Jürgen Geisler

• Torland, Anne Vold; Geisler, Jürgen; Azimzade, Youness; Frafjord, Astri; Nilsen, Hogne Røed & Buer, Linn [Vis alle 15 forfattere av denne artikkelen] (2026). Multi-platform analysis of the tumor immune microenvironment associated with breast cancer subtypes. Oncoimmunology. ISSN 2162-4011. 15(1). doi: 10.1080/2162402X.2025.2610535. Fulltekst i vitenarkiv Vis sammendrag

  Breast cancer is genetically and histologically heterogenous, and is influenced by a variety of factors, including the tumor microenvironment (TME). The PAM50 subtypes; Luminal A, Luminal B, Normal-like, Basal-like and Her2-enriched, are associated with different tumor phenotypes and overall survival. The quantity and quality of immune cell infiltration in breast tumors play a key role in cancer development and progression and are associated with survival and treatment response. We used multiplex immunohistochemistry, single-cell RNA sequencing, and two deconvolution algorithms to explore the immune landscape across PAM50 subtypes. Immunostaining of CD3+ T cells, tryptase+ mast cells, CD20+ B cells, CD68+ CD163+ macrophages, and CD66b+ granulocytes revealed marked differences in tumor immune infiltrates according to breast cancer subtypes. Luminal tumors were relatively deprived of T cells and B cells, while exhibiting sparse to moderate amounts of macrophage infiltration. In contrast, Her2-enriched tumors exhibited a moderate immune presence, with sparse to moderate T cell infiltration and moderate infiltration of B cells and macrophages. At the other end of the spectrum, Basal-like tumors stood out for their strikingly rich immune environment and are heavily infiltrated by T cells, B cells, and macrophages. The results from the single-cell and deconvolution analyses confirmed subtype-specific immune microenvironments, which also allowed us to observe increased levels of natural killer (NK) and CD8+ T cells in Her2-enriched and Basal-like subtypes. In conclusion, our findings demonstrate significant differences in the immune tumor microenvironmentbetween the established breast cancer molecular subtypes.

• Valachis, Antonis; Geisler, Jürgen; Karihtala, Peeter & Tuxen, Malgorzata K. (2026). Insights on postneoadjuvant treatment among patients with triple-negative breast cancer and residual disease after neoadjuvant therapy: can expert consensus help to interpret the current evidence? British Journal of Cancer. ISSN 0007-0920. doi: 10.1038/s41416-026-03452-8. Fulltekst i vitenarkiv
• Verrill, Mark; Lux, Michael Patrick; Gligorov, Joseph; Geisler, Jürgen; Duchnowska, Renata & Elsberger, Beatrix [Vis alle 7 forfattere av denne artikkelen] (2025). Genomic tests to guide management of breast cancer in Europe: regulation, reimbursement, adoption, and challenges. Future Oncology. ISSN 1479-6694. 21(27), s. 3573–3583. doi: 10.1080/14796694.2025.2577335. Fulltekst i vitenarkiv Vis sammendrag

  The integration of genomic tests such as the Oncotype DX Breast Recurrence Score® test, into routine clinical practice represents a significant advance in personalized breast cancer care. By supporting more tailored therapeutic decisions, these diagnostics can improve patient outcomes, while reducing risks of undertreatment, overtreatment, and associated side effects. Cost-effectiveness has already been demonstrated in numerous publications. However, for widespread adoption across Europe, four principal challenges must be overcome: regulation, technology assessment, reimbursement, and gaps in real-world evidence. Since May 2022, the European Union In Vitro Diagnostics Regulation (IVDR) has updated requirements for demonstrating clinical utility and analytical and scientific validity, creating new barriers for manufacturers regarding primary evidence generation. Variability in health technology assessment (HTA) frameworks and reimbursement mechanisms across countries further complicates adoption. Demonstrating real-world benefits of these technologies requires robust, representative data collections, yet current clinical trial evidence often underrepresents certain patient populations, raising equity concerns. Whilst the IVDR will help standardize regulatory requirements, challenges remain in harmonizing evidence standards for HTA and reimbursement. This review explores these barriers using the Oncotype DX® test as an exemplar. Evidence was drawn from targeted literature searches and reviews of regulatory, reimbursement, and gray literature relevant to European healthcare systems.

• Billaud, Amandine; Figlioli, Gisella; Mooser, Clémence; Casamassima, Irene; Azzoni, Violette & Srivatsa, Jahnavi [Vis alle 50 forfattere av denne artikkelen] (2025). Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer. Breast. ISSN 0960-9776. 85, s. 1–13. doi: 10.1016/j.breast.2025.104619. Fulltekst i vitenarkiv Vis sammendrag

  The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.

• Brems-Eskildsen, Anne Sofie; Kenholm, Julia; Brixen, Annette Torbøl; Rønlev, Jeanette Dupont; Stenbygaard, Lars & Danø, Hella [Vis alle 11 forfattere av denne artikkelen] (2025). A direct comparison of classical oral Navelbine vs metronomic Navelbine in metastatic breast cancer: results from the Danish Breast Cancer Group’s (DBCG) NAME-trial. Breast Cancer Research and Treatment. ISSN 0167-6806. 213(2), s. 237–246. doi: 10.1007/s10549-025-07777-5. Fulltekst i vitenarkiv
• Narimani, Sam; Hoff, Solveig Kristin Roth; Kurz, Kathinka Dæhli; Gjesdal, Kjell Inge; Geisler, Jürgen & Grøvik, Endre (2025). Sustainable deep learning-based breast lesion segmentation: impact of breast region segmentation on performance. BMC Medical Imaging. 25, s. 1–15. doi: 10.1186/s12880-025-01947-z. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Segmentation of breast lesions in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is critical for effective diagnosis. This study investigates the impact of breast region segmentation (BRS) on the performance of deep learning-based breast lesion segmentation (BLS) in breast DCE-MRI. Methods The study utilized the Stavanger Dataset, comprising 59 DCE-MRI scans, and employed the UNet++ architecture as the segmentation model. Four experimental approaches were designed to assess the influence of BRS on BLS: (1) Whole Volume (WV) without BRS, (2) WV with BRS, (3) BRS applied only to Selected Lesion-containing Slices (SLS), and (4) BRS applied to an Optimal Volume (OV). Data augmentation and oversampling techniques were implemented to address dataset limitations and enhance model generalizability. A systematic method was employed to determine OV sizes for patient’s DCE-MRI images ensuring full lesion inclusion. Model training and validation were conducted using a hybrid loss function—comprising Dice loss, focal loss, and cross-entropy loss—and a five-fold cross-validation strategy. Final evaluations were performed on a randomly split test dataset for each of the four approaches. Results The findings indicate that applying BRS significantly enhances model performance. The most notable improvement was observed in the fourth approach, BRS with OV, which achieved approximately a 50% increase in segmentation accuracy compared to the non-BRS baseline. Furthermore, the BRS with OV approach resulted in a substantial reduction in computational energy consumption—up to 450%, highlighting its potential as an environmentally sustainable solution for large-scale applications.

• Engebrethsen, Christina; Yndestad, Synnøve; Rasmussen, Mari Eskild; Janssen, Emiel; Gilje, Bjørnar & Blix, Egil Støre [Vis alle 16 forfattere av denne artikkelen] (2025). Neoadjuvant endocrine therapy with sequential palbociclib and chemotherapy based on Ki67 status in stage II-III breast cancer: An open-label, phase II study. Breast. ISSN 0960-9776. 85. doi: 10.1016/j.breast.2025.104672. Fulltekst i vitenarkiv
• Fjørtoft, Marit Otterlei; Garred, Øystein; Lingjærde, Ole Christian; Johannesen, Karin Teien; Ottestad, Lars & Bergheim, Inger Riise [Vis alle 29 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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

• Omland, Torbjørn; Heck, Siri Lagethon; Holte, Espen; Mecinaj, Albulena; Gynnild, Mari Nordbø & Fagerland, Morten [Vis alle 13 forfattere av denne artikkelen] (2025). Sacubitril/Valsartan and Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: The PRADA II Randomized Clinical Trial. Circulation. ISSN 0009-7322. 152(16), s. 1136–1145. doi: 10.1161/circulationaha.125.076616. Fulltekst i vitenarkiv Vis sammendrag

  Background: Anthracycline- and trastuzumab-associated cardiotoxicity may lead to cardiac dysfunction and dose reduction or halt in potentially life-saving adjuvant cancer therapy. Whether angiotensin receptor neprilysin inhibitors can prevent cancer therapy-related cardiac dysfunction and injury remains to be established. Methods: PRADA II was a randomized, parallel-group, placebo-controlled, double-blind multicenter trial conducted at 4 academic medical centers in Norway that evaluated the cardioprotective effect of sacubitril-valsartan vs. placebo administered concomitantly with anthracycline-containing breast cancer therapy and continued for 18 months. The target dose was 97/103 mg b.i.d. The primary outcome was change in left ventricular ejection fraction by cardiovascular magnetic resonance from prior to initiation of chemotherapy to 18 months after. Secondary outcomes included change in echocardiographic global longitudinal strain, circulating cardiac troponins, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Results: In total, 138 women (mean (±SD) age: 54.0 ± 9.4 years) were randomized. The overall decline in left ventricular ejection fraction from baseline to 18 months was 2.2 percentage points (95% confidence interval [CI], 1.1 to 3.3) in the placebo group and 1.1 percentage points (95% CI, -0.01 to 2.2) in the sacubitril-valsartan group. The between-group difference was 1.1 percentage points (95% CI, -0.4 to 2.7; P=0.16). Left ventricular global longitudinal strain was normal and remained stable in the sacubitril-valsartan group throughout the study (change from baseline to 18 months -0.32 [95% CI, -0.80 to 0.15]). In contrast, there was a progressive decline in the placebo group (change from baseline to 18 months 0.53 [95% CI, 0.05 to 1.00]). The between-group difference was -0.85 (95% CI, -1.52 to -0.18). The mean increases in NT-proBNP and cardiac troponin I concentrations from baseline to 18 months were greater in the placebo than in the sacubitril-valsartan group (log difference 0.303 (95% CI 0.0547 to 0.552) for NT-proBNP and 0.534 (95% CI 0.114 to 0.954) for cardiac troponin I). Conclusions: Anthracycline-based treatment for early breast cancer is associated with a reduction in left ventricular ejection fraction that was not significantly attenuated by sacubitril-valsartan.

• Valachis, Antonios; Karihtala, Peeter; Geisler, Jürgen & Tuxen, Malgorzata K. (2025). Metastatic triple-negative breast cancer – current treatment strategies in the Nordics: a modified Delphi study. Acta Oncologica. ISSN 0284-186X. 64, s. 349–357. doi: 10.2340/1651-226X.2025.42733. Fulltekst i vitenarkiv Vis sammendrag

  Background and purpose: This study aimed to assess current treatment strategies for metastatic triple-negative breast cancer (mTNBC) and the perceptions of clinical experts in Sweden, Denmark, Norway, Finland, and Iceland, comparing them to international guidelines to provide insights into how these therapies are implemented and adapted to national Nordic guidelines. Methods: A three-round modified Delphi method was followed with consensus defined as 70% agreement. A steering committee selected 20 experienced oncologists as panellists and developed the questionnaires. Questions included items related to treatment preferences in different treatment lines with different clinical scenarios in mTNBC patients. Results: In the first round, eight out of 33 questions on clinical treatment reached consensus with 14 out of 27 in the second round reaching consensus. In round three, eight out of eight questions reached consensus. The preferred treatment for mTNBC patients with PD-L1 positive was checkpoint inhibitors (CPI) in combination with chemotherapy. For patients with germline BRCA mutation and PD-L1 negative disease, PARP-inhibitors were preferred as 1L and sacituzumab govitecan (SG) in both 2L and later lines. Disagreement was observed for chemotherapy in later lines where evidence is sparse or lacking. Interpretation: The high level of consensus for new treatment strategies, such as CPI and PARP-inhibitors in 1L and SG in 2L or later lines, in comparison with the limited consensus for older treatments, such as chemotherapy, may reflect the growing academic evidence for different treatment strategies. Understanding the treatment patterns across different countries contributes to gaining consensus on the upcoming therapeutic advances.

• Zanti, Maria; O'Mahony, Denise; Parsons, Michael T.; Dorling, Leila; Dennis, Joe & Boddicker, Nicholas J. [Vis alle 50 forfattere av denne artikkelen] (2025). Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification. Nature Communications. 16(1). doi: 10.1038/s41467-025-59979-6. Fulltekst i vitenarkiv Vis sammendrag

  Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.

• Iversen, Gjertrud Titlestad; Loeng, Marie; Holth, Amalie Lund; Lønning, Per Eystein; Geisler, Jürgen & Knappskog, Stian (2025). Germline variants in CDKN2A wild-type melanoma prone families. Molecular Oncology. ISSN 1574-7891. 19(5), s. 1493–1507. doi: 10.1002/1878-0261.70020. Fulltekst i vitenarkiv Vis sammendrag

  Germline pathogenic variants in CDKN2A are well established as an underlying cause of familial malignant melanoma. While pathogenic variants in other genes have also been linked to melanoma, most familial cases remain unexplained. We assessed pathogenic germline variants in 360 cancer-related genes in 56 Norwegian melanoma-prone families. The index cases were selected based on familial history of melanoma and/or multiple primary melanomas, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants in BRCA2, MRE11, ATM, MSH2, CHEK2, and AR. One family member with melanoma (not index case) carried a pathogenic variant in MAP3K6. In addition, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance in xeroderma pigmentosum-related genes. In particular, XPCL48F was found in 8 indexes; thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (0.02–0.03; P-values from 0.007 to 0.014). In conclusion, we found that several melanoma-prone families have pathogenic variants in genes not usually linked to melanoma.

• Hoppe, Reiner; Winter, Stefan; Lo, Wing-Yee; Michailidou, Kyriaki; Bolla, Manjeet K. & Keeman, Renske [Vis alle 50 forfattere av denne artikkelen] (2025). Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer. NPJ breast cancer. 11(1), s. 1–15. doi: 10.1038/s41523-025-00733-y. Fulltekst i vitenarkiv Vis sammendrag

  The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.

• Hatletvedt, Nora Dortea; Engebrethsen, Christina; Geisler, Jürgen; Geisler, Stephanie; Aas, Turid & Lønning, Per Eystein [Vis alle 8 forfattere av denne artikkelen] (2025). The impact of functional MDM2-polymorphisms on neutrophil counts in breast cancer patients during neoadjuvant chemotherapy. BMC Cancer. 25(1). doi: 10.1186/s12885-025-13675-2. Fulltekst i vitenarkiv Vis sammendrag

  Background: Functional polymorphisms in the MDM2 promoters have been linked to cancer risk and several non-malignant conditions. Their potential role in bone marrow function during chemotherapy is largely unknown. Methods: We investigated the potential associations between genotypes of MDM2 SNP309 (rs2279744), SNP285 (rs117039649) and del1518 (rs3730485) and neutrophil counts in breast cancer patients receiving neoadjuvant sequential epirubicin and docetaxel, with additional G-CSF, in the DDP-trial (NCT00496795). We applied longitudinal ratios, post vs. pre-treatment, of neutrophil counts as our main measure. Differences by genotypes were tested by Jonckheere-Terpstra test for ranked alternatives, while dominant and recessive models were tested by Mann–Whitney U test, and additional sub-analyses were performed for genotype combinations. Results: The SNP309 reference T-allele was associated with a better sustained neutrophil count (p = 0.035). A similar association was observed for the alternative del-allele of the del1518 (p = 0.049). Additionally, in combined genotype-analyses, patients with the SNP309 TT genotype and at least one copy of the del1518 del-allele had particularly favorable sustained neutrophil counts during chemotherapy treatment (p = 0.005). Conclusions: Our study provides evidence that MDM2 promoter polymorphisms may be associated with neutrophil counts and bone marrow recovery during chemotherapy treatment in breast cancer patients.

• Narimani, Sam; Hoff, Solveig Kristin Roth; Kurz, Kathinka Dæhli; Gjesdal, Kjell Inge; Geisler, Jürgen & Grøvik, Endre (2025). Comparative analysis of deep learning architectures for breast region segmentation with a novel breast boundary proposal. Scientific Reports. 15, s. 1–11. doi: 10.1038/s41598-025-92863-3. Fulltekst i vitenarkiv Vis sammendrag

  Segmentation of the breast region in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is essential for the automatic measurement of breast density and the quantitative analysis of imaging findings. This study aims to compare various deep learning methods to enhance whole breast segmentation and reduce computational costs as well as environmental effect for future research. We collected fifty-nine DCE-MRI scans from Stavanger University Hospital and, after preprocessing, analyzed fifty-eight scans. The preprocessing steps involved standardizing imaging protocols and resampling slices to ensure consistent volume across all patients. Using our novel approach, we defined new breast boundaries and generated corresponding segmentation masks. We evaluated seven deep learning models for segmentation namely UNet, UNet++, DenseNet, FCNResNet50, FCNResNet101, DeepLabv3ResNet50, and DeepLabv3ResNet101. To ensure robust model validation, we employed 10-fold cross-validation, dividing the dataset into ten subsets, training on nine, and validating on the remaining one, rotating this process to use all subsets for validation. The models demonstrated significant potential across multiple metrics. UNet++ achieved the highest performance in Dice score, while UNet excelled in validation and generalizability. FCNResNet50, notable for its lower carbon footprint and reasonable inference time, emerged as a robust model following UNet++. In boundary detection, both UNet and UNet++ outperformed other models, with DeepLabv3ResNet also delivering competitive results.

• Schandiz, Hossein Khalkhali; Farkas, Lorant; Park, Daehoon; Liu, Yan; Andersen, Solveig Norheim & Sauer, Torill [Vis alle 7 forfattere av denne artikkelen] (2025). High Ki67 expression, HER2 overexpression, and low progesterone receptor levels in high-grade DCIS: significant associations with clinical practice implications. Frontiers in Oncology. 15. doi: 10.3389/fonc.2025.1467664. Fulltekst i vitenarkiv Vis sammendrag

  Simple summary: We investigated the role of Ki67, a ubiquitous marker in cancer, within the context of ductal carcinoma in situ (DCIS), a precursor of invasive breast cancer. Through rigorous analysis of histopathological and immunopathological samples from a substantial cohort, this study revealed robust correlations between heightened Ki67 expression, diminished progesterone (PR) levels, and HER2 overexpression, indicative of aggressive DCIS phenotypes. These findings offer novel insights into the surrogate immunomolecular subtyping landscape of DCIS, potentially refining risk stratification and therapeutic approaches. This elucidation underscores the translational significance of Ki67 as a prognostic and predictive biomarker in DCIS, with implications for personalized treatment paradigms and patient outcomes. Background: The Ki67 proliferation index is widely used in various tumors, including invasive breast carcinoma (IBC). However, its prognostic utility is often constrained by technical complexity. Its diagnostic and clinical significance in ductal carcinoma in situ (DCIS) remains uncertain. We studied Ki67 immunohistochemistry interobserver diagnostic agreement at different cutoff values in high-grade DCIS. Additionally, we investigated the associations between Ki67 expression, PR levels, and human epidermal growth factor receptor 2 (HER2) in high-grade DCIS among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched, and triple-negative)). Methods: Using histopathological specimens from 484 patients diagnosed with DCIS between 1996 and 2018, we implemented the 2013 St. Gallen recommendations for surrogate immunomolecular subtyping of IBC. Subtypes were classified, and the Ki67 interobserver diagnostic agreement between Counting Pathologist 1 (CP1) and CP2 was calculated using Cohen’s kappa coefficient at various cutoff values. Results: The Cohen’s kappa coefficient for interobserver agreement between CP1 and CP2 was κ = 0.586, indicating moderate agreement. Ki67 levels varied significantly among subtypes (p < 0.0001), with a median Ki67% being higher in cases with invasive components (p = 0.0351). Low PR combined with high Ki67% was significantly associated with HER2 overexpression (p = 0.0107). Conclusions: Interobserver agreement for the Ki67 count was moderate. Ki67 expression showed considerable variability in high-grade DCIS. Low PR levels combined with high Ki67 expression were linked to HER2 overexpression, showing possible clinical implications for identifying high-risk DCIS.

• Kastora, Stavroula L.; Pantiora, Eirini; Hong, Yong Hwa; Veeramani, Meenakshi; Azim, Hatem A & Chakrabarti, Rima [Vis alle 17 forfattere av denne artikkelen] (2025). Safety of topical estrogen therapy during adjuvant endocrine treatment among patients with breast cancer: A meta-analysis based expert panel discussion. Cancer Treatment Reviews. ISSN 0305-7372. 133. doi: 10.1016/j.ctrv.2025.102880. Fulltekst i vitenarkiv Vis sammendrag

  Importance Endocrine treatments, such as Tamoxifen (TAM) and/or Aromatase inhibitors (AI), are the adjuvant therapy of choice for hormone-receptor positive breast cancer. These agents are associated with menopausal symptoms, adversely affecting drug compliance. Topical estrogen (TE) has been proposed for symptom management, given its’ local application and presumed reduced bioavailability, however its oncological safety remains uncertain. Objective The present systematic review, meta-analysis and expert panel review aimed to evaluate the strength of the available evidence on the risk of recurrence and mortality when TE is utilised in congruence with TAM or AI treatment, among BC survivors. Data Sources Six databases and two prospective registers, were interrogated from inception to January 3rd, 2024. Search terms were Breast cancer AND Hormone replacement therapy AND topical/vaginal oestrogen AND recurrence/mortality. Study selection All study designs reporting the use vs. non-use of TE in breast cancer survivors receiving adjuvant endocrine treatment were included. Six observational studies were deemed eligible for inclusion. Data extraction and synthesis Sources of heterogeneity were explored using subgroup analysis by risk of bias, median follow-up period, node positivity and menopausal status. Trial sequential analysis was performed to quantify outcome reliability. A global expert panel was called to deliberate on the data, pinpoint areas of limited understanding, and determine the most important areas for future research. Main outcomes and measures Risk ratio effect sizes (RR) and corresponding 95 % Confidence Intervals (CI) of breast cancer recurrence and mortality in survivors on endocrine treatment (TAM and/or AI) exposed to TE were reported. Expert panel appraisal of meta-analysis evidence with definition of current knowledge gaps and future research aims. Results In 38 050 female patients receiving adjuvant endocrine treatment, of whom 1805 had been exposed to TE, TE exposure of those on AI, did not increase all-cause mortality (RR 0.99 [95 %CI 0.58, 1.69], I2 = 81 %, P = 0.96; moderate GRADE certainty). However, such exposure may convey an increased risk of recurrence (RR 2.51 [95 % CI 1.10, 5.72], I2 = 9 %, P = 0.03; low-GRADE certainty). Exposure to TE during TAM did not increase either recurrence risk or all-cause mortality. Clinical factors such as lymph node positivity at the time of diagnosis and menopausal status and follow-up time appeared to be significant confounders. Conclusions and relevance The use of TE does not appear to increase either recurrence or mortality risk among BC survivors treated with TAM. An increased recurrence risk, without an increase in mortality, cannot be ruled out when TE is used during AI.

• Schmiester, Leonard; Brasó-Maristany, Fara; González-Farré, Blanca; Pascual, Tomás; Gavilá, Joaquín & Tekpli, Xavier [Vis alle 11 forfattere av denne artikkelen] (2024). Computational Model Predicts Patient Outcomes in Luminal B Breast Cancer Treated with Endocrine Therapy and CDK4/6 Inhibition. Clinical Cancer Research. ISSN 1078-0432. 30(17), s. 3779–3787. doi: 10.1158/1078-0432.CCR-24-0244. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients with breast cancer. Experimental Design: A mechanistic mathematical model that accounts for protein signaling and drug mechanisms of action was developed and trained on extensive, publicly available data from breast cancer cell lines. The model was built to provide a patient-specific response score based on the expression of six genes (CCND1, CCNE1, ESR1, RB1, MYC, and CDKN1A). The model was validated in five independent cohorts of 148 patients in total with early-stage or advanced breast cancer treated with endocrine therapy and CDK4/6i. Response was measured either by evaluating Ki67 levels and PAM50 risk of relapse (ROR) after neoadjuvant treatment or by evaluating progression-free survival (PFS). Results: The model showed significant association with patient’s outcomes in all five cohorts. The model predicted high Ki67 [area under the curve; AUC (95% confidence interval, CI) of 0.80 (0.64–0.92), 0.81 (0.60–1.00) and 0.80 (0.65–0.93)] and high PAM50 ROR [AUC of 0.78 (0.64–0.89)]. This observation was not obtained in patients treated with chemotherapy. In the other cohorts, patient stratification based on the model prediction was significantly associated with PFS [hazard ratio (HR) = 2.92 (95% CI, 1.08–7.86), P = 0.034 and HR = 2.16 (1.02 4.55), P = 0.043]. Conclusions: A mathematical modeling approach accurately predicts patient outcome following CDK4/6i plus endocrine therapy that marks a step toward more personalized treatments in patients with Luminal B breast cancer.

• Karihtala, Peeter; Schiza, Aglaia; Fountzilas, Elena; Geisler, Jürgen; Meattini, Icro & Risi, Emanuela [Vis alle 8 forfattere av denne artikkelen] (2024). Clinical trials in older patients with cancer - typical challenges, possible solutions, and a paradigm of study design in breast cancer. Acta Oncologica. ISSN 0284-186X. 63, s. 441–447. doi: 10.2340/1651-226X.2023.40365. Fulltekst i vitenarkiv Vis sammendrag

  Background and purpose: While the prevalence of older breast cancer patients is rapidly increasing, these patients are greatly underrepresented in clinical trials. We discuss barriers to recruitment of older patients to clinical trials and propose solutions on how to mitigate these challenges and design optimal clinical trials through the paradigm of IMPORTANT trial. Patients and methods: This is a narrative review of the current literature evaluating barriers to including older breast cancer patients in clinical trials and how mitigating strategies can be implemented in a pragmatic clinical trial. Results: The recognized barriers can be roughly divided into trial design-related (e.g. the adoption of strict inclusion criteria, the lack of pre-specified age-specific analysis), patient-related (e.g. lack of knowledge, valuation of the quality-of-life instead of survival, transportation issues), or physician-related (e.g. concern for toxicity). Several strategies to mitigate barriers have been identified and should be considered when designing a clinical trial dedicated to older patients with cancer. The pragmatic, de-centralized IMPORTANT trial focusing on dose optimization of CDK4/6 -inhibitors in older breast cancer patients is a paradigm of a study design where different mitigating strategies have been adopted. Interpretation: Because of the existing barriers, older adults in clinical trials are considerably healthier than the average older patients treated in clinical practice. Thus, the study results cannot be generalized to the older population seen in daily clinical practice. Broader inclusion/exclusion criteria, offering telehealth visits, and inclusion of patient-reported, instead of physician-reported outcomes may increase older patient participation in clinical trials.

• Yildiz, Tugba Akman; Arendt, Lisa M.; Geisler, Jürgen; Kristensen, Vessela N.; Frigessi, Arnoldo & Luque, Alvaro Kohn (2024). Modeling of Mouse Experiments Suggests that Optimal Anti-Hormonal Treatment for Breast Cancer is Diet-Dependent. Bulletin of Mathematical Biology. ISSN 0092-8240. 86:42(4), s. 1–33. doi: 10.1007/s11538-023-01253-1. Fulltekst i vitenarkiv Vis sammendrag

  Estrogen receptor positive breast cancer is frequently treated with anti-hormonal treatment such as aromatase inhibitors (AI). Interestingly, a high body mass index has been shown to have a negative impact on AI efficacy, most likely due to disturbances in steroid metabolism and adipokine production. Here, we propose a mathematical model based on a system of ordinary differential equations to investigate the effect of high-fat diet on tumor growth. We inform the model with data from mouse experiments, where the animals are fed with high-fat or control (normal) diet. By incorporating AI treatment with drug resistance into the model and by solving optimal control problems we found differential responses for control and high-fat diet. To the best of our knowledge, this is the first attempt to model optimal anti-hormonal treatment for breast cancer in the presence of drug resistance. Our results underline the importance of considering high-fat diet and obesity as factors influencing clinical outcomes during anti-hormonal therapies in breast cancer patients.

• Bertelsen, Bjørn-Erik; Almås, Bjørg; Fjermeros, Kamilla; Viste, kristin; Geisler, Stephanie & Sauer, Torill [Vis alle 8 forfattere av denne artikkelen] (2024). Superior suppression of serum estrogens during neoadjuvant breast cancer treatment with letrozole compared to exemestane. Breast Cancer Research and Treatment. ISSN 0167-6806. 206(2), s. 347–358. doi: 10.1007/s10549-024-07313-x. Fulltekst i vitenarkiv Vis sammendrag

  Purpose The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast cancer in all phases of the disease. Although both drugs inhibit CYP19 (aromatase) and have been used for decades, a direct head-to-head, intra-patient-cross-over comparison of their ability to decrease estrogen synthesis in vivo is still lacking. Methods Postmenopausal breast cancer patients suitable for neoadjuvant endocrine therapy were randomized to receive either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for an initial treatment period, followed by a second treatment period on the alternative drug (intra-patient cross-over study design). Serum levels of estrone (E1), estradiol (E2), letrozole, exemestane, and 17-hydroxyexemestane were quantified simultaneously using a novel, ultrasensitive LC–MS/MS method established in our laboratory. Results Complete sets of serum samples (baseline and during treatment with letrozole or exemestane) were available from 79 patients, including 40 patients starting with letrozole (cohort 1) and 39 with exemestane (cohort 2). Mean serum estrone and estradiol levels in cohort 1 were 174 pmol/L and 46.4 pmol/L at baseline, respectively. Treatment with letrozole suppressed serum E1 and E2 to a mean value of 0.2 pmol/L and 0.4 pmol/L (P < 0.001). After the cross-over to exemestane, mean serum levels of E1 and E2 increased to 1.4 pmol/L and 0.7 pmol/L, respectively. In cohort 2, baseline mean serum levels of E1 and E2 were 159 and 32.5 pmol/L, respectively. Treatment with exemestane decreased these values to 1.8 pmol/L for E1 and 0.6 pmol/L for E2 (P < 0.001). Following cross-over to letrozole, mean serum levels of E1 and E2 were significantly further reduced to 0.1 pmol/L and 0.4 pmol/L, respectively. Serum drug levels were monitored in all patients throughout the entire treatment and confirmed adherence to the protocol and drug concentrations within the therapeutic range for all patients. Additionally, Ki-67 values decreased significantly during treatment with both aromatase inhibitors, showing a trend toward a stronger suppression in obese women. Conclusion To the best of our knowledge, we present here for the first time a comprehensive and direct head-to-head, intra-patient-cross-over comparison of the aromatase inhibitor letrozole and the aromatase inactivator exemestane concerning their ability to suppress serum estrogen levels in vivo. All in all, our results clearly demonstrate that letrozole therapy results in a more profound suppression of serum E1 and E2 levels compared to exemestane.

• Davidson, Aimee L.; Michailidou, Kyriaki; Parsons, Michael T.; Fortuno, Cristina; Bolla, Manjeet K. & Wang, Qin [Vis alle 50 forfattere av denne artikkelen] (2024). Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset. American Journal of Human Genetics. ISSN 0002-9297. 111(9), s. 2059–2069. doi: 10.1016/j.ajhg.2024.07.004. Fulltekst i vitenarkiv Vis sammendrag

  Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.

• Sharma, Abhibhav; Debik, Julia; Naume, Bjørn; Ohnstad, Hege Oma; Sahlberg, Guro Kristine Kleivi & Borgen, Elin [Vis alle 25 forfattere av denne artikkelen] (2024). Comprehensive multi-omics analysis of breast cancer reveals distinct long-term prognostic subtypes. Oncogenesis. 13(1), s. 1–13. doi: 10.1038/s41389-024-00521-6. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 35 forfattere av denne artikkelen] (2024). Deep learning for automated scoring of immunohistochemically stained tumour tissue sections – Validation across tumour types based on patient outcomes. Heliyon. 10(13), s. 1–19. doi: 10.1016/j.heliyon.2024.e32529. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Ohnstad, Hege Oma; Blix, Egil Støre; Akslen, Lars Andreas; Gilje, Bjørnar; Raj, Sunil Xavier & Skjerven, Helle [Vis alle 45 forfattere av denne artikkelen] (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), s. 1–12. doi: 10.1016/j.esmoop.2024.103475. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Yiangou, Kristia; Mavaddat, Nasim; Dennis, Joe; Zanti, Maria; Wang, Qin & Bolla, Manjeet K. [Vis alle 50 forfattere av denne artikkelen] (2024). Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction. Breast Cancer Research. ISSN 1465-5411. 26:189(1), s. 1–14. doi: 10.1186/s13058-024-01947-x. Fulltekst i vitenarkiv Vis sammendrag

  Background The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. Results The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Conclusions Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

• Tinholt, Mari; Tekpli, Xavier; Torland, Lilly Anne; Tahiri, Andliena; Geisler, Jürgen & Kristensen, Vessela N. [Vis alle 8 forfattere av denne artikkelen] (2024). The breast cancer coagulome in the tumor microenvironment and its role in prognosis and treatment response to chemotherapy. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. 22(5), s. 1319–1335. doi: 10.1016/j.jtha.2024.01.003. Fulltekst i vitenarkiv Vis sammendrag

  Background The procoagulant phenotype in cancer is linked to thrombosis, cancer progression, and immune response. A novel treatment that reduces the risk of both thrombosis and cancer progression without excess bleeding risk remains to be identified. Objectives Here, we aimed to broadly investigate the breast tumor coagulome and its relation to prognosis, treatment response to chemotherapy, and the tumor microenvironment. Methods Key coagulation-related genes (n = 35) were studied in a Norwegian cohort with tumor (n = 134) and normal (n = 189) tissue and in the Cancer Genome Atlas (n = 1052) data set. We performed gene set variation analysis in the Norwegian cohort, and in the Cancer Genome Atlas cohort, associations with the tumor microenvironment and prognosis were evaluated. Analyses were performed with cBioPortal, Estimation of Stromal and Immune cells in Malignant Tumors Using Expression Data, Tumor Immune Estimation Resource, the integrated repository portal for tumor–immune system interactions, Tumor Immune Single-cell Hub 2, and the receiver operating characteristic plotter. Six independent breast cancer cohorts were used to study the tumor coagulome and treatment response to chemotherapy. Results Twenty-two differentially expressed coagulation-related genes were identified in breast tumors. Several coagulome factors were correlated with tumor microenvironment characteristics and were expressed by nonmalignant cells in the tumor microenvironment. PLAT and F8 were independent predictors of better overall survival and progression-free survival, respectively. F12 and PLAU were predictors of worse progression-free survival. The PROCR-THBD-PLAT signature showed a promising predictive value (area under the curve, 0.75; 95% CI, 0.69-0.81; P = 3.6 × 10−17) for combination chemotherapy with fluorouracil, epirubicin, and cyclophosphamide. Conclusion The breast tumor coagulome showed potential in prediction of prognosis and chemotherapy response. Cells within the tumor microenvironment are sources of coagulome factors and may serve as therapeutic targets of coagulation factors.

• Mecinaj, Albulena; Gulati, Geeta; Ree, Anne Hansen; Gravdehaug, Berit; Røsjø, Helge Rørvik & Steine, Kjetil [Vis alle 10 forfattere av denne artikkelen] (2024). Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy–Related Cardiac Dysfunction. JACC: CardioOncology. 6(1), s. 83–95. doi: 10.1016/j.jaccao.2023.10.008. Fulltekst i vitenarkiv Vis sammendrag

  Background The impact of recent consensus definitions of cancer therapy–related cardiac dysfunction (CTRCD) from the European Society of Cardiology cardio-oncology guidelines on the reported incidence of CTRCD has not yet been assessed. Objectives The aim of this study was to assess the: 1) cumulative incidence; 2) point prevalence during and after adjuvant therapy; and 3) prognostic value of CTRCD as defined by different asymptomatic CTRCD guideline criteria. Methods The cumulative incidence and point prevalence of CTRCD were retrospectively assessed in 118 patients participating in the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial. Asymptomatic CTRCD was assessed using alternative cardiac troponin (cTn) 99th percentile upper reference limits (URLs) to define cTnT and cTnI elevation. Results The cumulative incidence of moderate or severe CTRCD was low (1.7%), whereas the cumulative incidence of mild asymptomatic CTRCD was higher and differed markedly according to the biomarker criteria applied, ranging from 49.2% of patients when cTnT greater than the sex-specific 99th percentile URL was used to define cTn elevation to 9.3% when sex-neutral cTnI was used. The point prevalence of CTRCD was highest at the end of anthracycline therapy (47.8%) and was driven primarily by asymptomatic cTn elevation. CTRCD during adjuvant therapy was not prognostic for CTRCD at extended follow-up of 24 months (Q1-Q3: 21-29 months) after randomization. Conclusions Mild asymptomatic CTRCD during adjuvant breast cancer therapy was frequent and driven mainly by cTn elevation and was not prognostic of subsequent CTRCD. The incidence of mild, asymptomatic CTRCD differed markedly depending on the cTn assay and whether sex-neutral or sex-dependent URLs were applied. (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy [PRADA]; NCT01434134)

• Schandiz, Hossein Khalkhali; Farkas, Lorant; Park, Daehoon; Liu, Yan; Andersen, Solveig Norheim & Geisler, Jürgen [Vis alle 7 forfattere av denne artikkelen] (2024). Low progesterone receptor levels in high-grade DCIS correlate with HER2 upregulation and the presence of invasive components. Frontiers in Oncology. 14:1347166, s. 1–10. doi: 10.3389/fonc.2024.1347166. Fulltekst i vitenarkiv Vis sammendrag

  Objective In this study, we investigated pivotal molecular markers in human high-grade breast ductal carcinoma in situ (DCIS). Expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2) was measured among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched and triple-negative). Methods In total, 357 DCIS cases were classified into respective subtypes, according to the 2013 St. Gallen guidelines. Each subtype was categorized into three subcategories: “Pure” (those without an invasive component), “W/invasive” (those with an invasive component), and “All” (the entire group of the given subtype). ER and PR expression were registered as intervals. Equivocal HER2 immunohistochemistry (IHC) cases (2+) were further investigated using dual-color in situ hybridization. Results The majority of patients (71%) were over the age of 50. We discovered no significant differences in the proportion of age between the “Pure” and “W/invasive” groups. There was no significant difference in ER/PR expression between “Pure” luminal subtypes of DCIS and “W/invasive” cases. We compared the HER2 IHC scores of “0”, “1+”, and “2+” among LumA and LumB HER2 subtypes and identified no statistically significant differences between “Pure” and “W/invasive” (p = 0.603). ER and PR expression ≥ 50% cutoff value was present in > 90% of all LumA cases. The incidences of cases with ER expression at cutoff values of < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). The proportion of cases with PR expression < 20% showed significant differences in the various luminal subtypes. In luminal B subtypes, low PR expression (< 20%) was significantly associated with both strong HER2 expression (3+) and the presence of an invasive component (p = 0.0001 and p = 0.0365, respectively). Conclusions ER and PR expression at ≥ 50% cutoff values were found in more than 90% of LumA cases. Samples with ER < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). Low PR expression in high-grade DCIS was strongly associated with HER2 overexpression (3+) and an invasive component (p = 0.0001 and p = 0.0365, respectively).

• Torland, Lilly Anne; Lai, Xiaoran; Kumar, Surendra; Riis, Margit; Geisler, Jürgen & Lüders, Torben [Vis alle 10 forfattere av denne artikkelen] (2024). Benign breast tumors may arise on different immunological backgrounds. Molecular Oncology. ISSN 1574-7891. 18(10), s. 2495–2509. doi: 10.1002/1878-0261.13655. Fulltekst i vitenarkiv Vis sammendrag

  Benign breast tumors are a nonthreatening condition defined as abnormal cell growth within the breast without the ability to invade nearby tissue. However, benign lesions hold valuable biological information that can lead us toward better understanding of tumor biology. In this study, we have used two pathway analysis algorithms, Pathifier and gene set variation analysis (GSVA), to identify biological differences between normal breast tissue, benign tumors and malignant tumors in our clinical dataset. Our results revealed that one-third of all pathways that were significantly different between benign and malignant tumors were immune-related pathways, and 227 of them were validated by both methods and in the METABRIC dataset. Furthermore, five of these pathways (all including genes involved in cytokine and interferon signaling) were related to overall survival in cancer patients in both datasets. The cellular moieties that contribute to immune differences in malignant and benign tumors were analyzed using the deconvolution tool, CIBERSORT. The results showed that levels of some immune cells were specifically higher in benign than in malignant tumors, and this was especially the case for resting dendritic cells and follicular T-helper cells. Understanding the distinct immune profiles of benign and malignant breast tumors may aid in developing noninvasive diagnostic methods to differentiate between them in the future.

• Valachis, Antonis; Biganzoli, Laura; Christopoulou, Athina; Fjermeros, Kamilla; Fountzila, Elena & Geisler, Jürgen [Vis alle 38 forfattere av denne artikkelen] (2024). Implementing geriatric assessment for dose optimization of CDK4/6 inhibitors in older breast cancer patients. Future Oncology. ISSN 1479-6694. 20(37), s. 2937–2948. doi: 10.1080/14796694.2024.2413841. Fulltekst i vitenarkiv Vis sammendrag

  Current evidence from both randomized trials and real-world studies suggests that older patients with advanced hormone receptor-positive/HER2-negative (HR+/HER2) breast cancer derive clinical benefit from the addition of CDK4/6 inhibitors to endocrine therapy. However, a higher risk for adverse events due to CDK4/6 inhibitors among older patients is evident, leading to a trend of initiating CDK4/6 inhibitors at lower dose in clinical practice, though without evidence. The aim of the IMPORTANT-trial, a pragmatic, multinational, open-label, partly decentralized randomized trial is to investigate whether lower starting dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to full dose in older (≥70 years old) patients with advanced HR+/HER2- breast cancer who are assessed as vulnerable or frail based on comprehensive geriatric assessment.

• Wang, Feng; Eikeland, Eline; Reidunsdatter, Randi Johansen; Hagen, Lars; Engstrøm, Monica Jernberg & Geisler, Jürgen [Vis alle 10 forfattere av denne artikkelen] (2024). Quantification of multiple steroid hormones in serum and human breast cancer tissue by liquid chromatography-tandem mass spectrometry analysis. Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1383104. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Systemic and local steroid hormone levels may function as novel prognostic and predictive biomarkers in breast cancer patients. We aimed at developing a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous measurement of multiple, biologically pivotal steroid hormones in human serum and breast cancer tissue. Methods: The quantitative method consisted of liquid-liquid extraction, Sephadex LH-20 chromatography for tissue extracts, and analysis of steroid hormones by liquid-chromatography-tandem mass spectrometry. We analyzed serum and tissue steroid hormone levels in 16 and 40 breast cancer patients, respectively, and assessed their correlations with clinical parameters. Results: The method included quantification of nine steroid hormones in serum [including cortisol, cortisone, corticosterone, estrone (E1), 17β-estradiol (E2), 17α-hydroxyprogesterone, androstenedione (A4), testosterone and progesterone) and six (including cortisone, corticosterone, E1, E2, A4, and testosterone) in cancer tissue. The lower limits of quantification were between 0.003–10 ng/ml for serum (250 µl) and 0.038–125 pg/mg for tissue (20 mg), respectively. Accuracy was between 98%-126%, intra-assay coefficient of variations (CV) was below 15%, and inter-assay CV were below 11%. The analytical recoveries for tissue were between 76%-110%. Tissue levels of E1 were positively correlated with tissue E2 levels (p<0.001), and with serum levels of E1, E2 and A4 (p<0.01). Tissue E2 levels were positively associated with serum E1 levels (p=0.02), but not with serum E2 levels (p=0.12). The levels of tissue E2 and ratios of E1 to A4 levels (an index for aromatase activity) were significantly higher in patients with larger tumors (p=0.03 and p=0.02, respectively). Conclusions: The method was convenient and suitable for a specific and accurate profiling of clinically important steroid hormones in serum. However, the sensitivity of the profile method in steroid analysis in tissue samples is limited, but it can be used for the analysis of steroids in breast cancer tissues if the size of the sample or its steroid content is sufficient.

• Touma, Joel; Pantalone, Mattia Russel; Rahbar, Afsar; Liu, Yan; Vetvik, Katja K & Sauer, Torill [Vis alle 8 forfattere av denne artikkelen] (2023). Human Cytomegalovirus Protein Expression Is Correlated with Shorter Overall Survival in Breast Cancer Patients: A Cohort Study. Viruses. 15(3), s. 1–13. doi: 10.3390/v15030732. Fulltekst i vitenarkiv Vis sammendrag

  Background: Human cytomegalovirus (HCMV) is increasingly suggested to be involved in human carcinogenesis and onco-modulation due to its ability to contribute to all hallmarks of cancer. Growing evidence demonstrates a link between HCMV infection and various malignancies, including breast cancer, which incidence and mortality are still on the rise. The etiology of breast cancer remains mostly unclear, leaving 80% of breast cancer cases considered to be sporadic. Identifying novel risk- and prognostic factors for improved breast cancer treatment and increased survival rates, were the objectives of this study. Methods: Automated immunohistochemical staining results for HCMV proteins in 109 breast tumors and lymph node metastasis were correlated with clinical follow-up data (&gt;10 years). Statistical analyses for median Overall Survival (OS) were performed. Results: Survival analyses revealed shorter median OS for patients with HCMV-IE positive tumors of 118.4 months compared to 202.4 months for HCMV-IE negative tumors. A higher number of HCMV-LA positive cells in the tumors was also associated with a shorter OS in patients (146.2 months vs. 151.5 months). Conclusions: Our findings suggest a link between HCMV-infections and breast cancer prognosis, which paves the way for potential novel clinical intervention and targeted therapy that may prolong the overall survival of selected patients with breast cancer.

• Wang, Feng; Giskeødegård, Guro F.; Skarra, Sissel; Engstrøm, Monica Jernberg; Hagen, Lars & Geisler, Jürgen [Vis alle 11 forfattere av denne artikkelen] (2023). Association of serum cortisol and cortisone levels and risk of recurrence after endocrine treatment in breast cancer. Clinical and Experimental Medicine. ISSN 1591-8890. 23(7), s. 3883–3893. doi: 10.1007/s10238-023-01109-x. Fulltekst i vitenarkiv Vis sammendrag

  Metabolic reprogramming in breast cancer involves changes in steroid hormone synthesis and metabolism. Alterations in estrogen levels in both breast tissue and blood may influence carcinogenesis, breast cancer growth, and response to therapy. Our aim was to examine whether serum steroid hormone concentrations could predict the risk of recurrence and treatment-related fatigue in patients with breast cancer. This study included 66 postmenopausal patients with estrogen receptor-positive breast cancer who underwent surgery, radiotherapy, and adjuvant endocrine treatment. Serum samples were collected at six different time points [before the start of radiotherapy (as baseline), immediately after radiotherapy, and then 3, 6, 12 months, and 7–12 years after radiotherapy]. Serum concentrations of eight steroid hormones (cortisol, cortisone, 17α-hydroxyprogesterone, 17β-estradiol, estrone, androstenedione, testosterone, and progesterone) were measured using a liquid chromatography–tandem mass spectrometry-based method. Breast cancer recurrence was defined as clinically proven relapse/metastatic breast cancer or breast cancer-related death. Fatigue was assessed with the QLQ-C30 questionnaire. Serum steroid hormone concentrations measured before and immediately after radiotherapy differed between relapse and relapse-free patients [(accuracy 68.1%, p  = 0.02, and 63.2%, p  = 0.03, respectively, partial least squares discriminant analysis (PLS-DA)]. Baseline cortisol levels were lower in patients who relapsed than in those who did not (p < 0.05). The Kaplan–Meier analysis showed that patients with high baseline concentrations of cortisol (≥ median) had a significantly lower risk of breast cancer recurrence than patients with low cortisol levels (<median) (p  = 0.02). During follow-up, there was a decrease in cortisol and cortisone concentrations in relapse-free patients, whereas these steroid hormones increased in patients who relapsed. In addition, steroid hormone concentrations immediately after radiotherapy were associated with treatment-related fatigue (accuracy of 62.7%, p  = 0.03, PLS-DA). However, baseline steroid hormone levels did not predict fatigue at 1 year or at 7–12 years. In conclusion, breast cancer patients with low baseline cortisol levels were more likely to experience recurrence. During follow-up, cortisol and cortisone levels decreased in relapse-free patients but increased in patients with recurrence. Thus, cortisol and cortisone may act as potential biomarkers indicating individual risk of recurrence.

• Geisler, Jürgen; Karihtala, Peeter; Tuxen, Malgorzata; Valachis, Antonis; Ahlin, Cecilia & Fosskaug, Cathrine Bergquist [Vis alle 28 forfattere av denne artikkelen] (2023). Current treatment landscape of HR+/HER2− advanced breast cancer in the Nordics: a modified Delphi study. Acta Oncologica. ISSN 0284-186X. 62(12), s. 1680–1688. doi: 10.1080/0284186X.2023.2254475. Fulltekst i vitenarkiv Vis sammendrag

  Background This Delphi study aimed to assess current perspectives on hormone receptor-positive/human epidermal growth factor receptor 2-negative(HR+/HER2−) advanced breast cancer (aBC) treatment strategies across the Nordics, and to establish where consensus exists across the Nordics on HR+/HER2− aBC treatment. Material and methods A modified, three-round Delphi method was followed. A steering committee was appointed for study coordination, panellist selection, and questionnaire development. The questionnaires covered relevant topics on HR+/HER2− aBC treatment: treatment patterns in different lines of therapy (first [1L], second [2L], and third [3L]), oligometastatic disease, de novo aBC, brain metastases, age as influential factor, visceral crisis, radiotherapy, diagnostics, and clinical guidelines. Both open and closed-ended questions were included. Consensus was defined as at least 70% agreement. Results In total, 28 experienced BC oncologists participated in the study from all five Nordic countries. Overall, topics reaching consensus included: preferred treatment approach in 1L and 2L therapy, treatment of oligometastatic disease, visceral crisis, brain metastases, and age-related treatment considerations. No consensus was reached for 3L therapy and local treatment for primary tumour in de novo aBC. Endocrine therapy (ET) combined with a cyclin-dependent kinase (CDK)4/6 inhibitor was the treatment of choice for 1L and 2L therapy. Treatment patterns in clinical practice did not always follow recommendations in current Nordic guidelines, as seen in the case of recently approved treatments. Discussion ET in combination with a CDK4/6 inhibitor is the preferred frontline treatment for HR+/HER2− aBC in the Nordics. The observed discrepancy between current guidelines and clinical practice could be due to differences in the reimbursement of novel treatments in the Nordics. Collaborative research efforts are warranted for topics that lack consensus.

• Schandiz, Hossein Khalkhali; Park, Daehoon; Liu, Yan; Lyngra, Marianne; Talleraas, Inger Solvang & Geisler, Jürgen [Vis alle 7 forfattere av denne artikkelen] (2023). Subtypes of high-grade breast ductal carcinoma in situ (DCIS): incidence and potential clinical impact. Breast Cancer Research and Treatment. ISSN 0167-6806. 201(2), s. 329–338. doi: 10.1007/s10549-023-07016-9. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Objective The purpose of this study was to investigate and classify the molecular subtypes of high-grade ductal carcinoma in situ (DCIS) and identify possible high-risk subtypes. The heterogenicity of DCIS with variable clinical and histopathological presentations has been recognized. Nevertheless, only histopathological grading and diameter are currently implemented in clinical decision-making following the diagnosis of DCIS. The molecular subtypes of DCIS and their IHC surrogate markers have not been defined in conventional treatment guidelines and recommendations. We applied the definitions of molecular subtypes according to the IHC surrogate markers defined for IBC and subclassified high-grade DCIS, accordingly. Methods Histopathological specimens were collected, revised, and regraded from 494 patients diagnosed with DCIS between 1996 and 2018. Other in situ and papillary lesions observed in breast biopsies were excluded from this study. 357 high-grade DCIS cases were submitted to IHC analysis. The markers investigated were ER, PR, HER2, and Ki67. Results 45 cases were classified as grade 1, 19 as grade 2, and 430 as grade 3. Sixty patients with high-grade DCIS had an additional invasive component in the surgical specimen. Thirty-three patients were diagnosed with recurrent DCIS or invasive cancer (minimum one year after their primary DCIS diagnosis). The proportions of luminal A and luminal B HER2-negative subtypes varied depending on whether 2011 or 2013 St. Gallen Consensus Conference guidelines were adopted. Luminal A was the most prevalent subtype, according to both classifications. The luminal B HER2-positive subtype was found in 22.1% of cases, HER2-enriched subtype in 21.8%, and TPN subtype in 5.6%. There were strong indications that HER2-enriched subtype was significantly more frequent among DCIS with invasive component ( p  = 0.0169). Conclusions High-grade DCIS exhibits all the molecular subtypes previously identified in IBC, but with a somewhat different distribution in our cohort. HER2-enriched subtype is substantially related to the presence of an invasive component in DCIS; consequently, it is regarded as a high-risk entity.

• Nikolaienko, Oleksii; Eikesdal, Hans Petter; Berge, Elisabet Ognedal; Gilje, Bjørnar; Lundgren, Steinar & Blix, Egil Støre [Vis alle 16 forfattere av denne artikkelen] (2023). Prenatal BRCA1 epimutations contribute significantly to triple-negative breast cancer development. Genome Medicine. 15(1). doi: 10.1186/s13073-023-01262-8. Fulltekst i vitenarkiv Vis sammendrag

  Background Normal cell BRCA1 epimutations have been associated with increased risk of triple-negative breast cancer (TNBC). However, the fraction of TNBCs that may have BRCA1 epimutations as their underlying cause is unknown. Neither are the time of occurrence and the potential inheritance patterns of BRCA1 epimutations established. Methods To address these questions, we analyzed BRCA1 methylation status in breast cancer tissue and matched white blood cells (WBC) from 408 patients with 411 primary breast cancers, including 66 TNBCs, applying a highly sensitive sequencing assay, allowing allele-resolved methylation assessment. Furthermore, to assess the time of origin and the characteristics of normal cell BRCA1 methylation, we analyzed umbilical cord blood of 1260 newborn girls and 200 newborn boys. Finally, we assessed BRCA1 methylation status among 575 mothers and 531 fathers of girls with (n = 102) and without (n = 473) BRCA1 methylation. Results We found concordant tumor and mosaic WBC BRCA1 epimutations in 10 out of 66 patients with TNBC and in four out of six patients with estrogen receptor (ER)-low expression (< 10%) tumors (combined: 14 out of 72; 19.4%; 95% CI 11.1–30.5). In contrast, we found concordant WBC and tumor methylation in only three out of 220 patients with 221 ER ≥ 10% tumors and zero out of 114 patients with 116 HER2-positive tumors. Intraindividually, BRCA1 epimutations affected the same allele in normal and tumor cells. Assessing BRCA1 methylation in umbilical WBCs from girls, we found mosaic, predominantly monoallelic BRCA1 epimutations, with qualitative features similar to those in adults, in 113/1260 (9.0%) of individuals, but no correlation to BRCA1 methylation status either in mothers or fathers. A significantly lower fraction of newborn boys carried BRCA1 methylation (9/200; 4.5%) as compared to girls (p = 0.038). Similarly, WBC BRCA1 methylation was found less common among fathers (16/531; 3.0%), as compared to mothers (46/575; 8.0%; p = 0.0003). Conclusions Our findings suggest prenatal BRCA1 epimutations might be the underlying cause of around 20% of TNBC and low-ER expression breast cancers. Such constitutional mosaic BRCA1 methylation likely arise through gender-related mechanisms in utero, independent of Mendelian inheritance.

• Figlioli, Gisella; Billaud, Amandine; Ahearn, Thomas U.; Antonenkova, Natalia N.; Becher, Heiko & Beckmann, Matthias W. [Vis alle 114 forfattere av denne artikkelen] (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), s. 578–587. doi: 10.1038/s41431-022-01257-w. Fulltekst i vitenarkiv Vis sammendrag

  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

• Morra, Anna; Schreurs, Maartje A. C.; Andrulis, Irene L.; Anton-Culver, Hoda; Augustinsson, Annelie & Beckmann, Matthias W. [Vis alle 125 forfattere av denne artikkelen] (2023). Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival. Cancer Medicine. 12(15), s. 16142–16162. doi: 10.1002/cam4.6272. Fulltekst i vitenarkiv Vis sammendrag

  Background - Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.<p> <p>Aim - To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.<p> <p>Methods - Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.<p> <p>Results - There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)].<p> <p>Conclusion - Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

• Figlioli, Gisella; Billaud, Amandine; Wang, Qin; Bolla, Manjeet K.; Dennis, Joe & Lush, Michael [Vis alle 96 forfattere av denne artikkelen] (2023). Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases. Cancers. 15(13). doi: 10.3390/cancers15133313. Fulltekst i vitenarkiv Vis sammendrag

  FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.

• Levi, Hagai; Carmi, Shai; Rosset, Saharon; Yerushalmi, Rinat; Zick, Aviad & Yablonski-Peretz, Tamar [Vis alle 155 forfattere av denne artikkelen] (2023). Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel. Journal of Medical Genetics. ISSN 0022-2593. 60(12), s. 1186–1197. doi: 10.1136/jmg-2023-109185. Fulltekst i vitenarkiv Vis sammendrag

  Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

• Morra, Anna; Mavaddat, Nasim; Muranen, Taru A.; Ahearn, Thomas U.; Allen, Jamie & Andrulis, Irene L. [Vis alle 84 forfattere av denne artikkelen] (2023). The impact of coding germline variants on contralateral breast cancer risk and survival. American Journal of Human Genetics. ISSN 0002-9297. 110(3), s. 475–486. doi: 10.1016/j.ajhg.2023.02.003. Fulltekst i vitenarkiv Vis sammendrag

  Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70–4.87), 2.31 (1.39–3.85), 8.29 (2.53–27.21), 2.25 (1.55–3.27), and 2.67 (1.33–5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13–2.07), 2.08 (0.95–4.57), and 1.39 (1.13–1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

• Mueller, Stefanie H.; Lai, Alvina G.; Valkovskaya, Maria; Michailidou, Kyriaki; Bolla, Manjeet K. & Wang, Qin [Vis alle 207 forfattere av denne artikkelen] (2023). Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry. Genome Medicine. 15(7). doi: 10.1186/s13073-022-01152-5. Fulltekst i vitenarkiv Vis sammendrag

  Background Low‐frequency variants play an important role in breast cancer (BC) susceptibility. Gene‐based meth‐ ods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene‐based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low‐frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single‐marker association results in the same cohort. Gene‐based associations were also combined in meta‐analysis across individu‐ als with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10−6) and AC058822.1 (P = 1.47 × 10−4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta‐analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Conclusions Using extended gene‐based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single‐marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10−5), demonstrating the importance of diversifying study cohorts.

• Yndestad, Synnøve; Engebrethsen, Christina; Herencia-Ropero, A.; Nikolaienko, Oleksii; Vintermyr, Olav Karsten & Lillestøl, Reidun Kristine [Vis alle 23 forfattere av denne artikkelen] (2023). Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer. JCO Precision Oncology (JCO PO). 7(7). doi: 10.1200/PO.23.00338. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Homologous recombination deficiency (HRD) is highly prevalent in triple-negative breast cancer (TNBC) and associated with response to PARP inhibition (PARPi). Here, we studied the prevalence of HRD in non-TNBC to assess the potential for PARPi in a wider group of patients with breast cancer. Methods HRD status was established using targeted gene panel sequencing (360 genes) and BRCA1 methylation analysis of pretreatment biopsies from 201 patients with primary breast cancer in the phase II PETREMAC trial (ClinicalTrials.gov identifier: NCT02624973). HRD was defined as mutations in BRCA1, BRCA2, BRIP1, BARD1, or PALB2 and/or promoter methylation of BRCA1 (strict definition; HRD-S). In secondary analyses, a wider definition (HRD-W) was used, examining mutations in 20 additional genes. Furthermore, tumor BRCAness (multiplex ligation-dependent probe amplification), PAM50 subtyping, RAD51 nuclear foci to test functional HRD, tumor-infiltrating lymphocyte (TIL), and PD-L1 analyses were performed. Results HRD-S was present in 5% of non-TNBC cases (n = 9 of 169), contrasting 47% of the TNBC tumors (n = 15 of 32). HRD-W was observed in 23% of non-TNBC (n = 39 of 169) and 59% of TNBC cases (n = 19 of 32). Of 58 non-TNBC and 30 TNBC biopsies examined for RAD51 foci, 4 of 4 (100%) non-TNBC and 13 of 14 (93%) TNBC cases classified as HRD-S had RAD51 low scores. In contrast, 4 of 17 (24%) non-TNBC and 15 of 19 (79%) TNBC biopsies classified as HRD-W exhibited RAD51 low scores. Of nine non-TNBC tumors with HRD-S status, only one had a basal-like PAM50 signature. There was a high concordance between HRD-S and either BRCAness, high TIL density, or high PD-L1 expression (each P < .001). Conclusion The prevalence of HRD in non-TNBC suggests that therapy targeting HRD should be evaluated in a wider breast cancer patient population. Strict HRD criteria should be implemented to increase diagnostic precision with respect to functional HRD.

• Dorling, Leila; Carvalho, Sara; Allen, Jamie; Parsons, Michael T.; Fortuno, Cristina & Kristensen, Vessela N. [Vis alle 50 forfattere av denne artikkelen] (2022). Breast cancer risks associated with missense variants in breast cancer susceptibility genes. Genome Medicine. 14(1), s. 1–17. doi: 10.1186/s13073-022-01052-8. Fulltekst i vitenarkiv Vis sammendrag

  Background: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to ana‑ lyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to fve in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best ftting models were well calibrated in the validation set. Conclusions: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility

• Reis, Joana; Boavida, João; Tran, Hang Thi; Lyngra, Marianne; Reitsma, Laurens Cornelus & Schandiz, Hossein Khalkhali [Vis alle 10 forfattere av denne artikkelen] (2022). Assessment of preoperative axillary nodal disease burden: breast MRI in locally advanced breast cancer before, during and after neoadjuvant endocrine therapy. BMC Cancer. 22(1), s. 1–11. doi: 10.1186/s12885-022-09813-9. Fulltekst i vitenarkiv Vis sammendrag

  Background Axillary lymph node (LN) metastasis is one of the most important predictors of recurrence and survival in breast cancer, and accurate assessment of LN involvement is crucial. Determining extent of residual disease is key for surgical planning after neoadjuvant therapy. The aim of the study was to evaluate the diagnostic reliability of MRI for nodal disease in locally advanced breast cancer patients treated with neoadjuvant endocrine therapy (NET). Methods Thirty-three clinically node-positive locally advanced breast cancer patients who underwent NET and surgery were prospectively enrolled. Two radiologists reviewed the axillary nodes at 3 separate time points MRI examinations at baseline (before the first treatment regimen), interim (following at least 2 months after the first cycle and prior to crossing-over), and preoperative (after the final administration of therapy and immediately before surgery). According to LN status after surgery, imaging features and diagnostic performance were analyzed. Results All 33 patients had a target LN reduction, the greatest treatment benefit from week 8 to week 16. There was a positive correlation between the maximal diameter of the most suspicious LN measured by MRI and pathology during and after NET, being highest at therapy completion (r = 0.6, P ≤ .001). Mean and median differences of maximal diameter of the most suspicious LN were higher with MRI than with pathology. Seven of 33 patients demonstrated normal posttreatment MRI nodal status (yrN0). Of these 7 yrN0, 3 exhibited no metastasis on final pathology (ypN0), 2 ypN1 and 2 ypN2. Reciprocally, MRI diagnosed 3 cases of ypN0 as yrN + . Diffusion -weighted imaging (DWI) was the only axillary node characteristic significant when associated with pathological node status (χ2(4) = 8.118, P = .072). Conclusion Performance characteristics of MRI were not completely sufficient to preclude surgical axillary staging. To our knowledge, this is the first study on MRI LN assessment following NET in locally advanced breast cancer, and further studies with larger sample sizes are required to consolidate the results of this preliminary study. Trial Registration Institutional Review Board approval was obtained (this current manuscript is from a prospective, open-label, randomized single-center cohort substudy of the NEOLETEXE trial). NEOLETEXE, a phase 2 clinical trial, was registered on March 23rd, 2015 in the National trial database of Norway and approved by the Regional Ethical Committee of the South-Eastern Health Region in Norway; registration number: REK-SØ-84–2015 .

• Bjørklund, Sunniva; Aure, Miriam Ragle; Häkkinen, Jari; Vallon-Christersson, Johan; Kumar, Surendra & Evensen, Katrine Bull [Vis alle 34 forfattere av denne artikkelen] (2022). Subtype and cell type specific expression of lncRNAs provide insight into breast cancer. Communications Biology. 5(1), s. 1–14. doi: 10.1038/s42003-022-03559-7. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Lirussi, Lisa; Ayyildiz, Dilara; Liu, Yan; Montaldo, Nicola Pietro; Huroz, Sergio Carracedo & Aure, Miriam Ragle [Vis alle 16 forfattere av denne artikkelen] (2022). A regulatory network comprising let-7 miRNA and SMUG1 is associated with good prognosis in ER+ breast tumours. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(18), s. 10449–10468. doi: 10.1093/nar/gkac807. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Single-strand selective uracil–DNA glycosylase 1 (SMUG1) initiates base excision repair (BER) of uracil and oxidized pyrimidines. SMUG1 status has been associated with cancer risk and therapeutic response in breast carcinomas and other cancer types. However, SMUG1 is a multifunctional protein involved, not only, in BER but also in RNA quality control, and its function in cancer cells is unclear. Here we identify several novel SMUG1 interaction partners that functions in many biological processes relevant for cancer development and treatment response. Based on this, we hypothesized that the dominating function of SMUG1 in cancer might be ascribed to functions other than BER. We define a bad prognosis signature for SMUG1 by mapping out the SMUG1 interaction network and found that high expression of genes in the bad prognosis network correlated with lower survival probability in ER+ breast cancer. Interestingly, we identified hsa-let-7b-5p microRNA as an upstream regulator of the SMUG1 interactome. Expression of SMUG1 and hsa-let-7b-5p were negatively correlated in breast cancer and we found an inhibitory auto-regulatory loop between SMUG1 and hsa-let-7b-5p in the MCF7 breast cancer cells. We conclude that SMUG1 functions in a gene regulatory network that influence the survival and treatment response in several cancers.

• Dixon-Suen, Suzanne C.; Lewis, Sarah; Martin, Richard M.; English, Dallas R.; Boyle, Terry & Giles, Graham G. [Vis alle 174 forfattere av denne artikkelen] (2022). Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study. British Journal of Sports Medicine. ISSN 0306-3674. 56(20), s. 1157–1170. doi: 10.1136/bjsports-2021-105132. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. Methods We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. Results Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). Conclusion Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

• Tahiri, Andliena; Puco, Katarina; Naji, Faris; Kristensen, Vessela N.; Alfsen, G. Cecilie & Farkas, Lorant [Vis alle 10 forfattere av denne artikkelen] (2022). Kinase activity profiling in renal cell carcinoma, benign renal tissue and in response to four different tyrosine kinase inhibitors. OncoTarget. 13(1), s. 970–981. doi: 10.18632/oncotarget.28257. Fulltekst i vitenarkiv Vis sammendrag

  Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip® technology. The aim of this study was to identify differences in PTK activity between normal and malignant kidney tissue obtained from the same patient, and to investigate the inhibitory effects of TKIs frequently used in the clinics: sunitinib, pazopanib, cabozantinib and tivozanib. Briefly, our results showed that 36 kinase substrates differs (FDR < 0.05) between normal and cancer kidney tissue, where members of the Src family kinases and the phosphoinositide-3-kinase (PI3K) pathway exhibit high activity in renal cancer. Furthermore, ex vivo treatment of clear cell RCC with TKIs revealed that pathways such as Rap1, Ras and PI3K pathways were strongly inhibited, whereas the neurotrophin pathway had increased activity upon TKI addition. In our assay, tivozanib and cabozantinib exhibited greater inhibitory effects on PTK activity compared to sunitinib and pazopanib, implying they might be better suitable as TKIs for selected RCC patients.

• Venizelos, Andreas; Engebrethsen, Christina; Deng, Wei; Geisler, Jürgen; Geisler, Stephanie & Iversen, Gjertrud Titlestad [Vis alle 18 forfattere av denne artikkelen] (2022). Clonal evolution in primary breast cancers under sequential epirubicin and docetaxel monotherapy. Genome Medicine. 14, s. 1–18. doi: 10.1186/s13073-022-01090-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Subclonal evolution during primary breast cancer treatment is largely unexplored. We aimed to assess the dynamic changes in subclonal composition of treatment-naïve breast cancers during neoadjuvant chemotherapy. Methods We performed whole exome sequencing of tumor biopsies collected before, at therapy switch, and after treatment with sequential epirubicin and docetaxel monotherapy in 51 out of 109 patients with primary breast cancer, who were included in a prospectively registered, neoadjuvant single-arm phase II trial. Results There was a profound and differential redistribution of subclones during epirubicin and docetaxel treatment, regardless of therapy response. While truncal mutations and main subclones persisted, smaller subclones frequently appeared or disappeared. Reassessment of raw data, beyond formal mutation calling, indicated that the majority of subclones seemingly appearing during treatment were in fact present in pretreatment breast cancers, below conventional detection limits. Likewise, subclones which seemingly disappeared were still present, below detection limits, in most cases where tumor tissue remained. Tumor mutational burden (TMB) dropped during neoadjuvant therapy, and copy number analysis demonstrated specific genomic regions to be systematically lost or gained for each of the two chemotherapeutics. Conclusions Sequential epirubicin and docetaxel monotherapy caused profound redistribution of smaller subclones in primary breast cancer, while early truncal mutations and major subclones generally persisted through treatment.

• Dennis, Joe; Tyrer, Jonathan P.; Walker, Logan C.; Michailidou, Kyriaki; Dorling, Leila & Kristensen, Vessela N. [Vis alle 50 forfattere av denne artikkelen] (2022). Rare germline copy number variants (CNVs) and breast cancer risk. Communications Biology. 5, s. 1–15. doi: 10.1038/s42003-021-02990-6. Fulltekst i vitenarkiv Vis sammendrag

  Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

• Ahearn, Thomas U.; Zhang, Haoyu; Michailidou, Kyriaki; Milne, Roger L.; Bolla, Manjeet K. & Dennis, Joe [Vis alle 205 forfattere av denne artikkelen] (2022). Common variants in breast cancer risk loci predispose to distinct tumor subtypes. Breast Cancer Research. ISSN 1465-5411. 24(1), s. 1–13. doi: 10.1186/s13058-021-01484-x. Fulltekst i vitenarkiv Vis sammendrag

  Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

• Mavaddat, Nasim; Dorling, Leila; Carvalho, Sara; Allen, Jamie; González-Neira, Anna & Keeman, Renske [Vis alle 94 forfattere av denne artikkelen] (2022). Pathology of tumors associated with pathogenic germline variants in 9 breast cancer susceptibility genes. JAMA Oncology. ISSN 2374-2437. 8(3). doi: 10.1001/jamaoncol.2021.6744. Fulltekst i vitenarkiv Vis sammendrag

  IMPORTANCE Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ ERBB2− high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ ERBB2+ and HR– ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger. CONCLUSIONS AND RELEVANCE The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

• Escala-Garcia, Maria; Canisius, Sander; Keeman, Renske; Beesley, Jonathan; Anton-Culver, Hoda & Arndt, Volker [Vis alle 105 forfattere av denne artikkelen] (2021). Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis. Scientific Reports. 11:19787, s. 1–11. doi: 10.1038/s41598-021-99409-3. Fulltekst i vitenarkiv Vis sammendrag

  Breast cancer metastasis accounts for most of the deaths from breast cancer. Identifcation of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identifed two germline variants on chromosome 1, rs138569520 and rs146023652, signifcantly associated with breast cancer-specifc survival (P= 3.19 × ­10−8 and 4.42 × ­10−8). In silico analysis suggested a potential regulatory efect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confrm the identifed associations.

• Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Keeman, Renske; Canisius, Sander & Ahearn, Thomas U. [Vis alle 50 forfattere av denne artikkelen] (2021). Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. Breast Cancer Research. ISSN 1465-5411. 23:86(1), s. 1–18. doi: 10.1186/s13058-021-01450-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

• Heck, Siri Lagethon; Mecinaj, Albulena; Ree, Anne Hansen; Hoffmann, Pavel; Schulz-Menger, Jeanette & Fagerland, Morten [Vis alle 12 forfattere av denne artikkelen] (2021). Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): Extended follow-up of a 2×2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Circulation. ISSN 0009-7322. 143(25), s. 2431–2440. doi: 10.1161/CIRCULATIONAHA.121.054698. Fulltekst i vitenarkiv Vis sammendrag

  Background: Adjuvant breast cancer therapy containing anthracyclines with or without anti–human epidermal growth factor receptor–2 antibodies and radiotherapy is associated with cancer treatment–related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. Methods: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. Results: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. Conclusions: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

• Park, Hanla A.; Neumeyer, Sonja; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin & Kristensen, Vessela N. [Vis alle 50 forfattere av denne artikkelen] (2021). Mendelian randomisation study of smoking exposure in relation to breast cancer risk. British Journal of Cancer. ISSN 0007-0920. 125(8), s. 1135–1145. doi: 10.1038/s41416-021-01432-8. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P  = 0.11 × 10 –2 ), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P  = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

• Bertelsen, Bjørn-Erik; Viste, Kristin; Helland, Thomas; Hagland, Magnus; Søiland, Håvard & Geisler, Jürgen [Vis alle 11 forfattere av denne artikkelen] (2021). Simultaneous Quantification of Aromatase Inhibitors and Estrogens in Postmenopausal Breast Cancer Patients. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 107(5), s. 1368–1374. doi: 10.1210/clinem/dgab923. Fulltekst i vitenarkiv Vis sammendrag

  Context Currently there are no assays that can simultaneously quantify serum levels of the third-generation aromatase inhibitors (AIs): letrozole, anastrozole, and exemestane, and the ultra-low levels of estrogens in postmenopausal breast cancer patients on AI treatment. Such measurements may be pivotal for the determination of optimal and individualized treatment regimens. We aimed at developing a liquid chromatography–tandem mass spectrometry (MS/MS) method for simultaneous assessment of letrozole, anastrozole, exemestane, and 17-hydroxyexemestane as well as subpicomolar levels of estradiol and estrone. Methods Internal standards, calibrators, serum samples, and quality controls were in fully automated steps transferred to a deep-well plate for a 2-step liquid-liquid extraction. The extracts were reconstituted and analytes were separated chromatographically using 2 serially coupled columns, then subject to MS/MS in electrospray ionization mode. The method was thoroughly validated and is traceable to 2 accredited estrogen methods. Results The measurement range for estrone and estradiol was 0.2 to 12 000 pmol/L and 0.8 to 13 000 pmol/L, and covered the expected therapeutic range for the AIs. All analytes had a precision of less than or equal to 13%, and accuracies within 100 ± 8%. As proof of concept, AI and estrogen levels were determined in serum samples from postmenopausal breast cancer patients under treatment. Conclusion We present here an assay suitable for the simultaneous measurement of serum levels of all third-generation AIs and ultra-low levels of estrogens, providing a powerful new tool to study drug efficacy and compliance. The method is highly valuable for postmenopausal patients whose pretreatment estradiol levels are below the threshold of detection for most routine assays, but still require suppression.

• Mecinaj, Albulena; Gulati, Geeta; Heck, Siri Lagethon; Holte, Espen; Fagerland, Morten Wang & Larsen, Alf Inge [Vis alle 10 forfattere av denne artikkelen] (2021). Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial. Cardio-Oncology. 7. doi: 10.1186/s40959-021-00115-w. Fulltekst i vitenarkiv Vis sammendrag

  Objective To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. Methods PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. Results The study is ongoing. Results will be published when the study is completed. Conclusion PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. Trial registration The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588). Registered 30 November 2018.

• Bahrami, Nazli; Jabeen, Shakila; Tahiri, Andliena; Sauer, Torill; Ødegård, Hilde Presterud & Geisler, Stephanie Beate [Vis alle 11 forfattere av denne artikkelen] (2021). Lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients: the potential role of the adipokine leptin. Breast Cancer Research and Treatment. ISSN 0167-6806. 190, s. 435–449. doi: 10.1007/s10549-021-06399-x. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Purpose The aromatase inactivator exemestane may cause clinical disease stabilization following progression on non-steroidal aromatase inhibitors like letrozole in patients with metastatic breast cancer, indicating that additional therapeutic effects, not necessarily related to estrogen-suppression, may be involved in this well-known “lack of cross-resistance”. Methods Postmenopausal women with ER positive, HER-2 negative, locally advanced breast cancer were enrolled in the NEOLETEXE-trial and randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) followed by the alternative aromatase inhibitor. Serum levels of 54 cytokines, including 12 adipokines were assessed using Luminex xMAP technology (multiple ELISA). Results Serum levels of leptin were significantly decreased during treatment with exemestane ( p  &lt; 0.001), regardless whether exemestane was given as first or second neoadjuvant therapy. In contrast, letrozole caused a non-significant increase in serum leptin levels in vivo. Conclusions Our findings suggest an additional and direct effect of exemestane on CYP-19 (aromatase) synthesis presumably due to effects on the CYP19 promoter use that is not present during therapy with the non-steroidal aromatase inhibitor letrozole. Our findings provide new insights into the influence of clinically important aromatase inhibitors on cytokine levels in vivo that contribute to the understanding of the clinically observed lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients. Trial registration Registered on March 23rd 2015 in the National trial database of Norway (Registration number: REK-SØ-84-2015).

• Rye, Inga Hansine; Huse, Kanutte; Josefsson, Sarah Elisabet; Kildal, Wanja; Danielsen, Håvard Emil Greger & Schlichting, Ellen [Vis alle 28 forfattere av denne artikkelen] (2021). Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression. Molecular Oncology. ISSN 1574-7891. 16(1), s. 88–103. doi: 10.1002/1878-0261.13047. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Touma, Joel Joul; Liu, Yan; Rahbar, Afsar; Pantalone, Mattia Russel; Almazan, Nerea Martin & Vetvik, Katja K [Vis alle 9 forfattere av denne artikkelen] (2021). Detection of human cytomegalovirus proteins in paraffin‐embedded breast cancer tissue specimens—a novel, automated immunohistochemical staining protocol. Microorganisms. 9(5), s. 1–16. doi: 10.3390/microorganisms9051059. Fulltekst i vitenarkiv Vis sammendrag

  Emerging evidence supports a significant association between human cytomegalovirus (HCMV) and human malignancies, suggesting HCMV as a human oncomodulatory virus. HCMV gene products are found in &gt;90% of breast cancer tumors and seem to be correlated with more aggressive disease. The definitive diagnosis of HCMV relies on identification of virus inclusions and/or viral proteins by different techniques including immunohistochemical staining. In order to reduce biases and improve clinical value of HCMV diagnostics in oncological pathology, automation of the procedure is needed and this was the purpose of this study. Tumor specimens from 115 patients treated for primary breast cancer at Akershus University Hospital in Norway were available for the validation of the staining method in this retrospective study. We demonstrate that our method is highly sensitive and delivers excellent reproducibility for staining of HCMV late antigen (LA), which makes this method useful for future routine diagnostics and scientific applications.

• Reis, Joana; Thomas, Owen; Lahooti, Maryam; Lyngra, Marianne; Schandiz, Hossein Khalkhali & Boavida, João [Vis alle 10 forfattere av denne artikkelen] (2021). Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial. Breast Cancer Research and Treatment. ISSN 0167-6806. 189, s. 711–723. doi: 10.1007/s10549-021-06343-z. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Purpose To correlate MRI morphological response patterns with histopathological tumor regression grading system based on tumor cellularity in locally advanced breast cancer (LABC)-treated neoadjuvant with third-generation aromatase inhibitors. Methods Fifty postmenopausal patients with ER-positive/HER-2-negative LABC treated with neoadjuvant letrozole and exemestane given sequentially in an intra-patient cross-over regimen for at least 4 months with MRI response monitoring at baseline as well as after at least 2 and 4 months on treatment. The MRI morphological response pattern was classified into 6 categories: 0/complete imaging response; I/concentric shrinkage; II/fragmentation; III/diffuse; IV/stable; and V/progressive. Histopathological tumor regression was assessed based on the recommendations from The Royal College of Pathologists regarding tumor cellularity. Results Following 2 and 4 months with therapy, the most common MRI pattern was pattern II (24/50 and 21/50, respectively). After 4 months on therapy, the most common histopathological tumor regression grade was grade 3 (21/50). After 4 months an increasing correlation is observed between MRI patterns and histopathology. The overall correlation, between the largest tumor diameter obtained from MRI and histopathology, was moderate and positive (r = 0.50, P-value = 2e-04). Among them, the correlation was highest in type IV (r = 0.53). Conclusion The type II MRI pattern “fragmentation” was more frequent in the histopathological responder group; and types I and IV in the non-responder group. Type II pattern showed the best endocrine responsiveness and a relatively moderate correlation between sizes obtained from MRI and histology, whereas type IV pattern indicated endocrine resistance but the strongest correlation between MRI and histology.

• Johnson, Nichola; Maguire, Sarah; Morra, Anna; Kapoor, Pooja Middha; Tomczyk, Katarzyna & Kristensen, Vessela N. [Vis alle 50 forfattere av denne artikkelen] (2021). CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers. British Journal of Cancer. ISSN 0007-0920. 124, s. 842–854. doi: 10.1038/s41416-020-01185-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P  = 3.1 × 10 –18 ); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P  = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P  = 6.9 × 10 –8 ). Conclusions The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

• Park, JooYong; Choi, Ji-Yeob; Choi, Jaesung; Chung, Seokang; Song, Nan & Park, Sue K [Vis alle 50 forfattere av denne artikkelen] (2021). Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies? Cancers. 13:2370(10), s. 1–21. doi: 10.3390/cancers13102370. Fulltekst i vitenarkiv Vis sammendrag

  In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

• Reis, Joana; Lindstrøm, Jonas Christoffer; Boavida, João; Gjesdal, Kjell-Inge; Park, Daehoon & Bahrami, Nazli [Vis alle 11 forfattere av denne artikkelen] (2020). Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments. Breast Cancer Research and Treatment. ISSN 0167-6806. 184(2), s. 407–420. doi: 10.1007/s10549-020-05852-7. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Purpose To assess the accuracy of magnetic resonance imaging (MRI) measurements in locally advanced oestrogen receptor-positive and human epidermal growth factor receptor 2-negative breast tumours before, during and after neoadjuvant endocrine treatment (NET) for evaluation of tumour response in comparison with clinical and pathological assessments. Methods This prospective study enrolled postmenopausal patients treated neoadjuvant with letrozole and exemestane given sequentially in an intra-patient cross-over regimen. Fifty-four patients were initially recruited, but only 35 fulfilled the inclusion criteria and confirmed to participate with a median age of 77. Tumours were scanned with MRI prior to treatment, during the eighth week of treatment and prior to surgery. Additionally, changes in longest diameter on clinical examination (CE) and tumour size at pathology were determined. Pre- and post-operative measurements of tumour size were compared in order to evaluate tumour response. Results The correlation between post-treatment MRI size and pathology was moderate and higher with a correlation coefficient ( r ) 0.64 compared to the correlation between CE and pathology r  = 0.25. Post-treatment MRI and clinical results had a negligible bias towards underestimation of lesion size. Tumour size on MRI and CE had 0.82 cm and 0.52 cm lower mean size than tumour size measured by pathology, respectively. Conclusions The higher correlation between measurements of residual disease obtained on MRI and those obtained with pathology validates the accuracy of imaging assessment during NET. MRI was found to be more accurate for estimating complete responses than clinical assessments and warrants further investigation in larger cohorts to validate this finding.

• Liu, Jingjing; Smissen, Wendy J. C. Prager van der; Collee, Margriet J.; Bolla, Manjeet K.; Wang, Qin & Kristensen, Vessela N. [Vis alle 82 forfattere av denne artikkelen] (2020). Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk. Scientific Reports. 10:9688(1), s. 1–14. doi: 10.1038/s41598-020-65665-y. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Bahrami, Nazli; Chang, Gregory; Kanaya, Noriko; Sauer, Torill; Park, Daehoon & Loeng, Marie [Vis alle 9 forfattere av denne artikkelen] (2020). Changes in serum estrogenic activity during neoadjuvant therapy with letrozole and exemestane. Journal of Steroid Biochemistry and Molecular Biology. ISSN 0960-0760. 200, s. 1–8. doi: 10.1016/j.jsbmb.2020.105641. Fulltekst i vitenarkiv Vis sammendrag

  The aromatase inhibitors (AIs), letrozole (Femar®/Femara®) and exemestane (Aromasin®), are widely used to treat estrogen receptor (ER) positive breast cancer in postmenopausal patients. In the setting of metastatic breast cancer, these drugs may be used after another causing new responses in selected patients after progressing on the first choice. The precise explanation for this “lack of cross resistance” is still missing. NEOLETEXE is a neoadjuvant, randomized, open-label, cross-over trial. Postmenopausal patients with ER-positive, HER-2 negative, locally advanced breast cancer were enrolled. All patients were randomized to treatment starting with either letrozole or exemestane for at least 2 months followed by another 2 months on the alternative AI. The total estrogenic activities in blood samples were determined using the AroER tri-screen assay developed in the Chen laboratory. Using this highly sensitive assay, estrogenic activity was detected at three time points for all patients. Importantly, a significantly higher total estrogenic activity was found during therapy with exemestane compared to letrozole in 21 out of 26 patients. When letrozole was included in the AroER tri-screen assay, the estrogenic activities in most samples collected during exemestane treatment were further reduced, suggesting that low levels of androgens remained in specimens obtained after exemestane treatment. Our results suggest the AroER tri-screen to be a very sensitive method to estimate the overall estrogen-mediated activity in human samples even during therapy with highly potent aromatase inhibitors. In the present study, serum estrogen activity was significantly higher during exemestane therapy when compared to letrozole therapy.

• Ny, Lars; Hernberg, Micaela M.; Nyakas, Marta Sølvi; Koivunen, Jussi Pekka; Oddershede, Lars & Yoon, Mie [Vis alle 9 forfattere av denne artikkelen] (2020). BRAF mutational status as a prognostic marker for survival in malignant melanoma: a systematic review and meta-analysis. Acta Oncologica. ISSN 0284-186X. s. 1–13. doi: 10.1080/0284186X.2020.1747636. Fulltekst i vitenarkiv Vis sammendrag

  Background: The analysis of the BRAF mutational status has been established as a standard procedure during diagnosis of advanced malignant melanoma due to the fact that BRAF inhibitors constitute a cornerstone in the treatment of metastatic disease. However, the general impact of BRAF mutational status on survival remains unclear. Our study aimed to assess the underlying prognostic significance of BRAF mutant versus wild type (WT) malignant melanoma on overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). Material and methods: A systematic literature search in EMBASE, Medline and Cochrane CENTRAL was performed. Studies were included if they reported survival outcomes for BRAF mutant versus WT patients as hazard ratios (HR) or in Kaplan-Meier (KM) curves. Random-effects meta-analysis models were used to pool HRs across the studies. Results: Data from 52 studies, representing 7519 patients, were pooled for analysis of OS. The presence of a BRAF mutation was statistically significantly associated with a reduced OS (HR [95% confidence interval (CI)]: 1.23 [1.09–1.38]), however, with substantial heterogeneity between the studies (I2: 58.0%). Meta-regression and sensitivity analyses showed that age, sex and BRAF mutation testing method did not have a significant effect on the OS HR. BRAF mutant melanoma showed comparable effect on DFS to non-BRAF mutant melanoma in stage I–III melanoma (combined HR: 1.16, 95% CI: 0.92–1.46), and on PFS in stage III–IV (HR: 0.98 (95% CI: 0.68−1.40)). Conclusion: Although there was substantial heterogeneity between the studies, the overall results demonstrated a poorer prognosis and OS in patients harbouring BRAF mutations. Future studies should take this into account when evaluating epidemiological data and treatment effects of new interventions in patients with malignant melanoma.

• Eikesdal, Hans Petter; Yndestad, Synnøve; Elzawahry, Asmaa; Llop-Guevara, Alba; Gilje, Bjørnar & Blix, Egil Støre [Vis alle 22 forfattere av denne artikkelen] (2020). Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Annals of Oncology. ISSN 0923-7534. 32(2), s. 1–10. doi: 10.1016/j.annonc.2020.11.009. Fulltekst i vitenarkiv Vis sammendrag

  Background The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure. Patients and methods In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples. Results The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response. Conclusion Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations. Trial registration ClinicalTrials.gov identifier: NCT02624973.

• Broberg, Agneta Månsson; Geisler, Jürgen; Tuohinen, Suvi; Skytta, Tanja; Hrafnkelsdóttir, Þórdís Jóna & Nielsen, Kirsten Melgaard [Vis alle 11 forfattere av denne artikkelen] (2020). Prevention, detection, and management of heart failure in patients treated for breast cancer. Current Heart Failure Reports. ISSN 1546-9530. 17(6), s. 397–408. doi: 10.1007/s11897-020-00486-8. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Purpose of Review Long-term survival has increased significantly in breast cancer patients, and cardiovascular side effects are surpassing cancer-related mortality. We summarize risk factors, prevention strategies, detection, and management of cardiotoxicity, with focus on left ventricular dysfunction and heart failure, during breast cancer treatment. Recent Findings Baseline treatment of cardiovascular risk factors is recommended. Anthracycline and trastuzumab treatment constitute a substantial risk of developing cardiotoxicity. There is growing evidence that this can be treated with beta blockers and angiotensin antagonists. Early detection of cardiotoxicity with cardiac imaging and circulating cardiovascular biomarkers is currently evaluated in clinical trials. Chest wall irradiation accelerates atherosclerotic processes and induces fibrosis. Immune checkpoint inhibitors require consideration for surveillance due to a small risk of severe myocarditis. Cyclin-dependent kinases4/6 inhibitors, cyclophosphamide, taxanes, tyrosine kinase inhibitors, and endocrine therapy have a lower-risk profile for cardiotoxicity. Summary Preventive and management strategies to counteract cancer treatment–related left ventricular dysfunction or heart failure in breast cancer patients should include a comprehensive cardiovascular risk assessment and individual clinical evaluation. This should include both patient and treatment-related factors. Further clinical trials especially on early detection, cardioprevention, and management are urgently needed.

• Kramer, Iris; Hooning, Maartje J.; Mavaddat, Nasim; Hauptmann, Michael; Keeman, Renske & Steyerberg, Ewout W. [Vis alle 54 forfattere av denne artikkelen] (2020). Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk. American Journal of Human Genetics. ISSN 0002-9297. 107(5), s. 837–848. doi: 10.1016/j.ajhg.2020.09.001. Fulltekst i vitenarkiv Vis sammendrag

  Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18–1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02–1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547–0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

• Tahiri, Andliena; Tekpli, Xavier; Somisetty, Venkata Satheesh; DeWijn, Rik; Luders, Torben & Bukholm, Ida Rashida Khan [Vis alle 9 forfattere av denne artikkelen] (2020). Loss of progesterone receptor is associated with distinct tyrosine kinase profiles in breast cancer. Breast Cancer Research and Treatment. ISSN 0167-6806. 183, s. 585–598. doi: 10.1007/s10549-020-05763-7. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Purpose The aim of this study was to assess protein tyrosine kinase profles in primary breast cancer samples in correlation with the distinct hormone and growth receptor profles ER, PR, and HER2. Experimental design Pamchip® microarrays were used to measure the phosphorylation of 144 tyrosine kinase substrates in 29 ER+breast cancer samples and cell lines MCF7, BT474 and ZR75-1. mRNA expression data from the METABRIC cohort and publicly available PR chip-sequencing data were used for validation purposes, together with RT-PCR. Results In ER+ breast tumors and cell lines, we observed that the loss of PR expression correlated to higher kinase activity in samples and cell lines that were HER2−. A number of kinases, representing mostly proteins within the PI3K/AKT pathway, were identifed as responsible for the diferential phosphorylation between PR− and PR+ in ER+/HER2− tumors. We used the METABRIC cohort to analyze mRNA expression from 977 ER+/HER2− breast cancers. Twenty four kinaseencoding genes were identifed as diferentially expressed between PR+ and PR−, dividing ER+/HER2− samples in two distinct clusters with signifcant diferences in survival (p<0.05). Four kinase genes, LCK, FRK, FGFR4, and MST1R, were identifed as potential direct targets of PR. Conclusions Our results suggest that the PR status has a profound efect on tyrosine kinases, especially for FGFR4 and LCK genes, in ER+/HER2− breast cancer patients. The infuence of these genes on the PI3K/AKT signaling pathway may potentially lead to novel drug targets for ER+/PR− breast cancer patients

• Nauclér, Cecilia Söderberg; Geisler, Jürgen & Vetvik, Katja K (2019). The emerging role of human cytomegalovirus infection in human carcinogenesis: a review of current evidence and potential therapeutic implications. OncoTarget. 10(42), s. 4333–4347. doi: 10.18632/oncotarget.27016. Fulltekst i vitenarkiv
• Langkjer, Sven Tyge; Kenholm, Julia; Jensen, Jeanette Dupont; Wedervang, Kim; Brixen, Annette Torbøl & Grunnet, Mie [Vis alle 16 forfattere av denne artikkelen] (2019). The NAME trial: a direct comparison of classical oral Navelbine versus metronomic Navelbine in metastatic breast cancer. Future Oncology. ISSN 1479-6694. 15(22), s. 2561–2569. doi: 10.2217/fon-2019-0124. Fulltekst i vitenarkiv Vis sammendrag

  Chemotherapy for metastatic breast cancer (MBC) is in general given in cycles of maximum tolerated doses to potentially maximize the therapeutic outcome. However, when compared with targeted therapies for MBC, conventional and dose intensified chemotherapy has caused only modest survival benefits during the recent decades, often compromising the quality of life considerably. Navelbine is an antineoplastic agent that has shown efficacy in the treatment of a variety of cancer types, including breast cancer. Early clinical trials involving both breast cancer and lung cancer patients suggest that metronomic dosing of Navelbine might be at least as effective as classical administration (once weekly, etc.). The NAME trial compares these two strategies of Navelbine administration in MBC patients.

• Bahrami, Nazli; Sauer, Torill; Engebretsen, Siri Strøm; Aljabri, Mohammad Belal; Bemanian, Vahid & Lindstrøm, Jonas Christoffer [Vis alle 17 forfattere av denne artikkelen] (2019). The NEOLETEXE trial: a neoadjuvant cross-over study exploring the lack of cross resistance between aromatase inhibitors. Future Oncology. ISSN 1479-6694. 15(32), s. 3675–3682. doi: 10.2217/fon-2019-0258. Fulltekst i vitenarkiv Vis sammendrag

  The aromatase inhibitor letrozole (Femar®) and the aromatase inactivator exemestane (Aromasin®) differ in their biochemical effect on the aromatase enzyme. Letrozole is a competitive aromatase inhibitor while exemestane binds irreversibly to the aromatase enzyme. This pharmacological difference is of clinical interest since a lack of cross-resistance has been documented. It has been demonstrated in several clinical trials that exemestane may cause a disease regression following resistance to nonsteroidal aromatase inhibitors. The exact mechanism(s) behind this phenomenon is yet unknown. Here, we present the NEOLETEXE trial with the aim of exploring the individual mechanisms involved behind the observed lack of cross resistance. Clinical trial registration: The trial has been approved by the Regional Ethics Committee of South-East Norway (project number 2015/84).

• Geisler, Jürgen; Touma, Joel; Rahbar, Afsar; Nauclér, Cecilia Söderberg & Vetvik, Katja K (2019). A review of the potential role of human cytomegalovirus (HCMV) infections in breast cancer carcinogenesis and abnormal immunity. Cancers. 11:1842(12), s. 1–13. doi: 10.3390/cancers11121842. Fulltekst i vitenarkiv Vis sammendrag

  Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15–20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in &gt;90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments.

• Costa, Helena; Touma, Joel Joul; Davoudi, Belghis; Benard, Melinda; Sauer, Torill & Geisler, Jürgen [Vis alle 9 forfattere av denne artikkelen] (2019). Human cytomegalovirus infection is correlated with enhanced cyclooxyrgenase-2 and 5-lipoxygenase protein expression in breast cancer. Journal of Cancer Research and Clinical Oncology. ISSN 0171-5216. 145(8), s. 2083–2095. doi: 10.1007/s00432-019-02946-8. Fulltekst i vitenarkiv

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• Vinje-Jakobsen, Victoria; Gynnild, Mari Nordbø; Mecinaj, Albulena; Wisløff, Torbjørn; Holte, Espen & Wethal, Torgeir [Vis alle 13 forfattere av denne artikkelen] (2026). The effect of sacubitril/valsartan on functional disability and skeletal muscle injury during breast cancer therapy: insights from the PRADA II trial. Fulltekst i vitenarkiv Vis sammendrag

  Background: Anthracycline therapy induces dose-dependent cardiotoxicity and systemic adverse effects, including functional disability. While sacubitril/valsartan attenuates early subclinical myocardial injury during breast cancer therapy, its impact on functional capacity and skeletal muscle injury remains unknown. Purpose: To evaluate whether sacubitril/valsartan attenuates anthracycline-induced decline in functional capacity and skeletal muscle injury compared to placebo. Methods: PRADA II was a randomised, double-blind, placebo-controlled multicentre trial including 138 women with early breast cancer receiving (neo)adjuvant anthracycline therapy±trastuzumab. Participants were randomised prior to anthracycline initiation to sacubitril/valsartan or placebo for 18 months. The predefined primary outcome of this substudy was change in maximal handgrip strength from baseline to 18 months. Secondary outcomes included changes in 6-minute walk distance and circulating creatine kinase (CK) and myoglobin concentrations. Assessments were performed at baseline, post-anthracycline (Visit 2), and at 18 months (Visit 3). Changes were analysed using generalised linear mixed models, and a two-sided alpha level of 0.05 was applied to the primary outcome of this predefined substudy. Results: Maximal handgrip strength declined in both groups from baseline to Visit 2, with partial recovery at Visit 3 in the sacubitril/valsartan group and continued decline in the placebo group. No significant between-group difference was observed in handgrip strength (between-group change from baseline to Visit 3: -0.3 kg, 95% CI -1.5 to 0.8, p=0.57). However, a greater decline from baseline to Visit 2 was observed with sacubitril/valsartan than placebo, corresponding to a between-group difference of -1.8 kg, 95% CI -3.0 to -0.6. 6-minute walk distance increased from baseline to both follow-up timepoints in the sacubitril/valsartan group, and a transient reduction was observed in the placebo group from baseline to Visit 2. Between-group changes did not differ at Visit 2 (8.8 m, 95% CI -19.3 to 36.9) or Visit 3 (13.6 m, 95% CI -13.3 to 40.5). CK and myoglobin were numerically higher in the placebo group from baseline to Visit 3, however, the confidence intervals for between-group differences included the null value (CK geometric mean ratio 1.17, 95% CI 0.94 to 1.45; myoglobin 1.10, 95% CI 0.98 to 1.23). Temporal changes by randomisation group are shown in Figure 1. Conclusions: Sacubitril/valsartan did not significantly attenuate anthracycline-related decline in functional capacity assessed by maximal handgrip strength and 6-minute walk distance or changes in biomarkers of skeletal muscle injury. These findings suggest a neutral effect of sacubitril/valsartan on functional capacity, without challenging its potential cardioprotective role during anthracycline therapy.

• Vinje-Jakobsen, Victoria; Orstad, Eivind Bjørkan; Gulati, Geeta; Nerdrum, Tone; Iqbal, Naveed & Schirmer, Henrik [Vis alle 9 forfattere av denne artikkelen] (2026). Incidence and severity of cancer-therapy-related cardiac dysfunction during contemporary breast cancer therapy in a real-world cohort. Fulltekst i vitenarkiv Vis sammendrag

  Background: Cancer therapy-related cardiac dysfunction (CTRCD) is a well-known complication in breast cancer patients exposed to anthracyclines and Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy. However, the incidence of CTRCD in unselected contemporary breast cancer populations treated according to current standard-of-care regimens remains incompletely investigated. Purpose: To determine the incidence of CTRCD in women receiving (neo-)adjuvant breast cancer therapy in a real-world setting. Methods: In this prospective observational study, women scheduled for (neo-)adjuvant breast cancer therapy were included. Participants were categorized into three treatment regimen groups: 1) anthracycline therapy only, 2) HER2-targeted therapy only, and 3) sequential treatment with anthracycline therapy followed by HER2-targeted therapy. The primary endpoint was the incidence of CTRCD, defined according to the echocardiographic criteria included in the 2022 ESC Cardio-Oncology Guidelines (Figure 1), from baseline to 12 months after completion of scheduled therapy. Echocardiography was assessed at baseline, after completion of scheduled therapy, and 12 months thereafter. In addition, echocardiography was performed every 3 months during HER2-targeted therapy and when clinically indicated. Results: In total, 515 women were included (median age: 53 years (IQR 45,64)). During follow-up, 123 (24%) developed CTRCD. Of these, 78% were classified as mild, 19% moderate, and 2% severe. The highest incidence of CTRCD was observed among participants receiving sequential anthracycline therapy (EC90 x 4) and HER2-targeted therapy (Table 1). This regimen also had the highest incidence of moderate and severe CTRCD (13%), compared with 4% in the anthracycline-only group and 1% in the HER2-only group. Overall, severe CTRCD was observed in 0.6% of all study participants. The cumulative incidence of the worst observed severity of CTRCD during follow-up, overall and by treatment regimen, is summarized in Table 1. Conclusion: In this real-world breast cancer cohort, nearly one in four women developed CTRCD during follow-up; however, most cases were categorised as mild. Moderate and severe cardiac dysfunction were primarily observed in patients receiving sequential anthracycline and HER2-targeted therapy. Severe CTRCD was rare in the overall study population.

• Vinje-Jakobsen, Victoria; Orstad, Eivind Bjørkan; Gulati, Geeta; Caliskan, Gulser; Nerdrum, Tone & Iqbal, Naveed [Vis alle 10 forfattere av denne artikkelen] (2026). Rationale, design and baseline characteristics of the cardio-oncology registry (CARE) study: a prospective, observational study of cardiotoxic effects during breast cancer therapy. European Heart Journal, Supplement. ISSN 1520-765X. 28(Supplement_8). doi: 10.1093/eurheartjsupp/suag097.103. Fulltekst i vitenarkiv Vis sammendrag

  Background: Anthracycline and Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy may induce cancer therapy-related cardiac dysfunction (CTRCD). Current guidelines recommend risk stratification using the Heart Failure Association–International Cardio-Oncology Society (HFA-ICOS) risk assessment tool. However, data on the incidence of CTRCD in contemporary breast cancer populations treated according to current standard-of-care regimens remain limited. Moreover, the actual cardiovascular risk associated with the HFA-ICOS risk categories in breast cancer treatment remains uncertain. Real-world evaluation of whether this consensus-based stratification appropriately separates patients according to subsequent CTRCD risk has been highlighted as a key research priority. Purpose: Overall, the study aims to determine the incidence of CTRCD and to evaluate cardiovascular risk stratification using the HFA-ICOS tool and its association with subsequent CTRCD. Methods: CARE is a prospective observational study including women scheduled for (neo)adjuvant anthracycline therapy and/or HER2-targeted therapy. Echocardiography, using standard and novel echocardiographic parameters, and circulating cardiac biomarkers were assessed at baseline (visit 1), after completion of scheduled therapy (visit 2), and 12 months after completion of scheduled therapy (visit 3). Participants were categorized into three treatment regimen groups: 1) Anthracycline therapy only, 2) HER2-targeted therapy only, and 3) HER2-targeted therapy sequentially to anthracyclines (Figure 1). The primary outcome is incidence of CTRCD. Secondary outcomes include HFA-ICOS risk stratification in relation to subsequent CTRCD. Results: In total, 515 women (median age (Q1,Q3): 53 (45,64) years) were included. Overall, 335 (63%) participants received anthracycline therapy only, 100 (15%) received HER2-targeted therapy only, and 80 (19%) received anthracycline therapy followed by HER2-targeted therapy. Baseline cardiovascular risk factors included hypertension in 20%, current smoking in 13%, diabetes in 7%, and a history of heart disease in 7.6%, while 3.5% had received previous anti-cancer treatment (Table 1). Conclusion: The CARE study is a large prospective observational cardio-oncology study evaluating the incidence of CTRCD after contemporary breast cancer therapy regimens. With systematic echocardiographic and biomarker assessment, the study will provide important insights into the incidence of CTRCD, the performance of the HFA-ICOS risk stratification tool and follow-up strategies in routine cardio-oncology care.Table 1Baseline Characteristics CARE  Figure 1Consort Diagram

• Gynnild, Mari Nordbø; Gulati, Geeta; Mecinaj, Albulena; Wethal, Torgeir; Holte, Espen & Vinje-Jakobsen, Victoria [Vis alle 11 forfattere av denne artikkelen] (2026). Baseline and early changes in cardiac biomarkers as predictors of global longitudinal strain deterioration during breast cancer therapy: a PRADAII substudy. Fulltekst i vitenarkiv Vis sammendrag

  Background: Cardiac biomarkers are recommended for risk stratification before and during potentially cardiotoxic cancer therapy, but the prognostic value of baseline levels and early changes for subsequent left ventricular (LV) dysfunction remains unclear. Objectives: To evaluate whether baseline and early changes in high-sensitivity cardiac troponins (hs-cTnI, hs-cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) predict changes in global longitudinal strain (GLS) over 18 months. Methods: In the randomized PRADAII, 138 women treated with anthracyclines (±trastuzumab) received sacubitril/valsartan or placebo and underwent serial biomarker sampling and cardiac imaging at baseline, post-anthracycline, and 18 months. Longitudinal changes in GLS and left ventricular ejection fraction (LVEF) were analyzed using adjusted linear mixed models, including exploratory analyses of combined, persistent, and peak biomarker elevations. Results: Mean age was 54.0±9.4 years. At baseline, no patients had hs-cTnI values above the sex-specific 99th percentile, 6 (4%) had hs-cTnT >99th percentile, and 16 (12%) had NT-proBNP >125 ng/L. Mean baseline GLS was −19.5±2.1% and CMR- and echocardiography-derived LVEF was 60.3±4.8% and 58.3±6.2%, respectively. GLS declined modestly over follow-up, with less deterioration in the sacubitril/valsartan group than in the placebo group (ΔΔ −1.26, 95% CI −2.19 to −0.33). Both hs-cTnI and hs-cTnT increased markedly after anthracycline therapy, with 16.7% and 71.7% exceeding the sex-specific 99th percentile at peak, whereas NT-proBNP showed modest changes with wide inter-individual variability. Transient and persistent troponin elevation occurred in 60.1% and 11.6%, respectively; corresponding NT-proBNP elevations in 5.1% and 7.3%, and combined troponin and NT-proBNP elevation in 9.4%. Baseline biomarker levels were not associated with GLS deterioration, and no biomarker–treatment interactions were observed (all p for interaction >0.27). Early post-anthracycline changes in hs-cTnI, hs-cTnT, or NT-proBNP were not predictive of subsequent GLS decline, nor were peak or persistent elevations (Table 1, Figure 1). No significant associations were observed between baseline or early biomarker levels and changes in LVEF assessed by echocardiography or CMR. Conclusions: In our breast cancer cohort with preserved baseline LV function, baseline levels and early changes in hs-cTnI, hs-cTnT, and NT-proBNP were not associated with subsequent deterioration in GLS over 18 months. Larger studies including higher-risk patients and clinical endpoints are needed to clarify the role of cardiac biomarkers in individualized cardiotoxicity risk stratification.

• Gynnild, Mari Nordbø; Gulati, Geeta; Mecinaj, Albulena; Wethal, Torgeir; Holte, Espen & Vinje-Jakobsen, Victoria [Vis alle 11 forfattere av denne artikkelen] (2026). Baseline and early changes in cardiac biomarkers as predictors of global longitudinal strain deterioration during breast cancer therapy: a PRADAII substudy. European Heart Journal, Supplement. ISSN 1520-765X. 28(Supplement_8). doi: 10.1093/eurheartjsupp/suag097.089. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Cardiac biomarkers are recommended for risk stratification before and during potentially cardiotoxic cancer therapy, but the prognostic value of baseline levels and early changes for subsequent left ventricular (LV) dysfunction remains unclear. Objectives To evaluate wheter baseline and early changes in high-sensitivity cardiac troponins (hs-cTnI, hs-cTnT) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) predict changes in global longitudinal strain (GLS) over 18 months. Methods In the randomized PRADAII, 138 women treated with anthracyclines (±trastuzumab) received sacubitril/valsartan or placebo and underwent serial biomarker sampling and cardiac imaging at baseline, post-anthracycline, and 18 months. Longitudinal changes in GLS and left ventricular ejection fraction (LVEF) were analyzed using adjusted linear mixed models, including exploratory analyses of combined, persistent, and peak biomarker elevations. Results Mean age was 54.0±9.4 years. At baseline, no patients had hs-cTnI values above the sex-specific 99th percentile, 6 (4%) had hs-cTnT &gt;99th percentile, and 16 (12%) had NT-proBNP &gt;125 ng/L. Mean baseline GLS was −19.5±2.1% and CMR- and echocardiography-derived LVEF was 60.3±4.8% and 58.3±6.2%, respectively. GLS declined modestly over follow-up, with less deterioration in the sacubitril/valsartan group than in the placebo group (ΔΔ −1.26, 95% CI −2.19 to −0.33). Both hs-cTnI and hs-cTnT increased markedly after anthracycline therapy, with 16.7% and 71.7% exceeding the sex-specific 99th percentile at peak, whereas NT-proBNP showed modest changes with wide inter-individual variability. Transient and persistent troponin elevation occurred in 60.1% and 11.6%, respectively; corresponding NT-proBNP elevations in 5.1% and 7.3%, and combined troponin and NT-proBNP elevation in 9.4%. Baseline biomarker levels were not associated with GLS deterioration, and no biomarker–treatment interactions were observed (all p for interaction &gt;0.27). Early post-anthracycline changes in hs-cTnI, hs-cTnT, or NT-proBNP were not predictive of subsequent GLS decline, nor were peak or persistent elevations (Table 1, Figure 1). No significant associations were observed between baseline or early biomarker levels and changes in LVEF assessed by echocardiography or CMR. Conclusions In our breast cancer cohort with preserved baseline LV function, baseline levels and early changes in hs-cTnI, hs-cTnT, and NT-proBNP were not associated with subsequent deterioration in GLS over 18 months. Larger studies including higher-risk patients and clinical endpoints are needed to clarify the role of cardiac biomarkers in individualized cardiotoxicity risk stratification.  

• Lee, Stephanie; Tahiri, Andliena; Gjesdal, Kjell Inge; Lüders, Torben; Reitsma, Laurens Cornelus & Lyngra, Marianne [Vis alle 10 forfattere av denne artikkelen] (2025). Radiogenomics during neoadjuvant therapy with aromatase inhibitors: integrating dynamic magnetic resonance data and molecular biology. Clinical Cancer Research. ISSN 1078-0432. 31(12_Supplement), s. 01–01. doi: 10.1158/1557-3265.sabcs24-p1-01-07. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background: Neoadjuvant treatment of locally advanced breast cancer (LABC) is now well-established and considerable progress has been made concerning drug development for subgroups of patients. However, reliable predictive markers are still lacking for many patients. Thus, radiological measures like repeated MRI of the breast and axilla, after 3 and 6 months of therapy, are used to follow the patients during neoadjuvant therapy to confirm successful downstaging. Although not established in clinical routine, dynamic MRI contains quantitative information that can provide valuable insight into the tumour microenvironment and, when combined with clinical and molecular data, has the potential to enhance the prediction of tumor responses. Here, we analyze split-dynamic MRI data in relation to clinicopathological and molecular data to further identify disease heterogeneity that can be used to improve prognostic accuracy and inform treatment decisions in breast cancer patients. Methods: This study reports results from eligible patients with ER pos., HER2 neg. LABC that were enrolled in the NEOLETEXE-trial (1). Clinicopathological, molecular, and advanced MRI data were acquired from this trial, collected before, during, and after neoadjuvant endocrine therapy (NET) with aromatase inhibitors given in sequence. MR images were generated using a split-dynamic technique that simultaneously acquires high spatial resolution and high temporal resolution images, providing information on tissue permeability and vascularity. The images underwent post-processing on the nordicICE software where parametric values were extracted based on whole-tumour volumes of interest. These parametric values were analysed in correlation with clinico-pathological data and with molecular findings from bulk RNA-seq and single cell data from a subset of the same patients. Results: From the kinetic MRI data, the volume transfer constant (Ktrans), a parameter reflecting capillary permeability, was significantly reduced after NET (p = 0.005). Bulk RNA-seq data was analysed for gene expression, pathway involvement, and cell type abundance before, during, and after treatment. Gene expression analysis revealed significant dysregulation of genes related to cell proliferation and cell cycle regulation following treatment. Biological pathway analysis revealed significant down-regulation of hemostatic activity and upregulation of cell cycle and interleukin signaling following treatment. Cell type analysis revealed a higher abundance of CD4+ T-cells and T-helper cells following treatment. These results will be further correlated with single cell data as well as measures of treatment response and clinical outcome. Conclusions: Our findings suggest that the addition of MRI data to clinicopathological and molecular data enhances the characterization of tumor responses during NET for locally advanced breast cancer. 1. The NEOLETEXE trial: a neoadjuvant cross-over study exploring the lack of cross resistance between aromatase inhibitors. Bahrami N. et al., Future Oncoloy 15 (32), 3675-3682, 2019. Citation Format: Stephanie Lee, Andliena Tahiri, Kjell-Inge Gjesdal, Torben Lüders, Laurens Reitsma, Marianne Lyngra, Alvaro Köhn-Luque, Vessela Kristensen, Jürgen Geisler, Jonn Terje Geitung. Radiogenomics during neoadjuvant therapy with aromatase inhibitors: integrating dynamic magnetic resonance data and molecular biology [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-01-07.

• Nawaz, Meh Sameen; Minh, Hang; Jabeen, Shakila; Bjørnetrø, Tonje; Geisler, Jürgen & Kristensen, Vessela N. [Vis alle 7 forfattere av denne artikkelen] (2025). Extracellular Vesicle-Associated Cytokines as Novel Biomarkers in ER+ Breast Cancer. Fulltekst i vitenarkiv
• Eide, Nils; Noer, Agate; Jespersen, Henrik; Jebsen, Peter Wilhelm & Geisler, Jürgen (2024). Delayed Distant Recurrence of a Uveal Melanoma 4 Decades after Enucleation. Case Reports in Oncology. 17(1), s. 1131–1139. doi: 10.1159/000541341. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: This report presents a case of an exceptionally delayed distant recurrence of a choroidal melanoma, occurring 4 decades after the enucleation of the affected eye. Case Presentation: In 1977, a 29-year-old man underwent enucleation for a choroidal melanoma. At the age of 68 years, he was diagnosed with advanced prostate cancer. Although the metastatic prostate cancer responded to treatment, a persistent lung lesion warranted further examination. A lung biopsy, somewhat surprisingly, confirmed the presence of melanoma metastasis, 4 decades after the enucleation. The cells were positive for Melan-A, while no BRAF mutation was identified. Two years later, new lesions appeared in the liver, and CT showed progression with multiple new sites. A liver biopsy revealed again melanoma recurrence, and its choroidal origin was verified by the presence of a GNA11 mutation. The patient underwent radiation therapy for the lung and liver lesions, followed by immunotherapy. However, the patient died 11 months after the recurrence in the liver. In this case report, the micrometastatic melanoma cells appear to have remained dormant for an extended period, before the patient’s treatment in 1977, but the reason for the late reactivation from the dormant state remains unclear. Conclusion: The recurrence of a choroidal melanoma is substantiated by the histopathological and molecular analyses, including the finding of a GNA11 mutation. This case exemplifies a remarkably delayed distant recurrence of a choroidal melanoma, which manifested clinically 40 years following enucleation.

• Fjermeros, Kamilla; Ghannoum, Salim; Geisler, Stephanie; Bhargava, Sameer; Tahiri, Andliena & Klajic, Jovana [Vis alle 32 forfattere av denne artikkelen] (2024). The NEOLETRIB trial: neoadjuvant treatment with Letrozole and Ribociclib in ER-positive, HER2-negative breast cancer. Future Oncology. ISSN 1479-6694. 20(32), s. 2457–2466. doi: 10.1080/14796694.2024.2377531. Fulltekst i vitenarkiv Vis sammendrag

  Chemotherapy is used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. However, studies have suggested that using aromatase inhibitors combined with CDK4/6-inhibitors might be an appropriate alternative in selected patients. Thus, the NEOLETRIB trial evaluates the response of ER-positive, HER2-negative luminal A/B breast cancer to the combination of letrozole and ribociclib in the neoadjuvant setting. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Our findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination and give new insights into the intra-tumoral changes during this treatment.

• Giskeødegård, Guro F.; Wang, Feng; Sauer, Torill; Selsås, Knut; Geisler, Jürgen & Bathen, Tone Frost (2023). Changes in serum metabolic profiles during breast cancer treatment with aromatase inhibitors. Fulltekst i vitenarkiv
• Giskeødegård, Guro F.; Wang, Feng; Sauer, Torill; Selsås, Knut; Geisler, Jürgen & Bathen, Tone Frost (2023). Changes in serum metabolic profiles during breast cancer treatment with aromatase inhibitors. Fulltekst i vitenarkiv
• Vinje, Victoria; Cao, Shu-qin; Heck, Siri Lagethon; Wisløff, Torbjørn; Klæboe, Lars Gunnar & Nilsen, Hilde Loge [Vis alle 9 forfattere av denne artikkelen] (2023). Rationale And Design Of The NARNIA Trial: The Effect Of NicotinAmide Riboside ON Myocardial And Skeletal Muscle Injury And Function In Patients With Metastatic Breast Cancer Receiving Anthracyclines. Fulltekst i vitenarkiv
• Wang, Feng; Giskeødegård, Guro F.; Skarra, Sissel; Engstrøm, Monica Jernberg; Hagen, Lars & Geisler, Jürgen [Vis alle 10 forfattere av denne artikkelen] (2022). Association of serum steroid hormone concentrations with endocrine treatment resistance in patients with breast cancer. Fulltekst i vitenarkiv
• Eikeland, Eline; Giskeødegård, Guro F.; Reidunsdatter, Randi Johansen; Engstrøm, Monica Jernberg; Hagen, Lars & Geisler, Jürgen [Vis alle 10 forfattere av denne artikkelen] (2022). Liquid Chromatography-Tandem Mass Spectrometry Analysis of Steroid Hormones in Serum and Breast Cancer Tissue. Fulltekst i vitenarkiv
• Schandiz, Hossein; Park, Daehoon; Kaiser, Yan Liu; Lyngra, Marianne; Talleraas, Ingrid Solvang & Geisler, Jürgen [Vis alle 7 forfattere av denne artikkelen] (2022). A novel diagnostics approach to Ductal Carcinoma In Situ (DCIS) with potential impact on the therapeutic algorithms. Cancer Prevention Research. ISSN 1940-6207. 15(12 Supplement 1; abstract A015). Fulltekst i vitenarkiv
• Reis, Joana; Lindstrøm, Jonas; Boavida, João; Gjesdal, Kjell-Inge; Sauer, Torill & Geisler, Jürgen [Vis alle 7 forfattere av denne artikkelen] (2021). Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: Comprehensive imaging analysis and correlation with clinical and pathological assessments. Fulltekst i vitenarkiv
• Broberg, Agneta Månsson; Tuohinen, Suvi; Skytta, Tanja; Geisler, Jürgen; Hrafnkelsdóttir, þórdís Jóna & Smáradóttir, Agnes [Vis alle 10 forfattere av denne artikkelen] (2020). The Establishment of the Nordic Cardio-Oncology Society. JACC: CardioOncology. 2(2), s. 333–335. doi: 10.1016/j.jaccao.2020.04.004. Fulltekst i vitenarkiv
• Reis, Joana; Kristiansen, Cathrine Helgestad; Boavida, João; Lindstrøm, Jonas Christoffer; Sauer, Torill & Geisler, Jürgen [Vis alle 7 forfattere av denne artikkelen] (2020). Dual-layer spectral detector CT: Clinical performance in patients with locally advanced breast cancer treated neoadjuvant with aromatase inhibitors. Annals of Oncology. ISSN 0923-7534. Fulltekst i vitenarkiv
• Bahrami, Nazli; Jabeen, Shakila; Sauer, Torill; Kristensen, Vessela N.; Gundersen, Joanna M. & Geisler, Jürgen (2019). The aromatase inactivator exemestane suppresses serum leptin levels significantly in vivo - in contrast to the aromatase inhibitor letrozole. Fulltekst i vitenarkiv
• Eikesdal, Hans Petter; Yndestad, Synnøve; Blix, Egil Støre; Lundgren, Steinar; Vagstad, Geirfinn & Espelid, Helge [Vis alle 13 forfattere av denne artikkelen] (2019). Neoadjuvant olaparib monotherapy in primary triple negative breast cancer. Fulltekst i vitenarkiv
• Eikesdal, Hans Petter; Clausen, Christina; Blix, Egil Støre; Lundgren, Steinar; Vagstad, Geirfinn & Espelid, Helge [Vis alle 13 forfattere av denne artikkelen] (2019). Neoadjuvant endocrine therapy with palbociclib in patients with high-risk breast cancer. Fulltekst i vitenarkiv

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