Publications by authors named "Lars A Akslen"

191 Publications

Detection and significance of small and low proliferation breast cancer.

J Med Screen 2021 Jun 22:9691413211023970. Epub 2021 Jun 22.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

Objectives: To determine the frequency and discuss possible implications of early breast cancer with particularly good prognosis and defined by tumor diameter and cell proliferation.

Setting: Detection of small and slowly growing tumors presents a challenge in breast cancer management, due to the risk of over-treatment. Here, we attempted to define a group of such tumors by combining small diameter (≤10 mm, T1ab tumors) with low tumor cell proliferation (≤10% Ki67 expression rate). These tumors were termed small low proliferation cancers (SLPC).

Methods: Two population-based cohorts were studied: a small research series ( = 534), and a nation-wide registry-based series of prospectively collected routine data ( = 8433). In the latter, we stratified by detection mode; screen-detected, interval, and breast cancers detected outside of screening. Patients were treated according to national guidelines at time of their diagnosis. For both cohorts, we compared tumor histopathology and risk of breast cancer death using a log-rank test for cases with SLPC versus non-SLPC.

Results: In the research series (median follow-up 151 months), the frequency of SLPC was 10% (54/534), with one breast cancer death compared with 78 among the remaining 480 cases of non-SLPC ( = 0.008). In the registry series (median follow-up 42 months), the frequency of SLPC was 10% (854/8433), with five deaths compared to 187 among the remaining 7579 cases ( = 0.0004).

Conclusions: SLPC was associated with very low risk of breast cancer death. Prospective randomized trials are needed to clarify whether less aggressive treatment could be a safe option for women with such early breast cancers.
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http://dx.doi.org/10.1177/09691413211023970DOI Listing
June 2021

Tumor-associated lymphocytes and macrophages are related to stromal elastosis and vascular invasion in breast cancer.

J Pathol Clin Res 2021 Sep 2;7(5):517-527. Epub 2021 Jun 2.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

The tumor microenvironment plays a critical role in breast cancer progression. Here, we investigated tumor-infiltrating lymphocytes (TILs) and associations with macrophage numbers, tumor stromal elastosis, vascular invasion, and tumor detection mode. We performed a population-based retrospective study using data from The Norwegian Breast Cancer Screening Program in Vestfold County (2004-2009), including 200 screen-detected and 82 interval cancers. The number of TILs (CD45+, CD3+, CD4+, CD8+, and FOXP3+) and tumor-associated macrophages (CD163+) was counted using immunohistochemistry on tissue microarray slides. Lymphatic and blood vessel invasion (LVI and BVI) were recorded using D2-40 and CD31 staining, and the amount of elastosis (high/low) was determined on regular HE-stained slides. High numbers of all TIL subsets were associated with LVI (p ≤ 0.04 for all), and high counts of several TIL subgroups (CD8+, CD45+, and FOXP3+) were associated with BVI (p ≤ 0.04 for all). Increased levels of all TIL subsets, except CD4+, were associated with estrogen receptor-negative tumors (p < 0.001) and high tumor cell proliferation by Ki67 (p < 0.001). Furthermore, high levels of all TIL subsets were associated with high macrophage counts (p < 0.001) and low-grade stromal elastosis (p ≤ 0.02). High counts of CD3+, CD8+, and FOXP3+ TILs were associated with interval detected tumors (p ≤ 0.04 for all). Finally, in the luminal A subgroup, high levels of CD3+ and FOXP3+ TILs were associated with shorter recurrence-free survival, and high counts of FOXP3+ were linked to reduced breast cancer-specific survival. In conclusion, higher levels of different TIL subsets were associated with stromal features such as high macrophage counts (CD163+), presence of vascular invasion, absence of stromal elastosis, as well as increased tumor cell proliferation and interval detection mode. Our findings support a link between immune cells and vascular invasion in more aggressive breast cancer. Notably, presence of TIL subsets showed prognostic value within the luminal A category.
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http://dx.doi.org/10.1002/cjp2.226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363927PMC
September 2021

Interval and Subsequent Round Breast Cancer in a Randomized Controlled Trial Comparing Digital Breast Tomosynthesis and Digital Mammography Screening.

Radiology 2021 07 11;300(1):66-76. Epub 2021 May 11.

From the Cancer Registry of Norway, PO 5313, Maiorstuen, 0304 Oslo, Norway (S.H., N.M., Å.S.H., A.S.D.); Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway (S.H.); Department of Radiology, University of Washington School of Medicine, Seattle, Wash (C.I.L.); Department of Health Services, University of Washington School of Public Health, Seattle, Wash (C.I.L.); Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, Australia (N.H.); Department of Radiology (H.S.A., I.S.H.), Department of Pathology (L.A.A.), and Mohn Medical Imaging and Visualization Centre (I.S.H.), Haukeland University Hospital, Bergen, Norway; and Department of Clinical Medicine (H.S.A., I.S.H.), Section for Pathology (L.A.A.), and Centre for Cancer Biomarkers CCBIO (L.A.A.), University of Bergen, Bergen, Norway.

Background Prevalent digital breast tomosynthesis (DBT) has shown higher cancer detection rates and lower recall rates compared with those of digital mammography (DM). However, data are limited on rates and histopathologic tumor characteristics of interval and subsequent round screen-detected cancers for DBT. Purpose To follow women randomized to screening with DBT or DM and to investigate rates and tumor characteristics of interval and subsequent round screen-detected cancers. Materials and Methods To-Be is a randomized controlled trial comparing the outcome of DBT and DM in organized breast cancer screening. The trial included 28 749 women, with 22 306 women returning for subsequent DBT screening 2 years later (11 201 and 11 105 originally screened with DBT and DM, respectively). Differences in rates, means, and distribution of histopathologic tumor characteristics between women prevalently screened with DBT versus DM were evaluated with Z tests, tests, and χ tests. Relative risk (RR) with 95% CIs was calculated for the cancer rates. Results Interval cancer rates were 1.4 per 1000 screens (20 of 14 380; 95% CI: 0.9, 2.1) for DBT versus 2.0 per 1000 screens (29 of 14 369; 95% CI: 1.4, 2.9; = .20) for DM. The rates of subsequent round screen-detected cancer were 8.1 per 1000 (95% CI: 6.6, 10.0) for women originally screened with DBT and 9.1 per 1000 (95% CI: 7.4, 11.0; = .43) for women screened with DM. The distribution of tumor characteristics did not differ between groups for either interval or subsequent screen-detected cancer. The RR of interval cancer was 0.69 (95% CI: 0.39, 1.22; = .20) for DBT versus DM, whereas RR of subsequent screen-detected cancer for women prevalently screened with DBT versus DM was 0.89 (95% CI: 0.67, 1.19; = .43). Conclusion Rates of interval or subsequent round screen-detected cancers and their tumor characteristics did not differ between women originally screened with digital breast tomosynthesis (DBT) versus digital mammography. The analysis suggests that the benefits of prevalent DBT screening did not come at the expense of worse downstream screening performance measures in a population-based screening program. © RSNA, 2021 See also the editorial by Taourel in this issue.
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http://dx.doi.org/10.1148/radiol.2021203936DOI Listing
July 2021

High PDGFRb Expression Predicts Resistance to Radiotherapy in DCIS within the SweDCIS Randomized Trial.

Clin Cancer Res 2021 Jun 5;27(12):3469-3477. Epub 2021 May 5.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Purpose: This study analyzes the potential of stromal platelet-derived growth factor receptor-beta (PDGFRb) expression as biomarker for radiotherapy (RT) benefit on ipsilateral breast events (IBE) in ductal carcinoma (DCIS). Improved identification of DCIS patients refractory to adjuvant whole-breast RT is needed. Predictive biomarker studies in DCIS have focused on tumor cell features rather than the tumor-associated stroma, despite growing evidence of its influence on therapy efficiency.

Experimental Design: Samples from the Swedish randomized radiotherapy DCIS trial (SweDCIS) were subjected to IHC analysis for stromal PDGFRb expression. IBE incidence at 10 years after breast-conserving surgery was the primary endpoint. Interactions between marker and treatment were analyzed.

Results: PDGFRb score was predictive for RT benefit with regard to IBE ( = 0.002 and = 0.008 adjusted multivariably). Patients of the PDGFRb group had a strong benefit from RT regarding IBE risk [HR, 0.23; 95% confidence interval (CI), 0.12-0.45; < 0.001] with an absolute risk reduction of 21% (cumulative risk 7% vs. 28%) at 10 years. No significant risk reduction by RT was observed for patients of the PDGFRb group (HR, 0.83; 0.51-1.34; = 0.444; cumulative risk 22% vs. 25%). The RT response-predictive effect of stromal PDGFRb was equally strong in analyses for and invasive IBE when analyzed separately ( IBE: = 0.029; invasive IBE: = 0.044).

Conclusions: Results suggest high stromal PDGFRb expression as a novel biomarker identifying DCIS patients who are refractory to standard whole-breast adjuvant RT. The data imply previously unrecognized fibroblast-mediated modulation of radiosensitivity of DCIS, which should be further explored from mechanistic and targeting perspectives.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4300DOI Listing
June 2021

Fibulin-2 expression associates with vascular invasion and patient survival in breast cancer.

PLoS One 2021 9;16(4):e0249767. Epub 2021 Apr 9.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

Stromal elastosis is related to good prognosis in breast cancer and fibulin-2 helps to stabilize elastic fibers in basement membranes. Here, we examined the level of perivascular fibulin-2 expression in relation to elastosis content, vascular invasion, molecular subtypes, tumour detection mode, and patient prognosis in breast cancer. We performed a population based retrospective study of invasive breast cancers from the Norwegian Breast Screening Program (Vestfold County, 2004-2009) including 200 screen-detected and 82 interval cancers. Perivascular fibulin-2 staining was semi-quantitatively graded based on immunohistochemistry (1-3) and dichotomized as high expression (grade 2-3) and low expression (grade 1). Elastosis content was graded on a 4-tiered scale and dichotomized as high (score 3) and low (score 0-2) expression, whereas lymphatic (LVI) and blood vessel invasion (BVI) were recorded as absent or present by immunohistochemistry. High perivascular fibulin-2 expression was strongly related to stromal elastosis (p<0.001), and inversely associated with BVI and LVI (p<0.001 for both). High fibulin-2 was associated with luminal breast cancer subgroups (p<0.001) and inversely with interval cancers compared with screen-detected tumours (p<0.001). By univariate analysis, low perivascular fibulin-2 was associated with reduced recurrence-free survival (p = 0.002) and disease specific survival (p = 0.019). Low perivascular fibulin-2 expression was strongly related to vascular invasion, low stromal elastosis, non-luminal breast cancer subtypes, interval presentation, and adverse prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249767PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034712PMC
October 2021

The epithelial-mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients.

J Pathol Clin Res 2021 May 19;7(3):253-270. Epub 2021 Feb 19.

Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

The prognostic importance of transcription factors promoting epithelial-mesenchymal transition (EMT) and angiogenesis has not been well explored in prostate cancer patients with long follow-up, nor the interplay between these factors. The objective of this study was to assess the individual protein expression and co-expression of Twist, Slug (Snai2), Snail (Snai1), and hypoxia-inducible factor-1 alpha (Hif-1α) in prostate cancer in relation to EMT, angiogenesis, hypoxia, tumour features, disease recurrence, and patient survival. Immunohistochemical staining was performed on tissue microarray sections from 338 radical prostatectomies with long follow-up. In addition, 41 cases of prostatic hyperplasia, 33 non-skeletal metastases, 13 skeletal metastases, and 33 castration-resistant prostate carcinomas were included. Our findings were validated in external gene expression data sets. Twist was overexpressed in primary prostate cancer and markedly reduced in distant metastases (p < 0.0005). Strong expression of Twist and Slug was associated with Hif-1α in localised prostate cancer (p ≤ 0.001), and strong Twist was associated with Hif-1α in castration-resistant carcinomas (p = 0.044). Twist, Slug, and increased Snail at the tumour stromal border were associated with vascular factors (p ≤ 0.045). Each of the three EMT-regulating transcription factors were associated with aggressive tumour features and shorter time to recurrence and cancer-specific death. Notably, the co-expression of factors demonstrated an enhanced influence on outcome. In the subgroup of E-cadherin carcinomas, strong Slug was associated with shorter time to all end points and was an independent predictor of time to multiple end points, including cancer-specific death (hazard ratio 3.0, p = 0.041). To conclude, we demonstrate an important relation between EMT, hypoxia, and angiogenesis and a strong link between the investigated EMT regulators and aggressive tumour features and poor patient outcome in prostate cancer. Despite the retrospective nature of this long-term study, our findings could have a significant impact on the future treatment of prostate cancer, where tailored therapies might be directed simultaneously against epithelial-mesenchymal phenotypes, angiogenesis, and tumour hypoxia.
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http://dx.doi.org/10.1002/cjp2.202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073012PMC
May 2021

Baseline microvessel density predicts response to neoadjuvant bevacizumab treatment of locally advanced breast cancer.

Sci Rep 2021 02 9;11(1):3388. Epub 2021 Feb 9.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, Haukeland University Hospital, University of Bergen, Bergen, Norway.

A subset of breast cancer patients benefits from preoperative bevacizumab and chemotherapy, but validated predictive biomarkers are lacking. Here, we aimed to evaluate tissue-based angiogenesis markers for potential predictive value regarding response to neoadjuvant bevacizumab treatment in breast cancer. In this randomized 1:1 phase II clinical trial, 132 patients with large or locally advanced HER2-negative tumors received chemotherapy ± bevacizumab. Dual Factor VIII/Ki-67 immunohistochemical staining was performed on core needle biopsies at baseline and week 12. Microvessel density (MVD), proliferative microvessel density (pMVD; Factor VIII/Ki-67 co-expression), glomeruloid microvascular proliferation (GMP), and a gene expression angiogenesis signature score, were studied in relation to pathologic complete response (pCR), clinico-pathologic features and intrinsic molecular subtype. We found that high baseline MVD (by median) significantly predicted pCR in the bevacizumab-arm (odds ratio 4.9, P = 0.012). High pMVD, presence of GMP, and the angiogenesis signature score did not predict pCR, but were associated with basal-like (P ≤ 0.009) and triple negative phenotypes (P ≤ 0.041). pMVD and GMP did also associate with high-grade tumors (P ≤ 0.048). To conclude, high baseline MVD significantly predicted response to bevacizumab treatment. In contrast, pMVD, GMP, and the angiogenesis signature score, did not predict response, but associated with aggressive tumor features, including basal-like and triple-negative phenotypes.
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http://dx.doi.org/10.1038/s41598-021-81914-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873274PMC
February 2021

AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer.

iScience 2020 Nov 7;23(11):101649. Epub 2020 Oct 7.

Department of Biomedicine, University of Bergen, 5021 Bergen, Norway.

The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation . -null mice did not exhibit a strong developmental phenotype, but enrichment of cells was required for mouse mammary gland reconstitution upon transplantation, and null mice had reduced incidence of driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.
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http://dx.doi.org/10.1016/j.isci.2020.101649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578759PMC
November 2020

CD24-targeted fluorescence imaging in patient-derived xenograft models of high-grade serous ovarian carcinoma.

EBioMedicine 2020 Jun 23;56:102782. Epub 2020 May 23.

Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Jonas Lies vei 91B, 5021 Bergen, Norway. Electronic address:

Background: The survival rate of patients with advanced high-grade serous ovarian carcinoma (HGSOC) remains disappointing. Clinically translatable orthotopic cell line xenograft models and patient-derived xenografts (PDXs) may aid the implementation of more personalised treatment approaches. Although orthotopic PDX reflecting heterogeneous molecular subtypes are considered the most relevant preclinical models, their use in therapeutic development is limited by lack of appropriate imaging modalities.

Methods: We developed novel orthotopic xenograft and PDX models for HGSOC, and applied a near-infrared fluorescently labelled monoclonal antibody targeting the cell surface antigen CD24 for non-invasive molecular imaging of epithelial ovarian cancer. CD24-Alexa Fluor 680 fluorescence imaging was compared to bioluminescence imaging in three orthotopic cell line xenograft models of ovarian cancer (OV-90, Skov-3 and Caov-3, n = 3 per model). The application of fluorescence imaging to assess treatment efficacy was performed in carboplatin-paclitaxel treated orthotopic OV-90 xenografts (n = 10), before the probe was evaluated to detect disease progression in heterogenous PDX models (n = 7).

Findings: Application of the near-infrared probe, CD24-AF680, enabled both spatio-temporal visualisation of tumour development, and longitudinal therapy monitoring of orthotopic xenografts. Notably, CD24-AF680 facilitated imaging of multiple PDX models representing different histological subtypes of the disease.

Interpretation: The combined implementation of CD24-AF680 and orthotopic PDX models creates a state-of-the-art preclinical platform which will impact the identification and validation of new targeted therapies, fluorescence image-guided surgery, and ultimately the outcome for HGSOC patients.

Funding: This study was supported by the H2020 program MSCA-ITN [675743], Helse Vest RHF, and Helse Bergen HF [911809, 911852, 912171, 240222, HV1269], as well as by The Norwegian Cancer Society [182735], and The Research Council of Norway through its Centers of excellence funding scheme [223250, 262652].
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http://dx.doi.org/10.1016/j.ebiom.2020.102782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248428PMC
June 2020

Exploring the effects of lifestyle on breast cancer risk, age at diagnosis, and survival: the EBBA-Life study.

Breast Cancer Res Treat 2020 Jul 20;182(1):215-227. Epub 2020 May 20.

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

Purpose: Whether an unfavorable lifestyle not only affects breast cancer risk, but also influences age at onset of breast cancer and survival, is under debate.

Methods: In a population-based cohort, the Energy Balance and Breast Cancer Aspects throughout life (EBBA-Life) study, a total of 17,145 women were included. During follow-up, 574 women developed invasive breast cancer. Breast cancer cases were followed for an additional 9.1 years. Detailed medical records were obtained. Cox's proportional hazard regression models were used to study the association between pre-diagnostic lifestyle factors (weight, physical activity, alcohol use, smoking, and hypertension), breast cancer risk, age at diagnosis, and survival.

Results: At study entry, 34.3% of the participating women were overweight and 30.7% were physically inactive. Mean age at breast cancer diagnosis was 58.0 years, and 78.9% of the tumors were estrogen receptor positive. Among menopausal women who did not use hormone therapy and had an unfavorable lifestyle (3-5 unfavorable factors), compared with women who had a favorable lifestyle, we observed a twofold higher risk for postmenopausal breast cancer (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.23-3.69), and they were 3.4 years younger at diagnosis (64.8 versus 68.2 years, P = 0.032). Breast cancer patients with an unfavorable lifestyle, compared with patients with a favorable lifestyle, had almost a two times higher overall mortality risk (HR 1.96, 95% CI 1.01-3.80).

Conclusions: Our study supports a healthy lifestyle improving breast cancer prevention, postponing onset of disease, and extending life expectancy among breast cancer patients.
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http://dx.doi.org/10.1007/s10549-020-05679-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275030PMC
July 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Stathmin expression associates with vascular and immune responses in aggressive breast cancer subgroups.

Sci Rep 2020 02 19;10(1):2914. Epub 2020 Feb 19.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, N-5021, Norway.

Studies indicate that stathmin expression associates with PI3K activation in breast cancer, suggesting stathmin as a marker for targetable patient subgroups. Here we assessed stathmin in relation to tumour proliferation, vascular and immune responses, BRCA1 germline status, basal-like differentiation, clinico-pathologic features, and survival. Immunohistochemical staining was performed on breast cancers from two series (cohort 1, n = 187; cohort 2, n = 198), and mass spectrometry data from 24 cases and 12 breast cancer cell lines was examined for proteomic profiles. Open databases were also explored (TCGA, METABRIC, Oslo2 Landscape cohort, Cancer Cell Line Encyclopedia). High stathmin expression associated with tumour proliferation, p53 status, basal-like differentiation, BRCA1 genotype, and high-grade histology. These patterns were confirmed using mRNA data. Stathmin mRNA further associated with tumour angiogenesis, immune responses and reduced survival. By logistic regression, stathmin protein independently predicted a BRCA1 genotype (OR 10.0, p = 0.015) among ER negative tumours. Cell line analysis (Connectivity Map) implied PI3K inhibition in tumours with high stathmin. Altogether, our findings indicate that stathmin might be involved in the regulation of tumour angiogenesis and immune responses in breast cancer, in addition to tumour proliferation. Cell data point to potential effects of PI3K inhibition in tumours with high stathmin expression.
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http://dx.doi.org/10.1038/s41598-020-59728-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031232PMC
February 2020

AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells.

J Thorac Oncol 2020 06 1;15(6):973-999. Epub 2020 Feb 1.

Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway; INSERM UMR 1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France. Electronic address:

Introduction: Acquired cancer therapy resistance evolves under selection pressure of immune surveillance and favors mechanisms that promote drug resistance through cell survival and immune evasion. AXL receptor tyrosine kinase is a mediator of cancer cell phenotypic plasticity and suppression of tumor immunity, and AXL expression is associated with drug resistance and diminished long-term survival in a wide range of malignancies, including NSCLC.

Methods: We aimed to investigate the mechanisms underlying AXL-mediated acquired resistance to first- and third-generation small molecule EGFR tyrosine kinase inhibitors (EGFRi) in NSCLC.

Results: We found that EGFRi resistance was mediated by up-regulation of AXL, and targeting AXL reduced reactivation of the MAPK pathway and blocked onset of acquired resistance to long-term EGFRi treatment in vivo. AXL-expressing EGFRi-resistant cells revealed phenotypic and cell signaling heterogeneity incompatible with a simple bypass signaling mechanism, and were characterized by an increased autophagic flux. AXL kinase inhibition by the small molecule inhibitor bemcentinib or siRNA mediated AXL gene silencing was reported to inhibit the autophagic flux in vitro, bemcentinib treatment blocked clonogenicity and induced immunogenic cell death in drug-resistant NSCLC in vitro, and abrogated the transcription of autophagy-associated genes in vivo. Furthermore, we found a positive correlation between AXL expression and autophagy-associated gene signatures in a large cohort of human NSCLC (n = 1018).

Conclusion: Our results indicate that AXL signaling supports a drug-resistant persister cell phenotype through a novel autophagy-dependent mechanism and reveals a unique immunogenic effect of AXL inhibition on drug-resistant NSCLC cells.
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http://dx.doi.org/10.1016/j.jtho.2020.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397559PMC
June 2020

HSP27 Expression as a Novel Predictive Biomarker for Bevacizumab: is it Cost Effective?

Pharmacoecon Open 2020 Sep;4(3):529-539

Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, UK.

Background: Despite the extensive use of bevacizumab in a range of oncology indications, the US FDA revoked its approval for breast cancers, and multiple negative trials in several solid malignancies have been reported, so the need for predictive biomarkers has increased. The development of predictive biomarkers for anti-angiogenic bevacizumab therapy has long been pursued but without success.

Introduction: Heat shock protein (HSP)-27 expression has recently been identified as a predictive biomarker for bevacizumab in treating metastatic melanoma. This study aimed to evaluate the cost effectiveness of HSP27 biomarker testing before administration of bevacizumab.

Methods: A partitioned survival analysis model with three mutually exclusive health states (progression-free survival, progressed disease, and death) was developed using a Norwegian health system perspective. The proportion of patients in each state was calculated using the area under the Kaplan-Meier curve for progression-free and overall survival derived from trials of bevacizumab and dacarbazine. Three strategies were compared: (1) test-treat with HSP27 biomarker and bevacizumab, (2) treat-all with dacarbazine without HSP27 testing, (3) treat-all with bevacizumab without HSP27 testing. Quality-adjusted life-years (QALYs) and costs were calculated for each strategy and discounted at 4%. A lifetime horizon was applied. Uncertainty analyses were performed. Expected value of perfect information (EVPI) was estimated to assess the potential value of further research to generate more evidence.

Results: Although the test-treat strategy was cost effective compared with treat-all with dacarbazine, it was not cost effective compared with treat-all with bevacizumab without HSP27 testing. However, EVPI results showed very minimal or no value in conducting further research efforts to reduce uncertainties around current information.

Conclusion: The results of this study suggested that testing for HSP27 expression before administering bevacizumab is not cost effective compared with treat-all with bevacizumab without testing. It indicates that HSP27 expression is not cost effective as a potential predictive biomarker for bevacizumab. This may not necessarily mean that HSP27 is a bad biomarker for bevacizumab, but it may mean that bevacizumab is much better than dacarbazine regardless of HSP27 expression, so patient stratification according to HSP27 status is meaningless. Or, indeed, it may imply that HSP27 is not sufficiently good at identifying the right patients for bevacizumab.
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http://dx.doi.org/10.1007/s41669-019-00193-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426343PMC
September 2020

Assessing Extraprostatic Extension with Multiparametric MRI of the Prostate: Mehralivand Extraprostatic Extension Grade or Extraprostatic Extension Likert Scale?

Radiol Imaging Cancer 2020 01 17;2(1):e190071. Epub 2020 Jan 17.

Departments of Radiology (L.A.R.R., A.L., J.M., M.B.), Pathology (O.J.H., K.G., L.A.A.), and Urology (C.B., A.H.), Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine (L.A.R.R., C.B., A.L., M.B.) and Centre for Cancer Biomarkers CCBIO (O.J.H., L.A.A.), University of Bergen, Jonas Liesvei 65, N-5021 Bergen, Norway.

Purpose: To validate the MRI grading system proposed by Mehralivand et al in 2019 (the "extraprostatic extension [EPE] grade") in an independent cohort and to compare the Mehralivand EPE grading system with EPE interpretation on the basis of a five-point Likert score ("EPE Likert").

Materials And Methods: A total of 310 consecutive patients underwent multiparametric MRI according to a standardized institutional protocol before radical prostatectomy was performed by using the same 1.5-T MRI unit at a single institution between 2010 and 2012. Two radiologists blinded to clinical information assessed EPE according to standardized criteria. On the basis of the readings performed until 2017, the diagnostic performance of EPE Likert and Mehralivand EPE score were compared using receiver operating characteristics (ROC) and decision curve methodology against histologic EPE as standard of reference. Prediction of biochemical recurrence-free survival (BRFS) was assessed by Kaplan-Meier analysis and log rank test.

Results: Of the 310 patients, 80 patients (26%) had EPE, including 33 with radial distance 1.1 mm or greater. Interrater reliability was fair (weighted κ 0.47 and 0.45) for both EPE grade and EPE Likert. Sensitivity for identifying EPE using EPE grade versus EPE Likert was 0.83 versus 0.86 and 0.86 versus 0.91 for radiologist 1 and 2, respectively. Specificity was 0.48 versus 0.58 and 0.39 versus 0.70 ( < .05 for radiologist 2). There were no significant differences in the ROC area under the curve or on decision curve analysis. Both EPE grade and EPE Likert were significant predictors of BRFS.

Conclusion: Mehralivand EPE grade and EPE Likert have equivalent diagnostic performance for predicting EPE and BRFS with a similar degree of observer dependence.© RSNA, 2020 MR-Imaging, Neoplasms-Primary, Observer Performance, Outcomes Analysis, Prostate, StagingSee also the commentary by Choyke in this issue.
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http://dx.doi.org/10.1148/rycan.2019190071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983691PMC
January 2020

Metabolic consequences of perioperative oral carbohydrates in breast cancer patients - an explorative study.

BMC Cancer 2019 Dec 4;19(1):1183. Epub 2019 Dec 4.

Department of Pathology, Stavanger University Hospital, Helse Stavanger HF, P.O. Box 8100, N-4068, Stavanger, Norway.

Background: The metabolic consequences of preoperative carbohydrate load in breast cancer patients are not known. The present explorative study investigated the systemic and tumor metabolic changes after preoperative per-oral carbohydrate load and their influence on tumor characteristics and survival.

Methods: The study setting was on university hospital level with primary and secondary care functions in south-west Norway. Serum and tumor tissue were sampled from a population-based cohort of 60 patients with operable breast cancer who were randomized to either per-oral carbohydrate load (preOp™; n = 25) or standard pre-operative fasting (n = 35) before surgery. Magnetic resonance (MR) metabolomics was performed on serum samples from all patients and high-resolution magic angle spinning (HR-MAS) MR analysis on 13 tumor samples available from the fasting group and 16 tumor samples from the carbohydrate group.

Results: Fourteen of 28 metabolites were differently expressed between fasting and carbohydrate groups. Partial least squares discriminant analysis showed a significant difference in the metabolic profile between the fasting and carbohydrate groups, compatible with the endocrine effects of insulin (i.e., increased serum-lactate and pyruvate and decreased ketone bodies and amino acids in the carbohydrate group). Among ER-positive tumors (n = 18), glutathione was significantly elevated in the carbohydrate group compared to the fasting group (p = 0.002), with a positive correlation between preoperative S-insulin levels and the glutathione content in tumors (r = 0.680; p = 0.002). In all tumors (n = 29), glutamate was increased in tumors with high proliferation (t-test; p = 0.009), independent of intervention group. Moreover, there was a positive correlation between tumor size and proliferation markers in the carbohydrate group only. Patients with ER-positive / T2 tumors and high tumor glutathione (≥1.09), high S-lactate (≥56.9), and high S-pyruvate (≥12.5) had inferior clinical outcomes regarding relapse-free survival, breast cancer-specific survival, and overall survival. Moreover, Integrated Pathway Analysis (IPA) in serum revealed activation of five major anabolic metabolic networks contributing to proliferation and growth.

Conclusions: Preoperative carbohydrate load increases systemic levels of lactate and pyruvate and tumor levels of glutathione and glutamate in ER-positive patients. These biological changes may contribute to the inferior clinical outcomes observed in luminal T2 breast cancer patients.

Trial Of Registration: ClinicalTrials.gov; NCT03886389. Retrospectively registered March 22, 2019.
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http://dx.doi.org/10.1186/s12885-019-6393-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894229PMC
December 2019

Influence of pre-operative oral carbohydrate loading vs. standard fasting on tumor proliferation and clinical outcome in breast cancer patients ─ a randomized trial.

BMC Cancer 2019 Nov 8;19(1):1076. Epub 2019 Nov 8.

Department of Pathology, Stavanger University Hospital, Helse Stavanger HF, P.O. Box 8100, N-4068, Stavanger, Norway.

Background: Conflicting results have been reported on the influence of carbohydrates in breast cancer.

Objective: To determine the influence of pre-operative per-oral carbohydrate load on proliferation in breast tumors.

Design: Randomized controlled trial.

Setting: University hospital with primary and secondary care functions in South-West Norway.

Patients: Sixty-one patients with operable breast cancer from a population-based cohort.

Intervention: Per-oral carbohydrate load (preOp™) 18 and 2-4 h before surgery (n = 26) or standard pre-operative fasting with free consumption of tap water (n = 35).

Measurements: The primary outcome was post-operative tumor proliferation measured by the mitotic activity index (MAI). The secondary outcomes were changes in the levels of serum insulin, insulin-c-peptide, glucose, IGF-1, and IGFBP3; patients' well-being, and clinical outcome over a median follow-up of 88 months (range 33-97 months).

Results: In the estrogen receptor (ER) positive subgroup (n = 50), high proliferation (MAI ≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p = 0.038). The CH group was more frequently progesterone receptor (PR) negative (p = 0.014). The CH group had a significant increase in insulin (+ 24.31 mIE/L, 95% CI 15.34 mIE/L to 33.27 mIE/L) and insulin c-peptide (+ 1.39 nM, 95% CI 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (- 0.26 nM; 95% CI - 0.46 nM to - 0.051 nM) compared to the fasting group. CH-intervention ER-positive patients had poorer relapse-free survival (73%) than the fasting group (100%; p = 0.012; HR = 9.3, 95% CI, 1.1 to 77.7). In the ER-positive patients, only tumor size (p = 0.021; HR = 6.07, 95% CI 1.31 to 28.03) and the CH/fasting subgrouping (p = 0.040; HR = 9.30, 95% CI 1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with relapse-free survival of 100% in the fasting group vs. 33% in the CH group (p = 0.015; HR = inf). The CH group reported less pain on days 5 and 6 than the control group (p <  0.001) but otherwise exhibited no factors related to well-being.

Limitation: Only applicable to T2 tumors in patients with ER-positive breast cancer.

Conclusions: Pre-operative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2 patients.

Trial Registration: CliniTrials.gov; NCT03886389. Retrospectively registered March 22, 2019.
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http://dx.doi.org/10.1186/s12885-019-6275-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842165PMC
November 2019

Integrin α11β1 is expressed in breast cancer stroma and associates with aggressive tumor phenotypes.

J Pathol Clin Res 2020 01 3;6(1):69-82. Epub 2019 Dec 3.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Cancer-associated fibroblasts are essential modifiers of the tumor microenvironment. The collagen-binding integrin α11β1 has been proposed to be upregulated in a pro-tumorigenic subtype of cancer-associated fibroblasts. Here, we analyzed the expression and clinical relevance of integrin α11β1 in a large breast cancer series using a novel antibody against the human integrin α11 chain. Several novel monoclonal antibodies against the integrin α11 subunit were tested for use on formalin-fixed paraffin-embedded tissues, and Ab 210F4B6A4 was eventually selected to investigate the immunohistochemical expression in 392 breast cancers using whole sections. mRNA data from METABRIC and co-expression patterns of integrin α11 in relation to αSMA and cytokeratin-14 were also investigated. Integrin α11 was expressed to varying degrees in spindle-shaped cells in the stroma of 99% of invasive breast carcinomas. Integrin α11 co-localized with αSMA in stromal cells, and with αSMA and cytokeratin-14 in breast myoepithelium. High stromal integrin α11 expression (66% of cases) was associated with aggressive breast cancer features such as high histologic grade, increased tumor cell proliferation, ER negativity, HER2 positivity, and triple-negative phenotype, but was not associated with breast cancer specific survival at protein or mRNA levels. In conclusion, high stromal integrin α11 expression was associated with aggressive breast cancer phenotypes.
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http://dx.doi.org/10.1002/cjp2.148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966706PMC
January 2020

Terminal digit preference: a source of measurement error in breast cancer diameter reporting.

Acta Oncol 2020 Mar 30;59(3):260-267. Epub 2019 Sep 30.

Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, Oslo, Norway.

Women diagnosed with breast cancer are offered treatment and therapy based on tumor characteristics, including tumor diameter. There is scarce knowledge whether tumor diameter is accurately reported, or whether it is unconsciously rounded to the nearest half-centimeter (terminal digit preference). This study aimed to assess the precision (number of digits) of breast cancer tumor diameters and whether they are affected by terminal digit preference. Furthermore, we aimed to assess the agreement between mammographic and histopathologic tumor diameter measurements. This national registry study included reported mammographic and registered histopathologic tumor diameter information from the Cancer Registry of Norway for invasive breast cancers diagnosed during 2012-2016. Terminal digit preference was assessed using histograms. Agreement between mammographic and histopathologic measurements was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Mammographic, histopathologic, or both tumor measurements were available for 7792, 13,541 and 6865 cases, respectively. All mammographic and 97.2% of histopathologic tumor diameters were recorded using whole mm. Terminal digits of zero or five were observed among 38.7% and 34.8% of mammographic and histopathologic measurements, respectively. There was moderate agreement between the two measurement methods (ICC = 0.52, 95% CI: 0.50-0.53). On average, mammographic measurements were 1.26 mm larger (95% limits of agreement: -22.29-24.73) than histopathologic measurements. This difference increased with increasing tumor size. Terminal digit preference was evident among breast cancer tumor diameters in this nationwide study. Further studies are needed to investigate the potential extent of under-staging and under-treatment resulting from this measurement error.
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http://dx.doi.org/10.1080/0284186X.2019.1669817DOI Listing
March 2020

Pathway times in the mammography programme before and after introduction of the breast cancer care pathway.

Tidsskr Nor Laegeforen 2019 09 9;139(12). Epub 2019 Sep 9.

Background: The purpose of introducing the 'cancer patient pathway for breast cancer' was to ensure a coherent treatment pathway without unnecessary delays. Radiologists and pathologists who work with breast diagnostics are involved in both cancer patient pathways and BreastScreen Norway. The extent to which this policy may have affected waiting times has not been analysed previously. This study presents waiting times in BreastScreen Norway before and after introduction of cancer patient pathway.

Material And Method: We analysed waiting times associated with 1 485 240 screening examinations undertaken as part of BreastScreen Norway in the period 01.7.2011-30.6.2018, stratified by breast diagnostic centre. Waiting times were defined as the number of calendar days from the a) screening examination to the dispatch of the negative results letter (dispatch time), b) screening examination to the date on which the follow-up examination was performed (follow-up examination time) and c) follow-up examination to diagnosis (diagnosis time). Data were retrieved from the Cancer Registry of Norway's databases. Use of these is set out in the Cancer Registry Regulations. We calculated median waiting times in addition to 90th percentiles.

Results: The median dispatch time was 13 days before the cancer patient pathway was introduced, and 12 days after. The median follow-up examination time increased from 23 to 27 days, while the median diagnosis time was 3 days both before and after introduction of the cancer patient pathway.

Interpretation: Dispatch and diagnosis times were unchanged, or slightly changed after introduction of the cancer patient pathway, while follow-up examination time increased somewhat. Introduction of the cancer patient pathway may have led to differential adjustments in priorities, workflows and access to resources between the breast diagnostic centres.
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http://dx.doi.org/10.4045/tidsskr.18.0322DOI Listing
September 2019

FOXC2 expression and epithelial-mesenchymal phenotypes are associated with castration resistance, metastasis and survival in prostate cancer.

J Pathol Clin Res 2019 10 1;5(4):272-286. Epub 2019 Oct 1.

Centre for Cancer Biomarkers CCBIO, and Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Epithelial-mesenchymal transition (EMT) is important for tumour cell invasion and metastasis and is a feature of aggressive carcinomas. EMT is characterised by reduced E-cadherin and increased N-cadherin expression (EN-switch), and increased expression of the EMT-regulating transcription factor Forkhead box protein C2 (FOXC2) has been associated with progression and poor prognosis in various malignancies. FOXC2 was recently highlighted as a novel therapy target in prostate cancer, but survival data on FOXC2 are lacking. This study evaluates the expression of FOXC2, E-cadherin and N-cadherin in different prostatic tissues focusing on EMT, clinico-pathological phenotype, recurrence and patient survival. Tissue microarray sections from 338 radical prostatectomies (1986-2007) with long and complete follow-up, 33 castration resistant prostate cancers, 33 non-skeletal metastases, 13 skeletal metastases and 41 prostatic hyperplasias were stained immunohistochemically for FOXC2, E-cadherin and N-cadherin. FOXC2 was strongly expressed in primary carcinomas, including castration resistant tumours and metastatic lesions as compared to benign prostatic hyperplasia. A hybrid epithelial-mesenchymal phenotype, with co-expression of E-cadherin and N-cadherin, was found in the majority of skeletal metastases and in a substantial proportion of castration resistant tumours. In localised carcinomas, the EN-switch was associated with adverse clinico-pathological variables, such as extra-prostatic extension, high pathological stage and lymph node infiltration. In univariate survival analyses of the clinically important, large subgroup of 199 patients with Gleason score 7, high FOXC2 expression and EN-switching were significantly associated with shorter time to clinical recurrence, skeletal metastases and cancer specific death. In multivariate Cox' survival analysis, high FOXC2 and the EN-switch, together with Gleason grade group (GG3 versus GG2), were independent predictors of time to these end-points. High FOXC2 gene expression (mRNA) was also related to patient outcome, validating our immunohistochemical findings. FOXC2 and factors signifying EMT or its intermediate states may prove important as biomarkers for aggressive disease and are potential novel therapy targets in prostate cancer.
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http://dx.doi.org/10.1002/cjp2.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817834PMC
October 2019

Two-view digital breast tomosynthesis versus digital mammography in a population-based breast cancer screening programme (To-Be): a randomised, controlled trial.

Lancet Oncol 2019 06 8;20(6):795-805. Epub 2019 May 8.

Department of Pathology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers, Haukeland University Hospital, Bergen, Norway; Deparment of Clinical Medicine, University of Bergen, Bergen, Norway.

Background: Digital breast tomosynthesis is an advancement of mammography, and has the potential to overcome limitations of standard digital mammography. This study aimed to compare first-generation digital breast tomo-synthesis including two-dimensional (2D) synthetic mammograms versus digital mammography in a population-based screening programme.

Methods: BreastScreen Norway offers all women aged 50-69 years two-view (craniocaudal and mediolateral oblique) mammographic screening every 2 years and does independent double reading with consensus. We asked all 32 976 women who attended the programme in Bergen in 2016-17, to participate in this randomised, controlled trial with a parallel group design. A study-specific software was developed to allocate women to either digital breast tomosynthesis or digital mammography using a 1:1 simple randomisation method based on participants' unique national identity numbers. The interviewing radiographer did the randomisation by entering the number into the software. Randomisation was done after consent and was therefore concealed from both the women and the radiographer at the time of consent; the algorithm was not disclosed to radiographers during the recruitment period. All data needed for analyses were complete 12 months after the recruitment period ended. The primary outcome measure was screen-detected breast cancer, stratified by screening technique (ie, digital breast tomosynthesis and digital mammography). A log-binomial regression model was used to estimate the efficacy of digital breast tomosynthesis versus digital mammography, defined as the crude risk ratios (RRs) with 95% CIs for screen-detected breast cancer for women screened during the recruitment period. A per-protocol approach was used in the analyses. This trial is registered at ClinicalTrials.gov, number NCT02835625, and is closed to accrual.

Findings: Between, Jan 14, 2016, and Dec 31, 2017, 44 266 women were invited to the screening programme in Bergen, and 32 976 (74·5%) attended. After excluding women with breast implants and women who did not consent to participate, 29 453 (89·3%) were eligible for electronic randomisation. 14 734 women were allocated to digital breast tomosynthesis and 14 719 to digital mammography. After randomisation, women with a previous breast cancer were excluded (digital breast tomosynthesis group n=314, digital mammography group n=316), women with metastases from melanoma (digital breast tomosynthesis group n=1), and women who informed the radiographer about breast symptoms after providing consent (digital breast tomosynthesis group n=39, digital mammography group n=34). After exclusions, information from 28 749 women were included in the analyses (digital breast tomosynthesis group n=14 380, digital mammography group n=14 369). The proportion of screen-detected breast cancer among the screened women did not differ between the two groups (95 [0·66%, 0·53-0·79] of 14 380 vs 87 [0·61%, 0·48-0·73] of 14 369; RR 1·09, 95% CI 0·82-1·46; p=0·56).

Interpretation: This study indicated that digital breast tomosynthesis including synthetic 2D mammograms was not significantly different from standard digital mammography as a screening tool for the detection of breast cancer in a population-based screening programme. Economic analyses and follow-up studies on interval and consecutive round screen-detected breast cancers are needed to better understand the effect of digital breast tomosynthesis in population-based breast cancer screening.

Funding: Cancer Registry of Norway, Department of Radiology at Haukeland University Hospital, University of Oslo, and Research Council of Norway.
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http://dx.doi.org/10.1016/S1470-2045(19)30161-5DOI Listing
June 2019

Prognostic value of uPAR expression and angiogenesis in primary and metastatic melanoma.

PLoS One 2019 14;14(1):e0210399. Epub 2019 Jan 14.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Angiogenesis is important for the progression of cutaneous melanoma. Here, we analyzed the prognostic impact of the angiogenic factor urokinase plasminogen activator resecptor (uPAR), vascular proliferation index (VPI) and tumor necrosis as a measure of hypoxia in a patient series of nodular melanomas (n = 255) and matched loco-regional metastases (n = 78). Expression of uPAR was determined by immunohistochemistry and VPI was assessed by dual immunohistochemistry using Factor-VIII/Ki67 staining. Necrosis was recorded based on HE-slides. As novel findings, high uPAR expression and high VPI were associated with each other, and with increased tumor thickness, presence of tumor necrosis, tumor ulceration, increased mitotic count and reduced cancer specific survival in primary melanoma. In matched cases, VPI was decreased in metastases, whereas the frequency of necrosis was increased. Our findings demonstrate for the first time the impact on melanoma specific survival of uPAR expression and VPI in primary tumors, and of increased necrosis as an indicator of tumor hypoxia in loco-regional metastases. These findings support the importance of tumor angiogenesis in melanoma aggressiveness, and suggest uPAR as an indicator of vascular proliferation and a potential biomarker in melanoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331131PMC
October 2019

Deblender: a semi-/unsupervised multi-operational computational method for complete deconvolution of expression data from heterogeneous samples.

BMC Bioinformatics 2018 Nov 7;19(1):408. Epub 2018 Nov 7.

Centre for Cancer Biomarkers CCBIO, Department of Informatics, University of Bergen, Bergen, Norway.

Background: Towards discovering robust cancer biomarkers, it is imperative to unravel the cellular heterogeneity of patient samples and comprehend the interactions between cancer cells and the various cell types in the tumor microenvironment. The first generation of 'partial' computational deconvolution methods required prior information either on the cell/tissue type proportions or the cell/tissue type-specific expression signatures and the number of involved cell/tissue types. The second generation of 'complete' approaches allowed estimating both of the cell/tissue type proportions and cell/tissue type-specific expression profiles directly from the mixed gene expression data, based on known (or automatically identified) cell/tissue type-specific marker genes.

Results: We present Deblender, a flexible complete deconvolution tool operating in semi-/unsupervised mode based on the user's access to known marker gene lists and information about cell/tissue composition. In case of no prior knowledge, global gene expression variability is used in clustering the mixed data to substitute marker sets with cluster sets. In addition, we integrate a model selection criterion to predict the number of constituent cell/tissue types. Moreover, we provide a tailored algorithmic scheme to estimate mixture proportions for realistic experimental cases where the number of involved cell/tissue types exceeds the number of mixed samples. We assess the performance of Deblender and a set of state-of-the-art existing tools on a comprehensive set of benchmark and patient cancer mixture expression datasets (including TCGA).

Conclusion: Our results corroborate that Deblender can be a valuable tool to improve understanding of gene expression datasets with implications for prediction and clinical utilization. Deblender is implemented in MATLAB and is available from ( https://github.com/kondim1983/Deblender/ ).
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http://dx.doi.org/10.1186/s12859-018-2442-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223087PMC
November 2018

Predictive value of angiogenic proteins in patients with metastatic melanoma treated with bevacizumab monotherapy.

J Pathol Clin Res 2019 01 9;5(1):53-62. Epub 2018 Nov 9.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

The incidence of malignant melanoma is rising worldwide and survival for metastatic disease is still poor. Recently, new treatment options have become available. Still, predictive biomarkers are needed to optimise treatment for this patient group. In this study, we investigated the predictive value of 60 angiogenic factors in patients with metastatic melanoma treated with the anti-vascular endothelial growth factor A antibody bevacizumab. Thirty-five patients were included in a clinical phase II trial and baseline serum samples were analysed by multiplex protein array. High-serum concentration of Activin A was significantly associated with objective response (OR) to treatment (p = 0.014). Candidate proteins that indicated a borderline association with treatment response were further investigated by immunohistochemistry. Strong expression of Activin A, interleukin-1β, and urokinase-type plasminogen activator receptor in metastases was significantly associated with OR (p = 0.011, p = 0.003, and p = 0.007, respectively), as well as with markers of activated angiogenesis, such as higher number of proliferating vessels and the presence of glomeruloid microvascular proliferations. Our findings indicate that these proteins may be potential predictive markers for treatment with bevacizumab monotherapy.
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http://dx.doi.org/10.1002/cjp2.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317286PMC
January 2019

Characterization of FGD5 Expression in Primary Breast Cancers and Lymph Node Metastases.

J Histochem Cytochem 2018 11 27;66(11):787-799. Epub 2018 Jul 27.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.

Faciogenital dysplasia 5 ( FGD5) amplification drives tumor cell proliferation, and is present in 9.5% of breast cancers. We describe FGD5 expression, assess associations between FGD5 amplification and FGD5 expression, and assess FGD5 expression in relation to proliferation and prognosis. FGD5 immunohistochemistry was done on primary tumors ( n=829) and lymph node metastases ( n=231) from a cohort of Norwegian patients. We explored associations between FGD5 amplification, FGD5 expression, and proliferation, and analyzed the prognostic value of FGD5 expression by estimating cumulative risks of death and hazard ratios (HRs). We identified nuclear and cytoplasmic expression in 64% and 73% of primary tumors, respectively, and found an association between gene amplification and nuclear expression ( p=0.02). The proportion of cases with FGD5 expression was higher in lymph node metastases, compared with primary tumors ( p=0.004 for nuclear and p=0.001 for cytoplasmic staining). Neither proliferation nor prognosis was associated with FGD5 expression (age-adjusted HR 1.12 [95% confidence interval = 0.89-1.41] for nuclear expression; and 0.88 [95% CI = 0.70-1.12] for cytoplasmic expression). FGD5 is expressed in a high proportion of breast cancers and lymph node metastases. There was a correlation between FGD5 amplification and nuclear expression, but no association between FGD5 expression and proliferation or prognosis.
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http://dx.doi.org/10.1369/0022155418792032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213565PMC
November 2018

Automated Volumetric Analysis of Mammographic Density in a Screening Setting: Worse Outcomes for Women with Dense Breasts.

Radiology 2018 08 26;288(2):343-352. Epub 2018 Jun 26.

From the Cancer Registry of Norway, Oslo, Norway (N.M., S.S., K.M.T., S.H.); Departments of Radiology (C.I.L.) and Medicine (J.G.E.), University of Washington School of Medicine, Seattle, Wash; Department of Clinical Medicine, Section for Pathology, Centre for Cancer Biomarkers (CCBIO), Bergen, Norway (L.A.A.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (L.A.A.); and Oslo Metropolitan University, Faculty of Health Science, Oslo, Norway (S.H.).

Purpose To describe screening outcomes from BreastScreen Norway stratified by volumetric breast density (VBD). Materials and Methods This retrospective study included data from 107 949 women aged 50-69 years (mean age ± standard deviation, 58.7 years ± 5.6) who underwent 307 015 screening examinations from 2007 to 2015. Automated software classified mammographic density as nondense (VBD <7.5%) or dense (VBD ≥7.5%). Rates and distributions of screening outcomes (recall, biopsy, screen-detected and interval breast cancer, positive predictive values of recall and of needle biopsy, sensitivity, specificity, and histopathologic tumor characteristics) were analyzed and stratified by density. Tests of proportions, including propensity score and t tests, were used. Results In 28% (87 021 of 307 015) of the screening examinations, the breasts were classified as dense. Recall rates for women with nondense versus dense breasts were 2.7% (5882 of 219 994) and 3.6% (3101 of 87 021); biopsy rates were 1.1% (2359 of 219 994) and 1.4% (1209 of 87 021); rates of screen-detected cancer were 5.5 (1210 of 219 994) and 6.7 (581 of 87 021) per 1000 examinations; and rates of interval breast cancer were 1.2 (199 of 165 324) and 2.8 (185 of 66 674) per 1000 examinations, respectively (P < .001 for all). Sensitivity was 82% (884 of 1083) for nondense breasts and 71% (449 of 634) for dense breasts, whereas specificity was 98% (160 973 of 164 440) and 97% (64 250 of 66 225), respectively (P < .001 for both). For screen-detected cancers, mean tumor diameter was 15.1 mm and 16.6 mm (P = .01), and lymph node-positive disease was found in 18% (170 of 936) and 24% (98 of 417) (P = .02) of women with nondense and dense breasts, respectively. Conclusion Screening examinations of women with dense breasts classified by using automated software resulted in higher recall rate, lower sensitivity, larger tumor diameter, and more lymph node-positive disease compared with women with nondense breasts.
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http://dx.doi.org/10.1148/radiol.2018172972DOI Listing
August 2018

Impact of pre-diagnostic triglycerides and HDL-cholesterol on breast cancer recurrence and survival by breast cancer subtypes.

BMC Cancer 2018 Jun 15;18(1):654. Epub 2018 Jun 15.

Department of Oncology, Oslo University Hospital, Ullevål, N-0424, Oslo, Norway.

Background: High triglycerides and low levels of high density lipoprotein (HDL)-cholesterol are observed to promote tumor growth. However, whether breast cancer heterogeneity may explain the contradictory influence of triglycerides and cholesterol observed on breast cancer prognosis remains unclear.

Methods: A population-based survival study among 464 breast cancer cases identified within the Tromsø study was conducted. Pre-diagnostic triglycerides, total-cholesterol and HDL-cholesterol were measured, and detailed clinical and histopathological data were obtained. Using tissue microarray, all breast cancer cases were reclassified into the following subtypes: Luminal A, Luminal B, HER2-enriched, and triple negative breast cancer (TNBC). Multivariable Cox proportional hazards regression models were used to study the associations between pre-diagnostic lipids and breast cancer recurrence, mortality, and survival.

Results: A total of 464 breast cancer patients, with mean age at diagnosis of 57.9 years, were followed for a mean 8.4 years. TNBC patients in the highest tertile of triglycerides (≥ 1.23 mmol/l) had 3 times higher overall mortality compared to TNBC patients in the lowest tertile (≤ 0.82 mmol/l) (HR 2.99, 95% CI 1.17-7.63), and the 5-year overall survival was 19% lower for TNBC patients in the highest vs. lowest tertile of triglycerides (65% vs. 84%). TNBC patients in the highest tertile of the HDL-cholesterol/total-cholesterol ratio (≥0.35), compared to those in the lowest tertile (≤0.27), had a 67% reduced overall mortality risk (HR 0.33, 95% CI 0.12-0.89). No associations were observed between lipids and prognostic outcome among breast cancer patients overall, or among patients with luminal A and luminal B subtypes. Among HER2-enriched patients, pre-diagnostic triglyceride level was inversely associated with overall mortality.

Conclusion: Our study suggests that pre-diagnostic triglycerides and the HDL-cholesterol/total-cholesterol ratio may independently provide unique information regarding prognostic outcome among triple negative breast cancer patients. However, a small sample size underlines the need for additional studies.
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http://dx.doi.org/10.1186/s12885-018-4568-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003110PMC
June 2018

High mortality due to cutaneous melanoma in Norway: a study of prognostic factors in a nationwide cancer registry.

Clin Epidemiol 2018 9;10:537-548. Epub 2018 May 9.

Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

Purpose: The purpose of this study was to examine why Norway has the highest rate of mortality due to cutaneous melanoma (CM) in Europe. The Norwegian Malignant Melanoma Registry (NMMR) enables the study of clinical and histopathological characteristics of patients who die due to CM.

Results: The NMMR and the Norwegian Cause of Death Registry provided data on the clinical and histopathological factors as well as the date and cause of death, through June 2015 for all first invasive CMs diagnosed in 2008-2012 (n=8087). Cox regression was used to estimate associations between clinical and pathological factors and CM-specific death. Multiple imputation was used to handle missing data.

Results: The CMs were equally distributed between men (49.9%) and women (50.1%), and the median follow-up was 4.0 years (range: 0.08-7.5 years). Trunk was the most common anatomic site (48%), superficial spreading melanoma was the dominant melanoma subtype (68.2%), median Breslow thickness was 1.0 mm, ulceration was present in 23% of CMs, and 91.8% of cases were in a local clinical stage at diagnosis. Compared to women, men were diagnosed at a higher age, with thicker and more-often-ulcerated tumor, and more often were in advanced clinical stages. During follow-up, 1015 patients died due to CM, representing 52.8% of all deaths. The nodular subtype made up the dominant proportion of fatal CM cases (55.3% in women, 64.6% in men). Sex, age, anatomic site (trunk), T-stage, ulceration, clinical stage, and having a second primary CM were associated with increased risk of CM-specific death.

Conclusion: Our data suggest that the high rate of mortality due to CM observed in Norway is attributable to the more advanced stage of the disease at diagnosis. Most high-risk cases occurred in male patients ≥70 years of age. Efforts to improve awareness and secondary prevention of CM, including warning signs of all melanoma subtypes, are required urgently and should be targeted toward men in particular.
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http://dx.doi.org/10.2147/CLEP.S151246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951132PMC
May 2018

Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance.

Front Cell Dev Biol 2018 17;6:41. Epub 2018 Apr 17.

Department of Population Sciences, Center for Cancer and Aging, City of Hope, Duarte, CA, United States.

The existence of rare cancer cells that sporadically acquire drug-tolerance through epigenetic mechanisms is proposed as one mechanism that drives cancer therapy failure. Here we provide evidence that specific microenvironments impose non-sporadic expression of proteins related to epithelial plasticity and drug resistance. Microarrays of robotically printed combinatorial microenvironments of known composition were used to make cell-based functional associations between microenvironments, which were design-inspired by normal and tumor-burdened breast tissues, and cell phenotypes. We hypothesized that specific combinations of microenvironment constituents non-sporadically impose the induction of the AXL and cKIT receptor tyrosine kinase proteins, which are known to be involved in epithelial plasticity and drug-tolerance, in an isogenic human mammary epithelial cell (HMEC) malignant progression series. Dimension reduction analysis reveals type I collagen as a dominant feature, inducing expression of both markers in pre-stasis finite lifespan HMECs, and transformed non-malignant and malignant immortal cell lines. Basement membrane-associated matrix proteins, laminin-111 and type IV collagen, suppress AXL and cKIT expression in pre-stasis and non-malignant cells. However, AXL and cKIT are not suppressed by laminin-111 in malignant cells. General linear models identified key factors, osteopontin, IL-8, and type VIα3 collagen, which significantly upregulated AXL and cKIT, as well as a plasticity-related gene expression program that is often observed in stem cells and in epithelial-to-mesenchymal-transition. These factors are co-located with AXL-expressing cells in normal and breast cancer tissues, and associated with resistance to paclitaxel. A greater diversity of microenvironments induced AXL and cKIT expression consistent with plasticity and drug-tolerant phenotypes in tumorigenic cells compared to normal or immortal cells, suggesting a reduced perception of microenvironment specificity in malignant cells. Microenvironment-imposed reprogramming could explain why resistant cells are seemingly persistent and rapidly adaptable to multiple classes of drugs. These results support the notion that specific microenvironments drive drug-tolerant cellular phenotypes and suggest a novel interventional avenue for preventing acquired therapy resistance.
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http://dx.doi.org/10.3389/fcell.2018.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913284PMC
April 2018
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