Publications by authors named "Gøril Knutsvik"

11 Publications

  • Page 1 of 1

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

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

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

Proliferasjonsmarkører ved brystkreft.

Authors:
Gøril Knutsvik

Tidsskr Nor Laegeforen 2017 Jun 6;137(11):822. Epub 2017 Jun 6.

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http://dx.doi.org/10.4045/tidsskr.17.0221DOI Listing
June 2017

Expression of Nestin associates with BRCA1 mutations, a basal-like phenotype and aggressive breast cancer.

Sci Rep 2017 04 24;7(1):1089. Epub 2017 Apr 24.

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

We here examined whether Nestin, by protein and mRNA levels, could be a predictor of BRCA1 related breast cancer, a basal-like phenotype, and aggressive tumours. Immunohistochemical staining of Nestin was done in independent breast cancer hospital cohorts (Series I-V, total 1257 cases). Also, TCGA proteomic data (n = 103), mRNA microarray data from TCGA (n = 520), METABRIC (n = 1992), and 6 open access breast cancer datasets (n = 1908) were analysed. Patients with Nestin protein expression in tumour cells more often had BRCA1 germline mutations (OR 8.7, p < 0.0005, Series III), especially among younger patients (<40 years at diagnosis) (OR 16.5, p = 0.003). Nestin protein positivity, observed in 9-28% of our hospital cases (Series I-IV), was independently associated with reduced breast cancer specific survival (HR = 2.0, p = 0.035) and was consistently related to basal-like differentiation (by Cytokeratin 5, OR 8.7-13.8, p < 0.0005; P-cadherin OR 7.0-8.9, p < 0.0005; EGFR staining, OR 3.7-8.2, p ≤ 0.05). Nestin mRNA correlated significantly with Nestin protein expression (ρ = 0.6, p < 0.0005), and high levels were seen in the basal-like intrinsic subtype. Gene expression signalling pathways linked to high Nestin were explored, and revealed associations with stem-like tumour features. In summary, Nestin was strongly associated with germline BRCA1 related breast cancer, a basal-like phenotype, reduced survival, and stemness characteristics.
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http://dx.doi.org/10.1038/s41598-017-00862-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430803PMC
April 2017

Extra-nodal extension is a significant prognostic factor in lymph node positive breast cancer.

PLoS One 2017 15;12(2):e0171853. Epub 2017 Feb 15.

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

Presence of lymph node (LN) metastasis is a strong prognostic factor in breast cancer, whereas the importance of extra-nodal extension and other nodal tumor features have not yet been fully recognized. Here, we examined microscopic features of lymph node metastases and their prognostic value in a population-based cohort of node positive breast cancer (n = 218), as part of the prospective Norwegian Breast Cancer Screening Program NBCSP (1996-2009). Sections were reviewed for the largest metastatic tumor diameter (TD-MET), nodal afferent and efferent vascular invasion (AVI and EVI), extra-nodal extension (ENE), number of ENE foci, as well as circumferential (CD-ENE) and perpendicular (PD-ENE) diameter of extra-nodal growth. Number of positive lymph nodes, EVI, and PD-ENE were significantly increased with larger primary tumor (PT) diameter. Univariate survival analysis showed that several features of nodal metastases were associated with disease-free (DFS) or breast cancer specific survival (BCSS). Multivariate analysis demonstrated an independent prognostic value of PD-ENE (with 3 mm as cut-off value) in predicting DFS and BCSS, along with number of positive nodes and histologic grade of the primary tumor (for DFS: P = 0.01, P = 0.02, P = 0.01, respectively; for BCSS: P = 0.02, P = 0.008, P = 0.02, respectively). To conclude, the extent of ENE by its perpendicular diameter was independently prognostic and should be considered in line with nodal tumor burden in treatment decisions of node positive breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171853PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310784PMC
August 2017

Tumour cell invasion into blood vessels is significantly related to breast cancer subtypes and decreased survival.

J Clin Pathol 2017 Apr 9;70(4):313-319. Epub 2016 Sep 9.

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

Aims: Vascular invasion in breast cancer is associated with increased risk of recurrence, metastases and death from disease. However, there are few studies discriminating between blood vessel invasion (BVI) and lymphatic vessel involvement (LVI).

Methods: A population-based series of 282 breast cancers was examined (200 screen-detected and 82 interval patients) with respect to BVI and LVI in addition to basic features and molecular subtypes, using CD31 and D2-40 antibodies. This series is part of the prospective Norwegian Breast Cancer Screening Program.

Results: The frequency of LVI and BVI was 25% and 15%, respectively. BVI was associated with HER2-positive and basal-like tumours, and several features of aggressive breast cancer, whereas LVI showed weaker associations. BVI was the strongest factor to predict interval cancer presentation. BVI showed significant associations with recurrence-free survival and disease-specific survival in univariate and multivariate analyses, whereas LVI was not significant.

Conclusions: Our findings indicate that BVI by tumour cells is strongly associated with aggressive tumour features including a basal-like phenotype, and BVI was an independent prognostic factor in contrast to what was found for LVI.
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http://dx.doi.org/10.1136/jclinpath-2016-203861DOI Listing
April 2017

QSOX1 expression is associated with aggressive tumor features and reduced survival in breast carcinomas.

Mod Pathol 2016 12 26;29(12):1485-1491. Epub 2016 Aug 26.

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

The biological role of quiescin sulfhydryl oxidase 1 (QSOX1) in tumor development is not well known, and its relation to breast cancer progression and prognosis is controversial. Here, our aim was to study the expression pattern and prognostic impact of QSOX1 in breast cancer, in relation to molecular subgroups and tumor cell proliferation. We examined a population-based series as part of the prospective Norwegian Breast Cancer Screening Program, including all women (50-69 years) diagnosed with breast cancer in one county of Norway during 1996-2003. QSOX1 expression was assessed by immunohistochemistry on tissue microarrays (n=458). Median follow-up time was 13 years. High expression of QSOX1 protein was associated with features of poor prognosis including high histologic grade, hormone receptor negativity, HER2 positivity, and increased tumor cell proliferation. High QSOX1 expression was further associated with reduced breast cancer-specific survival in both univariate and multivariate analysis, independent of molecular subtypes. High QSOX1 expression is a strong and independent factor of reduced survival in breast cancer, also reflected by elevated levels in more aggressive molecular subgroups. QSOX1 expression may represent a biomarker for aggressive disease and a potential treatment target.
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http://dx.doi.org/10.1038/modpathol.2016.148DOI Listing
December 2016

Evaluation of Tumor Cell Proliferation by Ki-67 Expression and Mitotic Count in Lymph Node Metastases from Breast Cancer.

PLoS One 2016 8;11(3):e0150979. Epub 2016 Mar 8.

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

Few studies have addressed the risk of recurrence by assessing proliferation markers in lymph node metastasis from breast cancer. Here, we aimed to examine Ki-67 expression and mitotic count in lymph nodes in comparison with primary tumors. A cohort of node positive breast cancer (n = 168) was studied as a part of the prospective Norwegian Breast Cancer Screening Program (1996-2009). The percentage of Ki-67 positivity was counted per 500 tumor cells in hot-spot areas (x630). Mitotic count was conducted in the most cellular and mitotic active areas in 10 high power fields (x400). Our results showed that Ki-67 and mitotic count were significantly correlated between primary tumor and lymph nodes (Spearman`s correlation 0. 56 and 0.46, respectively) and were associated with most of the histologic features of the primary tumor. Univariate survival analysis (log-rank test) showed that high Ki-67 and mitotic count in the primary tumor and lymph node metastasis significantly predicted risk of recurrence. In multivariate analysis, mitotic count in the lymph node metastasis was an independent predictor of tumor recurrence. In conclusion, proliferation markers in lymph node metastases significantly predicted disease free survival in node positive breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783103PMC
August 2016

Increased angiogenesis is associated with a 32-gene expression signature and 6p21 amplification in aggressive endometrial cancer.

Oncotarget 2015 Apr;6(12):10634-45

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

Background: Angiogenesis is a hallmark of cancer. The aim of this study was to explore whether microvessel proliferation is associated with gene expression profiles or copy number alterations in endometrial cancer.

Methods: A prospective series of endometrial carcinomas was studied for angiogenesis markers, gene expression profiles, and gene copy number data. For validation, an independent series of endometrial carcinomas as well as an external cohort of endometrial cancer patients were examined by gene expression microarrays.

Results: Increased microvessel proliferation (MVP) was associated with aggressive tumor features and reduced survival, and a 32-gene expression signature was found to separate tumors with high versus low MVP. An increased 32-gene signature score was confirmed to associate with high-grade tumor features and reduced survival by independent cohorts. Copy number studies revealed that amplification of the 6p21 region was significantly associated with MVP, a high 32-gene score, as well as reduced survival.

Conclusion: Increased MVP was significantly associated with aggressive endometrial cancer and reduced survival. Integrated analyses demonstrated significant associations between increased vascular proliferation, amplification of the 6p21 region, VEGF-A mRNA expression, and the 32-gene angiogenesis signature. Our findings indicate amplification of 6p21 as a possible driver of tumor vascular proliferation in endometrial cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496381PMC
http://dx.doi.org/10.18632/oncotarget.3521DOI Listing
April 2015

Evaluation of Ki67 expression across distinct categories of breast cancer specimens: a population-based study of matched surgical specimens, core needle biopsies and tissue microarrays.

PLoS One 2014 6;9(11):e112121. Epub 2014 Nov 6.

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

Introduction: Tumor cell proliferation in breast cancer is strongly prognostic and may also predict response to chemotherapy. However, there is no consensus on counting areas or cut-off values for patient stratification. Our aim was to assess the matched level of proliferation by Ki67 when using different tissue categories (whole sections, WS; core needle biopsies, CNB; tissue microarrays, TMA), and the corresponding prognostic value.

Methods: We examined a retrospective, population-based series of breast cancer (n = 534) from the Norwegian Breast Cancer Screening Program. The percentage of Ki67 positive nuclei was evaluated by visual counting on WS (n = 534), CNB (n = 154) and TMA (n = 459).

Results: The median percentage of Ki67 expression was 18% on WS (hot-spot areas), 13% on CNB, and 7% on TMA, and this difference was statistically significant in paired cases. Increased Ki67 expression by all evaluation methods was associated with aggressive tumor features (large tumor diameter, high histologic grade, ER negativity) and reduced patient survival.

Conclusion: There is a significant difference in tumor cell proliferation by Ki67 across different sample categories. Ki67 is prognostic over a wide range of cut-off points and for different sample types, although Ki67 results derived from TMA sections are lower compared with those obtained using specimens from a clinical setting. Our findings indicate that specimen specific cut-off values should be applied for practical use.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112121PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223011PMC
April 2016
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