lindemann, Kristina Yvonne Kathe; Bischof, Katharina; Aune, Guro; Vistad, Ingvild & Ingebrigtsen, Vibeke Anett [Show all 20 contributors for this article] (2024). 456 Molecular characteristics of gynaecological cancer patients in the IMPRESS-Norway trial – a national prospective, non-randomized clinical trial evaluating the efficacy of anti-cancer drugs on new indications. International Journal of Gynecological Cancer. ISSN 1048-891X. 34, p. A563–A564. doi: 10.1136/ijgc-2024-ESGO.1105. Full text in Research Archive
• Niehusmann, Pitt; Leske, Henning; Nygaard, Vigdis; Russnes, Hege Elisabeth Giercksky; Zhao, Sen & Latysheva, Anna [Show all 9 contributors for this article] (2024). Desmoplastic non-infantile ganglioglioma mimicking diffuse leptomeningeal glioneuronal tumor: precision diagnostics and therapeutic implications. Acta Oncologica. ISSN 0284-186X. 63(1), p. 392–394. doi: 10.2340/1651-226X.2024.31720. Full text in Research Archive
• Gjelberg, Hilde K.; Helgeland, Lars; Liseth, Knut; Micci, Francesca; Sandnes, Miriam & Russnes, Hege Elisabeth Giercksky [Show all 7 contributors for this article] (2023). Long-Smoldering T-prolymphocytic Leukemia: A Case Report and a Review of the Literature. Current Oncology. ISSN 1198-0052. 30(11), p. 10007–10018. doi: 10.3390/curroncol30110727. Full text in Research Archive Show summary

  T-prolymphocytic leukemia (T-PLL) is a rare malignancy of mature T-cells with distinct clinical, cytomorphological, and molecular genetic features. The disease typically presents at an advanced stage, with marked leukocytosis, B symptoms, hepatosplenomegaly, and bone marrow failure. It usually follows an aggressive course from presentation, and the prognosis is often considered dismal; the median overall survival is less than one year with conventional chemotherapy. This case report describes a patient with T-PLL who, after an unusually protracted inactive phase, ultimately progressed to a highly invasive, organ-involving disease. After initial treatments failed, a novel treatment approach resulted in a significant response.

• Bjørgo, Elisa; Fagereng, Gro Live; Russnes, Hege Elisabeth Giercksky; Smeland, Sigbjørn; Tasken, Kjetil & Helland, Åslaug (2023). ACTA Oncologica Nordic Precision Cancer Medicine Symposium 2023 – Merging Clinical Research and Standard Healthcare. Acta Oncologica. ISSN 0284-186X. Full text in Research Archive
• Heia, Ingvild; Tasken, Kjetil; Helland, Åslaug; Russnes, Hege Elisabeth Giercksky & Smeland, Sigbjørn (2023). Innføring av presisjonsmedisin innen kreft i Norge. [Journal]. Aftenposten (Innstikk «Persontilpasset behandling). Full text in Research Archive
• Eriksen, Kjersti Flugstad & Russnes, Hege Elisabeth Giercksky (2023). Patolog Hege Russnes ser tre hovedtrekk i forskning som gjør det viktig å være på kreftkonferanser. [Journal]. Dagens Medisin. Full text in Research Archive
• Tasken, Kjetil; Russnes, Hege Elisabeth Giercksky; Aas, Eline; Bjørge, Line; Blix, Egil Støre & Ahlquist, Terje C. [Show all 116 contributors for this article] (2022). A national precision cancer medicine implementation initiative for Norway. Nature Medicine. ISSN 1078-8956. 28(5), p. 885–887. doi: 10.1038/s41591-022-01777-4. Full text in Research Archive
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Show all 53 contributors for this article] (2022). Correction to: Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway (Journal of Translational Medicine, (2022), 20, 1, (225), 10.1186/s12967-022-03432-5). Journal of Translational Medicine. 20(1). doi: 10.1186/s12967-022-03518-0. Full text in Research Archive
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Show all 53 contributors for this article] (2022). Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway. Journal of Translational Medicine. 20(1), p. 1–11. doi: 10.1186/s12967-022-03432-5. Full text in Research Archive Show summary

  Background Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. Methods In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient’s tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system.

• Tasken, Kjetil; Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Smeland, Sigbjørn; Frich, Jan C. & Thoresen, Steinar [Show all 13 contributors for this article] (2022). Arendalsuka 2022: Nøkkelen til bedre kreftbehandling er samarbeid. [Internet]. Arendalsuka, Paneldebatt. Full text in Research Archive
• Russnes, Hege Elisabeth Giercksky (2020). Clinical trials in the era of precision cancer medicine–for the few or for the many? Acta Oncologica. ISSN 0284-186X. 59(7), p. 731–732. doi: 10.1080/0284186X.2020.1777582. Full text in Research Archive
• Cheng, Jiqiu; Demeulemeester, Jonas; Wedge, David C.; Vollan, Hans Kristian Moen; Pitt, Jason J. & Russnes, Hege Elisabeth Giercksky [Show all 18 contributors for this article] (2019). Correction to: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors (Nature Communications, (2017), 8, 1, (1221), 10.1038/s41467-017-01355-0). Nature Communications. 10(1). doi: 10.1038/s41467-019-08512-7. Full text in Research Archive
• Cheng, Jiqiu; Demeulemeester, Jonas; Wedge, David C.; Vollan, Hans Kristian Moen; Pitt, Jason J. & Russnes, Hege Elisabeth Giercksky [Show all 18 contributors for this article] (2018). Author Correction: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors. Nature Communications. 9(1). doi: 10.1038/s41467-018-07842-2. Full text in Research Archive

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