Publications by authors named "Marie-Louise Fjällskog"

37 Publications

Taxane-induced pain in breast cancer patients as perceived by nurses.

Acta Oncol 2021 Feb 10:1-7. Epub 2021 Feb 10.

Department of Public Health and Caring Sciences, Lifestyle and Rehabilitation in Long-Term Illness, Uppsala University, Uppsala, Sweden.

Introduction: Treatment with taxane-containing chemotherapy regimens is crucial for improving survival in patients with early-stage invasive breast cancer. Recent literature describes a high incidence of taxane-induced neuropathic pain or/and muscle and joint pain. For patients, oncology nurses can play an integral role as a resource for pain control. There is a knowledge gap regarding how nurses perceive patients' experienced taxane-induced pain and support from their organizations when caring for patients with such pain.

Aim: Investigate nurses' perceptions of occurrence of taxane-induced pain and identify organizational support for managing such pain.

Material And Methods: A cross-sectional observation study, conducted in 2017-2018, with a web-based questionnaire to 240 nurses working at oncology outpatient units in Sweden. The areas of concern were , , , , and , , , and were used to counteract such pain. Data were analyzed using descriptive statistics and a logistic regression model to estimate associations.

Results: One hundred sixty-one nurses completed the questionnaire, describing their perceptions of taxane-induced pain in patients with breast cancer. The prevalence and intensity of taxane-induced pain were experienced as divergent. Some consensus was found among the nurses regarding the start of the pain, but not when declined. The body areas where pain was expected to occur were the muscles, joints, legs, feet, and mainly the back of the trunk. Low use of local/national guidelines for managing taxane-induced pain was described. No relationship was found between factors related to the nurses' characteristics (age, work experience in oncology care, or specialist education in oncology) that significantly affected their perceptions regarding the occurrence of taxane-induced pain or pain intensity. Conclusion: This study highlights a need for attention to education and guidelines for how to observe, treat, and evaluate this particular type of pain.
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http://dx.doi.org/10.1080/0284186X.2021.1881816DOI Listing
February 2021

Ghrelin expression is associated with a favorable outcome in male breast cancer.

Sci Rep 2018 09 11;8(1):13586. Epub 2018 Sep 11.

Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden.

Ghrelin and obestatin are two gastrointestinal peptides, derived from a common precursor. Expression of both peptides have been found in breast cancer tissue and ghrelin has been associated with breast cancer development. Ghrelin expression is associated with longer survival in women diagnosed with invasive and node negative breast cancer. The clinical implications of the peptide expression in male breast cancer are unclear. The aim of this study was to investigate the role and potential clinical value of ghrelin and obestatin in male breast cancer. A tissue microarray of invasive male breast cancer specimens from 197 patients was immunostained with antibodies versus the two peptides. The expression of the peptides was correlated to previously known prognostic factors in breast cancer and to the outcome. No strong correlations were found between ghrelin or obestatin expression and other known prognostic factors. Only ghrelin expression was statistically significantly correlated to breast cancer-specific survival (HR 0.39, 95% CI 0.18-0.83) in univariate analyses and in multivariate models, adjusted for tumor size and node status (HR 0.38, 95% CI 0.17-0.87). HR for obestatin was 0.38 (95% CI 0.11-1.24). Ghrelin is a potential prognostic factor for breast cancer death in male breast cancer. Patients with tumors expressing ghrelin have a 2.5-fold lower risk for breast cancer death than those lacking ghrelin expression. Drugs targeting ghrelin are currently being investigated in clinical studies treating metabolic or nutritional disorders. Ghrelin should be further evaluated in forthcoming studies as a prognostic marker with the aim to be included in decision algorithms.
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http://dx.doi.org/10.1038/s41598-018-31783-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134078PMC
September 2018

Colored body images reveal the perceived intensity and distribution of pain in women with breast cancer treated with adjuvant taxanes: a prospective multi-method study of pain experiences.

Scand J Pain 2018 10;18(4):581-591

Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.

Background and aims Breast cancer is the most prevalent adult cancer worldwide. A broader use of screening for early detection and adjuvant systemic therapy with chemotherapy has resulted in improved survival rates. Taxane-containing chemotherapy is one of the cornerstones of the treatment. However, taxane-containing chemotherapy may result in acute chemotherapy-induced nociceptive and neuropathic pain. Since this pain may be an additional burden for the patient both during and after taxane chemotherapy, it is important to rapidly discover and treat it. There is yet no gold standard for assessing taxane-induced pain. In the clinic, applying multiple methods for collecting information on pain may better describe the patients' pain experiences. The aim was to document the pain during and after taxane through the contribution of different methods for collecting information on taxane-induced pain. Fifty-three women scheduled for adjuvant sequential chemotherapy at doses of ≥75 mg/m2 of docetaxel and epirubicin were enrolled in the study. Methods Prospective pain assessments were done on a visual analog scale (VAS) before and during each cycle of treatment for about 5 months, and using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire's (EORTC-QLQ-C30) two pain questions at baseline, 3 months, and 12 months. Participants scoring pain on the VAS >30 and undergoing an interview also colored their pain on a body image during treatment and at 12 months. Results Surprisingly widespread, intense pain was detected using a multi-method approach. The colored body image showed pain being perceived on 51% of the body surface area during treatment, and on 18% 12 months after inclusion. In general, the pain started and peaked in intensity after the first cycle of taxane. After Cycle 3, most women reported an increase in pain on the VAS. Some women continued to report some pain even during the epirubicin cycles. The VAS scores dropped after the last chemotherapy cycle, but not to the baseline level. At baseline, 3 months and 12 months after inclusion, the women who estimated VAS >30 reported higher levels of pain on the pain questions of the EORTC-QLQ-C30. Conclusions This study contributes information on how different pain assessment tools offer different information in the assessment of pain. The colored body image brings another dimension to pain diagnostics, providing additional information on the involved body areas and the pain intensities as experienced by the women. A multi-method approach to assessing pain offers many advantages. The timing of the assessment is important to properly assess pain. Implications Pain relief needs to be included in the chemotherapy treatment, with individual assessment and treatment of pain, in the same way as is done in chemotherapy-triggered nausea. There is a time window whereby the risk of pain development is at its highest within 24-48 h after receiving taxane chemotherapy. Proper attention to pain evaluation and treatment should be in focus during this time window.
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http://dx.doi.org/10.1515/sjpain-2018-0050DOI Listing
October 2018

Ghrelin is a prognostic marker and a potential therapeutic target in breast cancer.

PLoS One 2017 18;12(4):e0176059. Epub 2017 Apr 18.

Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden.

Ghrelin and obestatin are gastrointestinal peptides, encoded by the same preproghrelin gene. Both are expressed in breast cancer tissue and ghrelin has been implicated in breast cancer tumorigenesis. Despite recent advances in breast cancer management the need for new prognostic markers and potential therapeutic targets in breast cancer remains high. We studied the prognostic impact of ghrelin and obestatin in women with node negative breast cancer. Within a cohort of women with breast cancer with tumor size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy, 190 women were identified who died from breast cancer and randomly selected 190 women alive at the corresponding time as controls. Tumor tissues were immunostained with antibodies versus the peptides. Ghrelin expression was associated with better breast cancer specific survival in univariate analyses (OR 0.55, 95% CI 0.36-0.84) and in multivariate models, adjusted for endocrine treatment and age (OR 0.57, 95% CI 0.36-0.89). Obestatin expression was non-informative (OR 1.2, 95% CI 0.60-2.46). Ghrelin expression is independent prognostic factor for breast cancer death in node negative patients-halving the risk for dying of breast cancer. Our data implies that ghrelin could be a potential therapeutic target in breast cancer treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176059PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395214PMC
May 2017

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer.

Clin Cancer Res 2017 May 16;23(10):2575-2583. Epub 2016 Dec 16.

Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.

Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data Biomarkers were immunohistochemically assessed in 697 MBCs ( = 477, training; = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor. Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank = 0.013; HR = 1.77, 1.12-2.8 and = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed ( = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E = 0.016; HR = 2.38 (1.18-4.8), eIF5 = 0.022; HR = 2.55 (1.14-5.7); coexpression = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival. Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1952DOI Listing
May 2017

Women Treated for Breast Cancer Experiences of Chemotherapy-Induced Pain: Memories, Any Present Pain, and Future Reflections.

Cancer Nurs 2016 Nov/Dec;39(6):464-472

Author Affiliations: Department of Public Health and Caring Sciences, Uppsala University (Ms Hellerstedt-Börjesson, Drs Nordin, Holmström, and Arving); School of Health, Care and Social Welfare, Mälardalen University (Ms Holmström); and Department of Radiology, Oncology and Radiation Sciences, Uppsala University (Dr Fjällskog), Sweden.

Background: Breast cancer survivors make up a growing population facing treatment that poses long-standing adverse effects including chemotherapy-related body function changes and/or pain. There is limited knowledge of patients' lived experiences of chemotherapy-induced pain (CHIP).

Objective: The aim of this study was to explore CHIP and any long-standing pain experiences in the lifeworld of breast cancer survivors.

Methods: Fifteen women participated in a follow-up interview a year after having experienced CHIP. They were interviewed from a lifeworld perspective; the interviews were analyzed through guided phenomenology reflection.

Results: A past perspective: CHIP is often described in metaphors, leads to changes in a patient's lifeworld, and impacts lived time. The women become entirely dependent on others but at the same time feel isolated and alone. Existential pain was experienced as increased vulnerability. Present perspective: Pain engages same parts of the body, but at a lower intensity than during CHIP. The pain creates time awareness. Expected normality in relationships/daily life has not yet been achieved, and a painful existence emerges in-between health and illness. Future perspective: There are expectations of pain continuing, and there is insecurity regarding whom to turn to in such cases. A painful awareness emerges about one's own and others' fragile existence.

Conclusions: Experiencing CHIP can impact the lifeworld of women with a history of breast cancer. After CHIP, there are continued experiences of pain that trigger insecurity about whether one is healthy.

Implications For Practice: Cancer survivors would likely benefit from communication and information about and evaluation of CHIP.
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http://dx.doi.org/10.1097/NCC.0000000000000322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068191PMC
July 2017

Genome methylation patterns in male breast cancer - Identification of an epitype with hypermethylation of polycomb target genes.

Mol Oncol 2015 Oct 8;9(8):1565-79. Epub 2015 May 8.

Department of Oncology and Pathology, Clinical Sciences, and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden. Electronic address:

Male breast cancer (MBC) is a rare disease that shares both similarities and differences with female breast cancer (FBC). The aim of this study was to assess genome-wide DNA methylation profiles in MBC and compare them with the previously identified transcriptional subgroups of MBC, luminal M1 and M2, as well as the intrinsic subtypes of FBC. Illumina's 450K Infinium arrays were applied to 47 MBC and 188 FBC tumors. Unsupervised clustering of the most variable CpGs among MBC tumors revealed two stable epitypes, designated ME1 and ME2. The methylation patterns differed significantly between the groups and were closely associated with the transcriptional subgroups luminal M1 and M2. Tumors in the ME1 group were more proliferative and aggressive than ME2 tumors, and showed a tendency toward inferior survival. ME1 tumors also displayed hypermethylation of PRC2 target genes and high expression of EZH2, one of the core components of PRC2. Upon combined analysis of MBC and FBC tumors, ME1 MBCs clustered among luminal B FBC tumors and ME2 MBCs clustered within the predominantly luminal A FBC cluster. The majority of the MBC tumors remained grouped together within the clusters rather than being interspersed among the FBC tumors. Differences in the genomic location of methylated CpGs, as well as in the regulation of central canonical pathways may explain the separation between MBC and FBC tumors in the respective clusters. These findings further suggest that MBC is not readily defined using conventional criteria applied to FBC.
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http://dx.doi.org/10.1016/j.molonc.2015.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528783PMC
October 2015

Breast cancer with neoductgenesis: histopathological criteria and its correlation with mammographic and tumour features.

Int J Breast Cancer 2014 8;2014:581706. Epub 2014 Oct 8.

Department of Surgical Sciences, Uppsala University, 751 85 Uppsala, Sweden ; Department of Surgery, Uppsala Academic Hospital, 751 85 Uppsala, Sweden.

Introduction. Breast cancer with mammographic casting type calcifications, high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction, lymphocyte infiltration, and tenascin-C (TN-C) overexpression has been proposed to represent a more aggressive form of breast cancer and has been denominated as breast cancer with neoductgenesis. We developed histopathological criteria for neoductgenesis in order to study reproducibility and correlation with other tumour markers. Methods. 74 cases of grades 2 and 3 DCIS, with or without an invasive component, were selected. A combined score of the degree(s) of concentration of ducts, lymphocyte infiltration, and periductal fibrosis was used to classify cases as showing neoductgenesis, or not. Diagnostic reproducibility, correlation with tumour markers, and mammographic features were studied. Results. Twenty-three of 74 cases were diagnosed with neoductgenesis. The kappa value between pathologists showed moderate reproducibility (0.50) (95% CI; 0.41-0.60). Neoductgenesis correlated significantly with malignant type microcalcifications and TN-C expression (P = 0.008 and 0.04) and with ER, PR, and HER2 status (P < 0.00001 for all three markers). Conclusions. We developed histological criteria for breast cancer with neoductgenesis. Neoductgenesis, by our applied histopathological definition was related to more aggressive tumour biology and malignant mammographic calcifications.
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http://dx.doi.org/10.1155/2014/581706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220584PMC
November 2014

Cyclin E1 is a strong prognostic marker for death from lymph node negative breast cancer. A population-based case-control study.

Acta Oncol 2015 Apr 18;54(4):538-44. Epub 2014 Oct 18.

Department of Oncology, Uppsala University Hospital , Uppsala , Sweden.

Background: A large proportion of women with lymph node negative breast cancer treated with systemic adjuvant treatment do not benefit from such therapy since the patient is already cured by local treatment. Several studies have suggested that proliferation markers are strong prognostic factors in early breast cancer. Cyclins are probably the most specific markers of cell proliferation. Previously high expression of cyclin E has been associated with breast cancer recurrence.

Materials And Methods: In this study we investigate the prognostic value of cyclin E1 in node negative breast cancer patients. In a population-based cohort 186 women who died from breast cancer were defined as cases and 186 women alive at the corresponding time as controls. Inclusion criteria were tumour size ≤ 50 mm, no lymph node metastases and no adjuvant chemotherapy. The study was designed to detect an odds ratio of 2.5 with a power of 90% and significance level of 0.05. Cyclin E1 was determined with immunohistochemistry (IHC) on tissue microarray (TMA).

Results: High expression of cyclin E1 was significantly associated with breast cancer death, in both uni- and multivariate analyses with odds ratios (OR) 2.3 [univariate, 95% confidence interval (CI) 1.5-3.6] and 2.1 (multivariate, 95% CI 1.2-3.5).

Discussion: Cyclin E1 is a strong prognostic factor for breast cancer death in a population-based and node negative patient cohort and can identify high-risk patients in this group.
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http://dx.doi.org/10.3109/0284186X.2014.965274DOI Listing
April 2015

A Comparison of Tumor Biology in Primary Ductal Carcinoma In Situ Recurring as Invasive Carcinoma versus a New In Situ.

Int J Breast Cancer 2013 29;2013:582134. Epub 2013 Dec 29.

Department of Surgery, Uppsala University, Uppsala, Sweden.

Introduction. About half of all new ipsilateral events after a primary ductal carcinoma in situ (DCIS) are invasive carcinoma. We studied tumor markers in the primary DCIS in relation to type of event (invasive versus in situ). Methods. Two hundred and sixty-six women with a primary DCIS from two source populations, all with a known ipsilateral event, were included. All new events were regarded as recurrences. Patient and primary tumor characteristics (estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, and Ki67) were evaluated. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses. Results. One hundred and thirty-six of the recurrences were invasive carcinoma and 130 were in situ. The recurrence was more often invasive if the primary DCIS was ER+ (OR 2.5, 95% CI 1.2-5.1). Primary DCIS being HER2+ (OR 0.5, 95% CI 0.3-0.9), EGFR+ (OR 0.4, 95% CI 0.2-0.9), and ER95-/HER2+ (OR 0.2, 95% CI 0.1-0.6) had a lower risk of a recurrence being invasive. Conclusions. In this study, comparing type of recurrence after a DCIS showed that the ER-/HER2+ tumors were related to a recurrence being a new DCIS. And surprisingly, tumors being ER+, HER2-, and EGFR- were related to a recurrence being invasive cancer.
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http://dx.doi.org/10.1155/2013/582134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893751PMC
February 2014

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer.

Mod Pathol 2014 09 24;27(9):1223-30. Epub 2014 Jan 24.

1] Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Australia [2] Department of Pathology and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.

Male breast cancer is poorly understood with a large proportion arising in the familial context particularly with the BRCA2 germline mutation. As phenotypic and genotypic differences between sporadic and familial male breast cancers have been noted, we investigated the importance of a hypoxic drive in these cancers as this pathway has been shown to be of importance in familial female breast cancer. Expression of two major hypoxia-induced proteins, the hypoxia-inducible factor-1α (HIF1A) and the carbonic anhydrase IX (CA9), examined within a large cohort including 61 familial (3 BRCA1, 28 BRCA2, 30 BRCAX) and 225 sporadic male breast cancers showed that 31% of all male breast cancers expressed either HIF1A (25%) and/or CA9 (8%) in the combined cohort. Expression of HIF1A correlated with an increased incidence of a second-major malignancy (P=0.04), histological tumor type (P=0.005) and basal phenotype (P=0.02). Expression of CA9 correlated with age (P=0.004) in sporadic cases and an increased tumor size (P=0.003). Expression of HIF1A was prognostic for disease-specific survival in sporadic male breast cancers (HR: 3.8, 95% CI: 1.5-9.8, P=0.006) but not within familial male breast cancer, whereas CA9 was only prognostic in familial male breast cancers (HR: 358.0, 95% CI: 9.3-13781.7, P=0.002) and not in sporadic male breast cancer. This study found that hypoxic drive is less prevalent in male breast cancer compared with female breast cancer, possibly due to a different breast microenvironment. The prognostic impact of HIF1A is greatest in sporadic male breast cancers with an alternate dominant mechanism for the oncogenic drivers suggested in high risk familial male breast cancers.
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http://dx.doi.org/10.1038/modpathol.2013.231DOI Listing
September 2014

Women with breast cancer: experience of chemotherapy-induced pain: triangulation of methods.

Cancer Nurs 2015 Jan-Feb;38(1):31-9

Author Affiliations: Department of Public Health and Caring Sciences, Uppsala University, Sweden (Mrs Hellerstedt-Börjesson and Drs Nordin, Holmström, and Arving); Department of Global Public Health and Primary Care, University of Bergen, Norway (Dr Nordin); School of Health, Care and Social Welfare, Mälardalen University, Sweden (Dr Holmström); and Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Sweden (Dr Fjällskog).

Background: Chemotherapy treatment for cancer diseases can cause body pain during adjuvant therapy.

Objective: The aim was to describe the perceived impact of adjuvant chemotherapy-induced pain (CHIP) on the daily lives of women with newly diagnosed breast cancer, using triangulation.

Method: Fifty-seven women scheduled for chemotherapy in doses of 75 mg/m or greater of epirubicin and/or docetaxel participated. Twenty-two of these women registered pain with values of 4 or more on the visual analog scale on day 10 following chemotherapy. Of these 22, 16 participated in an interview and colored a printed body image. A qualitative thematic stepwise analysis of the interviews was performed.

Results: Chemotherapy-induced pain had a profound impact on daily life. Ten women reported the worst possible pain, with visual analog scale scores of 8 to 10. Three different categories crystallized: perception (A) of manageable pain, which allowed the women to maintain their daily lives; perception (B) of pain beyond imagination, whereby the impact of pain had become more complex; and perception (C) of crippling pain, challenging the women's confidence in survival.

Conclusions: The findings highlight the inability to capture CHIP with 1 method only; it is thus necessary to use complimentary methods to capture pain. We found that pain had a considerable impact on daily life, with surprisingly high scores of perceived pain, findings that to date have been poorly investigated qualitatively.

Implications For Practice: Nurses need to (1) better identify, understand and treat CHIP, using instruments and protocols; and (2) provide improved communication about pain and pain management.
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http://dx.doi.org/10.1097/NCC.0000000000000124DOI Listing
June 2016

The prognostic value of mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A, and Ki67, alone and in combinations, in node-negative premenopausal breast cancer.

PLoS One 2013 4;8(12):e81902. Epub 2013 Dec 4.

Department of Clinical Sciences, Division of Oncology, Lund University, Lund, Sweden ; Skåne Department of Oncology, Skåne University Hospital, Lund, Sweden.

Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off ≥10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95%CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95%CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95%CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95%CI: 1.1-6.7), and cyclin A (HR=2.7, 95%CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081902PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852976PMC
September 2014

Molecular subtypes in ductal carcinoma in situ of the breast and their relation to prognosis: a population-based cohort study.

BMC Cancer 2013 Oct 30;13:512. Epub 2013 Oct 30.

Department of Surgical Science, Uppsala University, Uppsala SE-75105, Sweden.

Background: Different molecular subtypes of breast cancer have been identified based on gene expression profiling. Treatment suggestions based on an approximation of these subtypes by immunohistochemical criteria have been published by the St Gallen international expert consensus panel. Ductal carcinoma in situ (DCIS) can be classified into the same molecular subtypes. Our aim was to study the relation between these newly defined subtypes and prognosis in DCIS.

Methods: TMA including 458 women from a population-based cohort with DCIS diagnosed 1986-2004 was used. Stainings for ER, PR, HER2 and Ki67 were used to classify the surrogate molecular subtypes according to the St Gallen criteria from 2011. The associations with prognosis were examined using Kaplan-Meier analyses and Cox proportional hazards regression models.

Results: Surrogate molecular subtyping could be done in 381 cases. Mean follow up was 164 months. Of the classified DCIS 186 were Luminal A (48.8%), 33 Luminal B/HER2- (8.7%), 74 Luminal B/HER2+ (17.4%), 61 HER2+/ER- (16.0%) and 27 Triple Negative (7.1%). One hundred and two women had a local recurrence of which 58 were invasive. Twenty-two women had generalised disease, 8 without a prior local recurrence. We could not find a prognostic significance of the molecular subtypes other than a higher risk of developing breast cancer after more than 10 years of follow-up among women with a Triple Negative DCIS (OR 3.2; 95% CI 1.1-9.8).

Conclusions: The results from this large population-based cohort, with long-term follow up failed to demonstrate a prognostic value for the surrogate molecular subtyping of DCIS using the St Gallen criteria up to ten years after diagnosis. More than ten years after diagnosis Triple Negative DCIS had an elevated risk of recurrence.
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http://dx.doi.org/10.1186/1471-2407-13-512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228470PMC
October 2013

The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naïve women with N0/N1 primary breast cancer.

Springerplus 2013 Dec 14;2(1):111. Epub 2013 Mar 14.

Division of Oncology, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Barngatan 2B, SE-221 85 Lund, Sweden.

Background: The aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naïve breast cancer patients.

Methodsdesign: In the present study, including 1,854 patients, Ki67 was used in the index (KiGE), since it is the generally accepted proliferation marker in clinical routine. The low KiGE-group was defined as histological grade 1 patients and grade 2 patients which were ER-positive and had low Ki67 expression. All other patients made up the high KiGE-group. The KiGE-index separated patients into two groups with different prognosis. In multivariate analysis, KiGE was significantly associated with disease-free survival, when adjusted for age at diagnosis, tumor size and adjuvant endocrine treatment (hazard ratio: 3.5, 95% confidence interval: 2.6-4.7, P<0.0001).

Discussion: We have confirmed a prognostic index based on a proliferation marker (Ki67), histological grade, and ER for identification of a low-risk group of patients with N0/N1 primary breast cancer. For this low-risk group constituting 57% of the patients, with a five-year distant disease-free survival of 92%, adjuvant chemotherapy will have limited effect and may be avoided.
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http://dx.doi.org/10.1186/2193-1801-2-111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613571PMC
December 2013

Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact.

Acta Oncol 2013 Jan 29;52(1):102-9. Epub 2012 Aug 29.

Center for Clinical Research, Västmanland County Hospital, Västerås, Sweden.

Background: Male breast cancer (MBC) is an uncommon disease and there is limited information on the prognostic impact of routinely used clinicopathological parameters.

Material And Methods: In a retrospective setting, we reviewed 197 MBC patients with accessible paraffin-embedded tumor tissue and clinicopathological data. Immunohistochemical (IHC) stainings were performed on tissue microarrays and histological grading on conventional slides. Cox proportional regression models were applied for uni- and multivariate analyses using breast cancer death as the event.

Results: Estrogen receptor (ER) and progesterone receptor positivity were demonstrated in 93% and 77% of patients, respectively. Nottingham histologic grade (NHG) III was seen in 41% and HER2 positivity in 11%. Classification into molecular subtypes using IHC markers according to three alternative definitions revealed luminal A and luminal B in 81% vs. 11%; 48% vs. 44% and 41% vs. 42% of cases. Two cases of basal-like were identified, but no cases of HER2-like. Factors associated with an increased risk of breast cancer death were node positivity (HR 4.5; 95% CI 1.8-11.1), tumor size > 20 mm (HR 3.3; 95% CI 1.4-7.9) and ER negativity (HR 10.9; 95% CI 3.2-37.9). No difference in breast cancer death between the luminal subgroups was demonstrated, regardless of definition.

Conclusion: MBC tumors were more often of high grade, whereas HER2 overexpression was as frequent as in FBC. Lymph nodes, tumor size and ER status were independent predictors of breast cancer death. The prognostic impact of molecular subtyping in MBC seems to differ from that previously established in FBC.
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http://dx.doi.org/10.3109/0284186X.2012.711952DOI Listing
January 2013

High proliferation is associated with inferior outcome in male breast cancer patients.

Mod Pathol 2013 Jan 24;26(1):87-94. Epub 2012 Aug 24.

Department of Oncology, Center for Clinical Research, Västmanland County Hospital, Västerås, Sweden.

Assessment of proliferation is important in female breast cancer and individual treatment decisions are based upon its results, especially in the luminal subgroups. Gene expression analyses fail to group male breast cancer into the intrinsic subgroups previously established in female breast cancer. Even though proliferation has been shown to divide male breast cancer into molecular subgroups with different prognoses, the clinical importance of proliferation markers has not yet been elucidated. Previous studies in male breast cancer have demonstrated contradictory results regarding the prognostic impact of histological grade and Ki-67, parameters strongly associated with proliferation. The aim of the present project was to study proliferation in male breast cancer by assessing other proliferation-related markers viz. cyclins A, B, D1 and mitotic count. A total of 197 male breast cancer cases with accessible paraffin-embedded material and outcome data were investigated. Immunohistochemical stainings were performed on tissue microarrays. Kaplan-Meier estimates and the Cox proportional regression models were used for survival analyses with breast cancer death as the event. The subset of patients with high expression of cyclin A (hazard ratio (HR) 3.7; P=0.001) and B (HR 2.7; P=0.02) demonstrated a poorer survival. Furthermore, high mitotic count was associated with an increased risk of breast cancer death (HR 2.5; P=0.01). In contrast, cyclin D1 overexpression was predictive of better breast cancer survival (HR 0.3; P=0.001). In conclusion, high levels of cyclin A and B expression and an elevated mitotic count result in a two to threefold higher risk for breast cancer death, whereas cyclin D1 overexpression halves the risk. The clinical utility of these proliferation markers needs further elucidation.
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http://dx.doi.org/10.1038/modpathol.2012.145DOI Listing
January 2013

Design of the study: how can health care help female breast cancer patients reduce their stress symptoms? A randomized intervention study with stepped-care.

BMC Cancer 2012 May 4;12:167. Epub 2012 May 4.

Department of Public Health and Caring Sciences, Uppsala University, Uppsala, SE-751 22, Sweden.

Background: A life threatening illness such as breast cancer can lead to a secondary diagnosis of PTSD (post traumatic stress disorder) with intrusive thoughts and avoidance as major symptoms. In a former study by the research group, 80% of the patients with breast cancer reported a high level of stress symptoms close to the diagnosis, such as intrusive thoughts and avoidance behavior. These symptoms remained high throughout the study. The present paper presents the design of a randomized study evaluating the effectiveness and cost-effectiveness of a stress management intervention using a stepped-care design.

Method: Female patients over the age of 18, with a recent diagnosis of breast cancer and scheduled for adjuvant treatment in the form of chemotherapy, radiation therapy and/or hormonal therapy are eligible and will consecutively be included in the study. The study is a prospective longitudinal intervention study with a stepped-care approach, where patients will be randomised to one of two interventions in the final stage of treatment. The first step is a low intensity stress-management intervention that is given to all patients. Patients who do not respond to this level are thereafter given more intensive treatment at later steps in the program and will be randomized to more intensive stress-management intervention in a group setting or individually. The primary out-come is subjective distress (intrusion and avoidance) assessed by the Impact of Event Scale (IES). According to the power-analyses, 300 patients are planned to be included in the study and will be followed for one year. Other outcomes are anxiety, depression, quality of life, fatigue, stress in daily living and utilization of hospital services. This will be assessed with well-known psychometric tested questionnaires. Also, the cost-effectiveness of the intervention given in group or individually will be evaluated.

Discussion: This randomized clinical trial will provide additional empirical evidence regarding the effectiveness of a stress-management program given in group or individually during adjuvant therapy in terms of decreased stress, minimizing fatigue, and maintaining or enhancing patients' quality of life and psychological well-being.

Trial Registration: ClinicalTrials.gov Identifier: NCT01555645.
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http://dx.doi.org/10.1186/1471-2407-12-167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422160PMC
May 2012

Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker.

Breast Cancer Res 2012 Feb 14;14(1):R31. Epub 2012 Feb 14.

Department of Oncology, Clinical Sciences, Lund University, Barngatan 2B, SE 22185 Lund, Sweden.

Introduction: Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC).

Methods: A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs.

Results: Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC.

Conclusions: We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.
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http://dx.doi.org/10.1186/bcr3116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496149PMC
February 2012

Inflammatory cells in node-negative breast cancer.

Acta Oncol 2012 May 24;51(5):680-6. Epub 2012 Jan 24.

Department of Oncology and Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

Background: To study the impact of inflammatory cells in a clinically well-defined cohort of women with node-negative breast cancer in a nested case-control study design.

Material And Methods: The cohort was comprised of 190 women who died from breast cancer and 190 women still alive at the date of death for the corresponding breast cancer patients were used as controls. The inclusion criteria included; a tumour size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy. Immunohistochemical stainings for CD3, CD4, CD8, FoxP3, CD20, tryptase and CD68 were performed on TMA blocks, evaluated and correlated to each other and to age, tumour size, histological grade, ER, PgR, Ki67 and cyclin A.

Results: There was no difference regarding the amount or content of inflammatory cells in the cases compared to controls. T- and B-cells were highly correlated to each other but these cell types correlated to a lesser extent to macrophages and not at all to mast cells. A weak tendency of correlations between all the subsets of inflammatory cells and histological grade, Ki67 and cyclin A was observed, although a negative correlation was seen for mast cells.

Conclusion: The amount or content of inflammatory cells in invasive breast cancer did not appear to influence death in node-negative breast cancer.
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http://dx.doi.org/10.3109/0284186X.2011.652737DOI Listing
May 2012

Expression of ghrelin is correlated to a favorable outcome in invasive breast cancer.

Acta Oncol 2012 Mar 9;51(3):386-93. Epub 2011 Nov 9.

Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden.

Background: Expression of the peptide hormones ghrelin and obestatin has previously been demonstrated in human mammary glands. However, the clinical implications of the expression of these peptides in breast cancer are unclear. The aim of this study was to investigate the potential clinical value of ghrelin and obestatin as breast cancer biomarkers.

Methods: A tissue microarray containing breast cancer specimens from 144 patients was immunostained with antibodies directed towards ghrelin and obestatin. Using varying cut-offs, the expression of the two peptides was evaluated and correlated to previously known prognostic factors in breast cancer and to the outcome. Cox regression analysis was used to assess whether these markers may predict survival of breast cancer patients.

Results: Moderate to strong immunoreactivity for ghrelin and obestatin was observed in 71.5% and 77.1% of the cases, respectively. Ghrelin and obestatin expression was significantly but weakly correlated to low histological grade, estrogen receptor positivity, small tumor size and low proliferation. Only ghrelin expression was significantly correlated to better recurrence-free and breast cancer-specific survival (HR = 0.3-0.4, p = 0.02-0.05) in both uni- and multivariate analyses. The optimal cut-off was any ghrelin expression versus none. Reproducibility between the two readers was very good for both stainings with kappa values of 0.94-1.00.

Conclusions: Patients with tumors expressing ghrelin had 2.5-3 times lower risk for recurrence or breast cancer death than those lacking ghrelin expression. Ghrelin expression is easily assessable with high reproducibility using immunohistochemistry. Further investigations are needed to establish the clinical significance of ghrelin as a biomarker in breast cancer.
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http://dx.doi.org/10.3109/0284186X.2011.631576DOI Listing
March 2012

Similarities and differences in the characteristics and primary treatment of breast cancer in men and women - a population based study (Sweden).

Acta Oncol 2011 Oct 11;50(7):1083-8. Epub 2011 Aug 11.

Department of Radiology, Oncology and Radiation Science, Uppsala University Hospital, Sweden.

Purpose: Male breast cancer (MBC) is an uncommon disease. In the absence of randomized studies, current guidelines are mainly based on data on the management of female breast cancer (FBC). In light of concerns regarding the quality and extent of management in men, the aim of the present study was to investigate whether there are differences in tumor characteristics, treatment and outcome in male compared with FBC patients.

Methods: Cohorts of male and female breast cancer were retrospectively analyzed. All male patients diagnosed with invasive breast cancer between 1993 and 2007 were identified from the Regional Breast Cancer Register of the Uppsala-Örebro Region in Sweden. To increase the power of the study and obtain comparable cohorts we sampled four FBC patients (n = 396) for each MBC patient (n = 99) with similar age at diagnosis and time of diagnosis.

Results: No differences were seen in stage at diagnosis between MBC and FBC. Men underwent mastectomy more often than women (92% vs. 44%, p < 0.001). Radiotherapy was delivered less often to MBC than FBC (44% vs. 56%, p = 0.034), but radiotherapy given after mastectomy (44% vs. 39%, p = 0.47) did not differ between the groups. No differences were found regarding adjuvant chemotherapy (16% vs. 21%; p = 0.31) or adjuvant endocrine therapy (59% vs. 52%, p = 0.24). Both overall survival (41% vs. 55%, p = 0.001) and relative survival (74% vs. 88%, p = 0.015) were inferior in MBC compared to FBC.

Conclusion: Concerns regarding less extensive treatment in MBC patients were not supported by this study. Although no differences in the stage of the disease or treatment intensity could be demonstrated, outcome was inferior in the male group.
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http://dx.doi.org/10.3109/0284186X.2011.602114DOI Listing
October 2011

Combination of the proliferation marker cyclin A, histological grade, and estrogen receptor status in a new variable with high prognostic impact in breast cancer.

Breast Cancer Res Treat 2012 Jan 18;131(1):33-40. Epub 2011 Feb 18.

Department of Oncology, Clinical Sciences Lund, Lund University, Skåne University Hospital, SE-22185 Lund, Sweden.

Global gene expression profiles, consisting mainly of genes associated with proliferation, have been shown to subdivide histological grade 2 breast cancers into groups with different prognosis. We raised the question whether this subdivision could be done using a single proliferation marker, cyclin A. Furthermore, we combined cyclin A (CA), histological grade (G), and estrogen receptor--ER (E) into a new variable, CAGE. Our aim was to investigate not only the prognostic importance of cyclin A alone but also the value of the combination variable CAGE. In 219 premenopausal node-negative patients, cyclin A was assessed using immunohistochemistry on tissue microarrays. High cyclin A was defined as above the seventh decile of positive cells. Only 13% of the patients received adjuvant systemic therapy. Cox proportional hazards regression was used to model the impact of the factors on distant disease-free survival (DDFS). Cyclin A divided histological grade 2 tumors into two groups with significantly different DDFS (hazard ratio [HR]: 15, P < 0.001). When stratifying for ER status, cyclin A was a prognostic factor only in the ER positive subgroup. We found that CAGE was an independent prognostic factor for DDFS in multivariate analysis (HR: 4.1, P = 0.002), together with HER2. CAGE and HER2 identified 53% as low-risk patients with a 5-year DDFS of 95%. A new prognostic variable was created by combining cyclin A, histological grade, and ER (CAGE). CAGE together with HER2 identified a large low-risk group for whom adjuvant chemotherapy will have limited efficacy and may be avoided.
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http://dx.doi.org/10.1007/s10549-011-1386-5DOI Listing
January 2012

High-resolution genomic profiling of male breast cancer reveals differences hidden behind the similarities with female breast cancer.

Breast Cancer Res Treat 2011 Oct 27;129(3):747-60. Epub 2010 Nov 27.

Department of Oncology, Clinical Sciences, Lund University, BMC C13, 22184 Lund, Sweden.

Male breast cancer (MBC) is extremely rare and poorly characterized on the molecular level. Using high-resolution genomic data, we aimed to characterize MBC by genomic imbalances and to compare it with female breast cancer (FBC), and further to investigate whether the genomic profiles hold any prognostic information. Fifty-six fresh frozen MBC tumors were analyzed using high-resolution tiling BAC arrays. Significant regions in common between cases were assessed using Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. A publicly available genomic data set of 359 FBC tumors was used for reference purposes. The data revealed a broad pattern of aberrations, confirming that MBC is a heterogeneous tumor type. Genomic gains were more common in MBC than in FBC and often involved whole chromosome arms, while losses of genomic material were less frequent. The most common aberrations were similar between the genders, but high-level amplifications were more common in FBC. We identified two genomic subgroups among MBCs; male-complex and male-simple. The male-complex subgroup displayed striking similarities with the previously reported luminal-complex FBC subgroup, while the male-simple subgroup seems to represent a new subgroup of breast cancer occurring only in men. There are many similarities between FBC and MBC with respect to genomic imbalances, but there are also distinct differences as revealed by high-resolution genomic profiling. MBC can be divided into two comprehensive genomic subgroups, which may be of prognostic value. The male-simple subgroup appears notably different from any genomic subgroup so far defined in FBC.
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http://dx.doi.org/10.1007/s10549-010-1262-8DOI Listing
October 2011

[Ki-67 and cyclin A--prognostic factors in breast cancer. Time to introduce proliferation markers in clinical routine].

Lakartidningen 2010 Mar 10-16;107(10):672-5

Gynonkologiska kliniken, Universitetssjukhuset, Orebro.

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April 2010

Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer.

Acta Oncol 2010 Aug;49(6):816-20

Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.

Unlabelled: Patients with low-risk node negative breast cancer have an excellent prognosis with 5% breast cancer mortality at 10 years. However, prognostic factors are needed to identify poor prognostic patients who might benefit from adjuvant systemic therapy. Proliferation has been identified as the most important component of gene expression profiles. Cyclin B is a proliferative marker easily assessed by immunohistochemistry. We wanted to examine cyclin B as a prognostic factor in low-risk breast cancer patients.

Patients And Methods: Using an experimental study design, we compared women dying early from their breast cancer (n=17) with women free from relapse more than eight years after initial diagnosis (n=24). All women had stage I, node negative and hormone receptor positive disease. None had received adjuvant chemotherapy. Tumor samples were immunostained for cyclin B using commercial antibodies.

Results: The mean percentage of cyclin B (12%) was significantly higher (p=0.001) in women dying from their breast cancer compared with women free from relapse (5%). High cyclin B (> or =9%) identified 11/17 patients dying from breast cancer and low cyclin B identified 22/24 patients free from relapse. The sensitivity and specificity of cyclin B was 65% and 92%, respectively.

Discussion: We found that low-risk node negative patients with high expression of cylin B had a significantly worse outcome than patients with low expression of cyclin B. Cyclin B could separate patients with poor survival from those with good survival with 80% accuracy. We suggest that cyclin B might be a potent prognostic factor in this low-risk patient group.
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http://dx.doi.org/10.3109/02841861003691937DOI Listing
August 2010

Cyclin A is a proliferative marker with good prognostic value in node-negative breast cancer.

Cancer Epidemiol Biomarkers Prev 2009 Sep 25;18(9):2501-6. Epub 2009 Aug 25.

Department of Oncology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.

Background: Proliferative markers are not recommended as prognostic factors for clinical use in breast cancer due to lack of standardization in methodology. However, proliferation is driving several gene expression signatures emphasizing the need for a reliable proliferative marker for clinical use. Studies suggest that cyclin A is a prognostic marker with satisfying reproducibility. We investigated cyclin A as a prognostic marker in node-negative breast cancer using previously defined cutoff values.

Patients And Methods: In a case-control study, we defined 190 women who died from breast cancer as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size
Results: We found a statistically significant association between expression of cyclin A and breast cancer death in a univariate model: odds ratio for cyclin A(ave) 2.7 [95% confidence interval (CI), 1.7-4.3] and cyclin A(max) 3.4 (CI, 2.1-5.5). Corresponding odds ratio for Ki67 were Ki67(ave) 1.9 (CI, 1.2-3.1) and Ki67(max) 1.7 (CI, 1.1-2.7) and for grade 3.1 (CI, 1.8-5.1). Cyclin A was strongly correlated to Ki67 and grade why a model including all was not appropriate.

Conclusions: Cyclin A is a prognostic factor for breast cancer death in node-negative patients using standardized methodology regarding scoring and cutoff values. Adding cyclin A as a proliferative marker to established clinicopathologic factors will improve the separation of low and high risk breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-09-0169DOI Listing
September 2009

Aberrant expression of cyclin E in low-risk node negative breast cancer.

Acta Oncol 2008 ;47(8):1539-45

Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden.

Background: Cyclin E is a cell cycle regulatory protein which occurs in G1, peaks in late G1 and is degraded in early S-phase. Cyclin E overexpression appears to be an independent prognostic factor for overall survival in breast cancer. Nuclear cyclin A is a reliable marker for S-and G2-phases. Consequently, aberrant expression of cyclin E can be detected by simultaneous immunostainings for cyclin A and cyclin E. Studies have shown that aberrant cyclin E might provide additional prognostic information compared to that of cyclin E alone. This study aimed to investigate cyclin E and aberrant cyclin E expression in low-risk node negative breast cancer.

Material And Methods: We compared women that died from their breast cancer (n=17) with women free from relapse > 8 years after initial diagnosis (n=24). All women had stage I, low risk breast cancer. The groups were matched regarding tumour size, receptor status, adjuvant chemotherapy and tumour differentiation. Tumour samples were analysed regarding expression of cyclin A, cyclin E and double-stained tumour cells using immunoflourescence staining and digital microscopy.

Results: No differences were seen regarding expression of cyclin E or aberrant cyclin E in cases compared to controls.

Discussion: We conclude that neither cyclin E nor aberrant cyclin E is a prognostic factor in low-risk node negative breast cancer patients.
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http://dx.doi.org/10.1080/02841860701856581DOI Listing
December 2008

Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors.

Neuroendocrinology 2008 18;88(1):53-8. Epub 2008 Feb 18.

Department of Oncology, Uppsala University, Uppsala, Sweden.

Unlabelled: Treatment with combined streptozotocin and liposomal doxorubicin is safe and efficient in patients with endocrine pancreatic tumors (EPTs). No cardiac toxicity was reported.

Background: The combination of streptozotocin and doxorubicin has been shown to be superior to streptozotocin and fluorouracil in the treatment of metastatic EPTs. However, the risk of cardiac toxicity from anthracyclins hampers the usefulness of the drug combination. Liposomal doxorubicin has a lower frequency of cardiac adverse events compared to doxorubicin. We wanted to assess the efficacy and safety of combined streptozotocin and liposomal doxorubicin in patients with metastatic EPTs.

Methods: Thirty patients with metastatic EPTs were recruited from three medical centers in Norway and Sweden during a time period of 3 years. All patients had histopathologically confirmed diagnoses and bidimensionally measurable lesions. 30 mg/m(2) of liposomal doxorubicin was administered on day 1 of each cycle. During the first course, 1 g of streptozotocin was given on 5 consecutive days. Thereafter, 2 g of streptozotocin was given on day 1 only. Treatment was repeated every 3 weeks.

Results: Twelve of 30 patients (40%) achieved an objective radiological response with a median duration of 9 months. Stabilization of disease was achieved in 17 of 30 patients (57%) for a median duration of 11 months. Only one patient had progressive disease as best response. The 2-year progression-free survival was 18% and the 2-year overall survival was 72%. The treatment was well tolerated. None of the patients experienced cardiac toxicity.

Conclusion: We conclude that combined streptozotocin and liposomal doxorubicin is a safe and efficient treatment for EPTs. The efficacy seems to be comparable to that of combined streptozotocin and doxorubicin, whereas the cardiac toxicity clearly favors using the liposomal drug combination.
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http://dx.doi.org/10.1159/000117575DOI Listing
December 2008

Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas.

Acta Oncol 2007 ;46(6):741-6

Department of Oncology, University Hospital, Uppsala, Sweden.

Platelet-derived growth factor receptor (PDGFR) beta signaling is involved in autocrine growth stimulation of tumor cells, tumor angiogenesis and regulation of tumor interstitial fluid pressure. Development of PDGFR antagonists has further increased the interest for PDGFR as targets for anticancer treatments. Malignant endocrine pancreatic tumors (EPTs) express PDGFR beta both in stroma and on tumor cells. To investigate the role of PDGFR beta signaling in EPTs we compared PDGFR beta expression in normal endocrine pancreas to malignant EPTs and metastases. PDGFR beta expression was examined by immunohistochemistry using specific polyclonal antibodies in ten tissue samples from normal endocrine pancreas, 21 from primary EPTs and 19 from metastases. In eight patients we compared the expression in normal endocrine pancreas to the corresponding primary tumor and metastases, in two patients normal tissue to the primary tumor and in 11 patients primary tumors to the corresponding metastases. Six of ten tissues containing normal pancreas stained negative for PDGFR beta on endocrine cells, while seven of ten stained positive in the stroma. Eighteen of 21 (86%) primary tumors stained positive for PDGFR beta on tumor cells and all had positive stroma stainings. All 19 metastases stained positive for PDGFR beta on tumor cells and in evaluable stroma (n=16). We have found that PDGFR beta is more frequently expressed in primary EPTs and metastases as compared to normal endocrine pancreatic tissue. This is also true for PDGFR beta expression in the corresponding stroma. We suggest that new therapeutic options to inhibit the growth and spread of EPTs could include targeting of PDGFR beta.
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http://dx.doi.org/10.1080/02841860601048388DOI Listing
October 2007