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  • 1. Aaltonen, Kirsimari
    et al.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Landberg, Göran
    Eerola, Hannaleena
    Aittomäki, Kristiina
    Heikkilä, Päivi
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer2009In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 113, no 1, p. 75-82Article in journal (Refereed)
    Abstract [en]

    Cyclins D1 and E play an important role in breast carcinogenesis. High cyclin E expression is common in hormone receptor negative and high grade aggressive breast cancer, whereas cyclin D1 in hormone receptor positive and low grade breast cancer. Experimental data has suggested that cyclin D1 and E mediate cell proliferation by different mechanisms in estrogen receptor (ER) positive and negative breast cancer. To test this hypotheses in large breast cancer material and to clarify the histopathological correlations of cyclin E and D1, especially the association with proliferation, we analyzed cyclin E and D1 immunohistochemical expression on breast tumour microarrays consisting of 1348 invasive breast cancers. High cyclin D1 expression was associated with high grade (P<0.0005), high cyclin A (P<0.0005) and Ki67 (P<0.0005) expression among ER positive but with low grade (P=0.05) and low Ki67 (P=0.01) expression among ER negative breast cancers. Cyclin E and D1 expression correlated positively in ER positive (P<0.0005) but had a negative correlation in ER negative tumours (P=0.004). Cyclin E associated with high grade among all tumours (P<0.0005). In conclusion, the findings of this study show that cyclin D1 has separate roles, and proliferation is driven by different mechanisms in ER positive and negative breast cancers.

  • 2.
    Ahlin, Cecilia
    et al.
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Lundgren, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Embretsen-Varro, Elin
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Jirstrom, Karin
    Lund Univ, Dept Pathol & Oncol, Lund, Sweden..
    Blomqvist, Carl
    Orebro Univ, Dept Oncol, Orebro, Sweden.;Univ Helsinki, Dept Oncol, Helsinki, Finland..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers2017In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 164, no 3, p. 667-678Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (rho 0.19, p = 0.006) and B (rho 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.

  • 3.
    Bens, Annet
    et al.
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Papadopoulos, Fotios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Pukkala, Eero
    Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, Helsinki, Finland.;Univ Tampere, Fac Social Sci, Tampere, Finland..
    Ekbom, Anders
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Gissler, Mika
    THL Natl Inst Hlth & Welf, Informat Serv Dept, Helsinki, Finland.;Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Mellemkjaer, Lene
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Worse survival after breast cancer in women with anorexia nervosa2018In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, no 2, p. 495-500Article in journal (Refereed)
    Abstract [en]

    A history of anorexia nervosa has been associated with a reduced risk of developing breast cancer. We investigated survival after breast cancer among women with a prior anorexia nervosa diagnosis compared with women in a population comparison group. This register-based study included combined data from Sweden, Denmark and Finland. A total of 76 and 1462 breast cancer cases identified among 22,654 women with anorexia nervosa and 224,619 women in a population comparison group, respectively, were included in the study. Hazard ratios (HR) for overall and breast cancer-specific mortality after breast cancer diagnosis were estimated using Cox regression. Cause of death was available only for Swedish and Danish women; therefore, the analysis on breast cancer-specific mortality was restricted to these women. We observed 23 deaths after breast cancer among anorexia nervosa patients and 247 among population comparisons. The overall mortality after the breast cancer diagnosis was increased in women with a history of anorexia nervosa compared with population comparisons (HR 2.5, 95% CI 1.6-3.9) after adjustment for age, period and extent of disease. Results were similar for overall (HR 2.3, 95% CI 1.4-3.6) and breast cancer-specific mortality (HR 2.1, 95% CI 1.3-3.6) among Swedish and Danish women. We found that female breast cancer patients with a prior diagnosis of anorexia nervosa have a worse survival compared with other breast cancer patients.

  • 4.
    Berglund, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wigertz, Annette
    Adolfsson, Jan
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Fornander, Tommy
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lambe, Mats
    Impact of comorbidity on management and mortality in women diagnosed with breast cancer2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 135, no 1, p. 281-289Article in journal (Refereed)
    Abstract [en]

    To investigate associations between comorbidity burden, management, and mortality in women with breast cancer. A total of 42,646 women diagnosed with breast cancer between 1992 and 2008 were identified in two Clinical Quality Registers in Central Sweden. Breast cancer-specific, conditional breast cancer, competing-cause and all-cause mortality were estimated in relation to comorbidity burden assessed by the Charlson comorbidity index. All analyses were stratified by stage at diagnosis using competing risk analyses, and all-cause mortality was estimated as a function of follow-up time. Following adjustment for age and calendar period, breast conserving surgery was significantly less likely to be offered to women with severe comorbidity (OR 0.63; 95 % CI 0.58-0.69). Similarly, the proportion treated with radiotherapy, tamoxifen, or chemotherapy was lower in women with severe compared to those with no comorbidity. In women with early stage disease, breast cancer-specific mortality was higher among patients with severe comorbidity (sHR 1.47; 95 % CI 1.11-1.94). In all stages of breast cancer, conditional breast cancer and competing-cause mortality were elevated in women with severe comorbidity. For all stages, the relative risk of all-cause mortality between women with severe versus no comorbidity varied by time since diagnosis, and was most pronounced at early follow-up. Comorbidity affects treatment decisions and mortality. In women with early stage breast cancer, severe comorbidity was associated not only with conditional breast cancer, competing-cause and all-cause mortality, but also breast cancer-specific mortality. The observed differences in breast cancer-specific mortality may be due to less extensive treatment, impaired tumor defense and differences in general health status and lifestyle factors.

  • 5. Bjohle, J.
    et al.
    Bergqvist, J.
    Gronowitz, J. Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Johansson, H.
    Carlsson, L.
    Einbeigi, Z.
    Linderholm, B.
    Loman, N.
    Malmberg, M.
    Soderberg, M.
    Sundquist, M.
    Walz, T. M.
    Ferno, M.
    Bergh, J.
    Hatschek, T.
    Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 139, no 3, p. 751-758Article in journal (Refereed)
    Abstract [en]

    The primary objective was to estimate serum thymidine kinase 1 (TK1) activity, reflecting total body cell proliferation rate including cancer cell proliferation, in women with loco regional inoperable or metastatic breast cancer participating in a prospective and randomized study. Secondary objectives were to analyze TK1 in relation to progression-free survival (PFS), overall survival (OS), therapy response and other tumour characteristics, including CA 15-3, widely used as a standard serum marker for disease progression. TK1 and CA 15-3 were analysed in 198 serum samples collected prospectively from women included in the randomized TEX trial between December 2002 and June 2007. TK1 activity was determined by the ELISA based DiviTum (TM) assay, and CA 15-3 analyses was generated with the electrochemiluminescence immunoassay Cobas Elecsys CA 15-3 II. High pre-treatment TK1 activity predicted shorter PFS (10 vs. 15 months p = 0.02) and OS (21 vs. 38 months, p < 0.0001), respectively. After adjustment for age, metastatic site and study treatment TK1 showed a trend as predictor of PFS (p = 0.059) and was an independent prognostic factor for OS, (HR 1.81, 95 % confidence interval (CI) 1.26-2.61, p = 0.001). There was a trend of shortened OS for women with high CA 15-3 (p = 0.054) in univariate analysis, but not after adjustment for the above mentioned covariates. Both TK1 (p = 0.0011) and CA 15-3 (p = 0.0004) predicted response to treatment. There were statistically different distributions of TK1 and CA 15-3 in relation to the site of metastases. TK1 activity measured by DiviTum (TM) predicted therapy response, PFS and OS in loco regional inoperable or disseminated breast cancer. These results suggest that this factor is a useful serum marker. In the present material, a prognostic value of CA 15-3 could not be proven.

  • 6. Dalberg, Kristina
    et al.
    Hellborg, Henrik
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Paget's disease of the nipple in a population based cohort2008In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 111, no 2, p. 313-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Paget's disease of the nipple is a rare form of breast cancer characterised by the presence of intraepidermal tumour cells. It is often associated with ductal carcinoma in situ (DCIS) and/or invasive cancer in the breast parenchyma. We have studied the presentation and symptoms of Paget's disease, local control and breast cancer corrected survival following breast conserving surgery or mastectomy. PATIENTS AND METHODS: The study is based on 223 women with histological verified Paget's disease of the nipple diagnosed between 1976 and 2001 at 13 Swedish hospitals. All women s charts were reviewed. All recurrences and deaths were registered. A comparison was made for differences in breast cancer-corrected survival (BCS) and disease-free survival (DFS) in univariate analyses. RESULTS: The median follow-up was 12 (4-28) years. In a vast majority (98%), the main presenting symptom was eczema or ulceration of the nipple. The diagnosis of an underlying breast malignancy was established in 79% of the women before surgery. A cone excision of the nipple-areola complex was performed in 43 women and 169 women had a mastectomy. Eleven elderly women were not operated. One hundred and seventeen women had a non-invasive Paget of which 40 had an underlying DCIS. Invasive cancer was seen in 68 women. In 38 cases the histopathological report did not state if the tumour was invasive or not. Thirty-three women died from breast cancer. In operated women BCS and DFS at 10 years were 87% and 82%, respectively. The 10-year BCS for non-operated patients (n = 11) was 34%. At 10 years, the cumulative local recurrence rate was 9%, 8% among women undergoing mastectomy and 16% among those treated with breast conserving surgery. In univariate analysis the type of surgery, cone excision or mastectomy, had no statistically significant impact on BCS or DFS. Risk factors for breast cancer death and recurrence were having an underlying invasive cancer compared with an in situ carcinoma and having a palpable tumour in the breast. CONCLUSION: The main presenting symptoms were eczema or ulceration of the nipple. Patients with non invasive Pagets disease of the nipple had an excellent cancer outcome. Selected patients with Paget's disease of the nipple were treated with breast conserving surgery with survival rates similar to those achieved with mastectomy.

  • 7.
    Fredholm, Hanna
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, S-17176 Stockholm, Sweden..
    Magnusson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindström, Linda S.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Kings Coll London, Fac Life Sci & Med, Div Canc Studies, London, England..
    Fält, Sonja Eaker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Bergh, Jonas
    Karolinska Inst, Karolinska Univ Hosp, Dept Pathol & Oncol, Canc Ctr Karolinska & Karolinska Oncol,Radiumhemm, Stockholm, Sweden..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, Div Canc Studies, London, England..
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frisell, Jan
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, S-17176 Stockholm, Sweden..
    Fredriksson, Irma
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, S-17176 Stockholm, Sweden..
    Long-term outcome in young women with breast cancer: a population-based study2016In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 160, no 1, p. 131-143Article in journal (Refereed)
    Abstract [en]

    Whether young age at diagnosis of breast cancer is an independent risk factor for death remains controversial, and the question whether young age should be considered in treatment decisions is still to be answered. From a population-based cohort of 22,017 women with breast cancer, all women < 35 years (n = 471) were compared to a random sample of 700 women aged 35-69 years from the same cohort. Information on patient and tumor characteristics, treatment, and follow-up was collected from the medical records. Tissue microarrays were produced for analysis of classical biomarkers. Breast cancer-specific survival (BCSS), distant disease-free survival (DDFS), and locoregional recurrence-free survival (LRFS) by age were compared using women 50-69 years as reference. At 10 years follow-up, women < 35 years and 35-39 years had a worse BCSS [age < 35 years 69 % (HR 2.75, 95 % CI 1.93-3.94), age 35-39 years 76 % (HR 2.33, 95 % CI 1.54-3.52), age 40-49 years 84 % (HR 1.53, 95 % CI 0.97-2.39), and age 50-69 years 89 % (reference)]. The worse BCSS was statistically significant in stages I-IIa and Luminal B tumors. At multivariate analysis age < 35 years and 35-39 years confined a risk in LRFS (HR 2.13, 95 % CI 1.21-3.76 and HR 1.97, 95 % CI 1.06-3.68) but not in DDFS and BCSS. In the subgroup of women < 40 years with luminal tumors stage I-IIa, low age remained an independent risk factor also in DDFS (HR 1.87, 95 % CI 1.03-3.44). Young women have a high risk of systemic disease even when diagnosed in an early stage. The excess risk of relapse is most pronounced in Luminal B tumors, where low age is an independent prognostic factor of DDFS and LRFS.

  • 8. Harris, Holly R.
    et al.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Wolk, Alicja
    Folate intake and breast cancer mortality in a cohort of Swedish women2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 132, no 1, p. 243-250Article in journal (Refereed)
    Abstract [en]

    Folate may influence breast cancer development and progression through its role in one-carbon metabolism. However, epidemiologic data on the relation between folate and breast cancer survival are limited. We investigated whether dietary folate intake was associated with survival in 3,116 women diagnosed with breast cancer in the population-based Swedish Mammography Cohort. Participants completed a 67-item food frequency questionnaire in 1987. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for death from breast cancer and death from any cause. During 25,716 person-years of follow-up from 1987 to 2008, there were 852 deaths with 381 breast cancer deaths. Dietary folate intake was inversely associated with breast cancer and overall mortality. Women in the highest quartile of folate intake had a multivariable HR (95% CI) of death from breast cancer of 0.78 (0.58-1.03) compared to those in the lowest quartile (P (trend) = 0.03). The corresponding HR (95% CI) for death from any cause was 0.79 (0.66-0.96; P (trend) = 0.004). The protective association between dietary folate intake and breast cancer death was strongest among those with ER-negative tumors (HR = 0.42; 95% = CI 0.22-0.79; P (trend) = 0.01) comparing the highest to lowest quartile. Our findings suggest that folate intake before breast cancer diagnosis may improve breast cancer and overall survival. While these findings need to be confirmed in future studies, they do offer assurance that dietary folate intake at the levels observed in our population does not unfavorably affect survival after breast cancer.

  • 9. Harris, Holly R.
    et al.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Wolk, Alicja
    Selenium intake and breast cancer mortality in a cohort of Swedish women2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 134, no 3, p. 1269-1277Article in journal (Refereed)
    Abstract [en]

    Selenium is an important cofactor in the production of antioxidant enzymes that may influence cancer progression. Selenium intake and cancer survival has not been extensively studied; however, selenium supplementation has been demonstrated to reduce cancer mortality in nutritional intervention trials. We investigated whether dietary selenium intake was associated with survival among 3,146 women diagnosed with invasive breast cancer in the population-based Swedish Mammography Cohort. Selenium intake before breast cancer diagnosis was estimated using a food frequency questionnaire completed in 1987. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for death from breast cancer, non-breast cancer death, and death from any cause. During 28,172 person-years of follow-up from 1987 to 2009, there were 416 breast cancer-specific deaths and 964 total deaths. Dietary selenium intake was inversely associated with breast cancer-specific mortality and overall mortality. Women in the highest quartile of selenium intake had a multivariable HR (95 % CI) of death from breast cancer of 0.69 (0.52-0.92) compared with those in the lowest quartile (P (trend) = 0.009). The inverse association between dietary selenium intake and breast cancer death appeared strongest among women who had ever smoked (HR = 0.34; 95 % CI 0.14-0.83; P (trend) = 0.01) comparing the highest to lowest quartile. Our findings suggest that selenium intake before breast cancer diagnosis may improve breast cancer-specific survival and overall survival. However, these results may be limited to populations with low intakes of selenium.

  • 10. Hatschek, T.
    et al.
    Carlsson, L.
    Einbeigi, Z.
    Lidbrink, E.
    Linderholm, B.
    Lindh, B.
    Loman, N.
    Malmberg, M.
    Rotstein, S.
    Soderberg, M.
    Sundquist, M.
    Walz, T. M.
    Hellstrom, M.
    Svensson, H.
    Åstrom, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Brandberg, Y.
    Carstensen, J.
    Ferno, M.
    Bergh, J.
    Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 131, no 3, p. 939-947Article in journal (Refereed)
    Abstract [en]

    Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin(A (R))) and paclitaxel (Taxol(A (R))) alone (ET) or in combination with capecitabine (Xeloda(A (R)), TEX). Starting doses for ET were epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2), and for TEX epirubicin 75 mg/m(2), paclitaxel 155 mg/m(2), and capecitabine 825 mg/m(2) BID for 14 days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8 months for patients treated with ET, and 12.4 months for those treated with TEX (HR 0.84, 95% CI 0.65-1.07, P = 0.16); median OS was 26.0 months for women in the ET versus 29.7 months in the TEX arm (HR 0.84, 95% CI 0.63-1.11, P = 0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (chi(2) 3.66, P = 0.16). TTF was significantly longer for patients treated with TEX, 6.0 months, versus 5.2 months following ET (HR 0.73, 95% CI 0.58-0.93, P = 0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.

  • 11.
    Hellmen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Moller, Maria
    Blankenstein, Marinus A.
    Andersson, Leif
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Expression of different phenotypes in cell lines from canine mammary spindle-cell tumours and osteosarcomas indicating a pluripotent mammary stem cell origin2000In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 61, no 3, p. 197-210Article in journal (Refereed)
    Abstract [en]

    Mammary spindle-cell tumours and sarcomas seem to be restricted to dogs and humans. Two cell lines from spontaneous primary canine mammary spindle-cell tumours (CMT-U304 and CMT-U309) and two cell lines from spontaneous primary canine mammary osteosarcomas (CMT-U334 and CMT-U335) were established to study the mesenchymal phenotypes of mammary tumours in the female dog. The cells from the spindle-cell tumours expressed cytokeratin, vimentin and smooth muscle actin filaments. When these cells were inoculated subcutaneously into female and male nude mice they formed different types of mesenchymal tumours such as spindle-cell tumours, fibroma and rhabdomyoid tumours (n = 6/8). The cells from the osteosarcomas expressed vimentin filaments and also formed different types of mesenchymal tumours such as chondroid, rhabdomyoid, smooth muscle-like and spindle-cell tumours (n = 6/10). The cell lines CMT-U304, CMT-U309 and CMT-U335 had receptors for progesterone but none of the four cell lines had receptors for estrogen. All four cell lines and their corresponding primary tumours showed identical allelic patterns in microsatellite analysis. By in situ hybridization with genomic DNA we could verify that all formed tumours but one were of canine origin. Our results support the hypothesis that canine mammary tumours are derived from pluripotent stem cells.

  • 12. Johansson, Ida
    et al.
    Nilsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Berglund, Pontus
    Strand, Carina
    Jonsson, Goran
    Staaf, Johan
    Ringner, Markus
    Nevanlinna, Heli
    Barkardottir, Rosa B.
    Borg, Ake
    Olsson, Hakan
    Luts, Lena
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hedenfalk, Ingrid
    High-resolution genomic profiling of male breast cancer reveals differences hidden behind the similarities with female breast cancer2011In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 129, no 3, p. 747-760Article in journal (Refereed)
    Abstract [en]

    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.

  • 13. Johnatty, Sharon
    et al.
    Couch, Fergus
    Fredericksen, Zachary
    Tarrell, Robert
    Spurdle, Amanda
    Beesley, Jonathan
    Chen, Xiaoqing
    Gschwantler-Kaulich, Daphne
    Singer, Christian
    Fuerhauser, Christine
    Fink-Retter, Anneliese
    Domchek, Susan
    Nathanson, Katherine
    Pankratz, Vernon
    Lindor, Noralane
    Godwin, Andrew
    Caligo, Maria
    Hopper, John
    Southey, Melissa
    Giles, Graham
    Justenhoven, Christina
    Brauch, Hiltrud
    Hamann, Ute
    Ko, Yon-Dschun
    Heikkinen, Tuomas
    Aaltonen, Kirsimari
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Nevanlinna, Heli
    Hall, Per
    Czene, Kamila
    Liu, Jianjun
    Peock, Susan
    Cook, Margaret
    Platte, Radka
    Gareth Evans, D.
    Lalloo, Fiona
    Eeles, Rosalind
    Pichert, Gabriella
    Eccles, Diana
    Davidson, Rosemarie
    Cole, Trevor
    Cook, Jackie
    Douglas, Fiona
    Chu, Carol
    Hodgson, Shirley
    Paterson, Joan
    Hogervorst, Frans
    Rookus, Matti
    Seynaeve, Caroline
    Wijnen, Juul
    Vreeswijk, Maaike
    Ligtenberg, Marjolijn
    van der Luijt, Rob
    van Os, Theo
    Gille, Hans
    Blok, Marinus
    Issacs, Claudine
    Humphreys, Manjeet
    McGuffog, Lesley
    Healey, Sue
    Sinilnikova, Olga
    Antoniou, Antonis
    Easton, Douglas
    Chenevix-Trench, Georgia
    No evidence that GATA3 rs570613 SNP modifies breast cancer risk2009In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 117, no 2, p. 371-9Article in journal (Refereed)
    Abstract [en]

    GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (P (trend) = 0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [Garcia-Closas M et al. (2007) Cancer Epidemiol Biomarkers Prev 16:2269-2275]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (OR(per-allele) = 1.00, 95% CI 0.94-1.05), in ER negative BCAC cases (OR(per-allele) = 1.02, 95% CI 0.91-1.13), in BRCA1 mutation carriers RR(per-allele) = 0.99, 95% CI 0.90-1.09) or BRCA2 mutation carriers (RR(per-allele) = 0.93, 95% CI 0.80-1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women.

  • 14.
    Karakatsanis, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Christiansen, Peer Michael
    Aarhus Univ Hosp, Randers Reg Hosp, Dept Surg, Breast Unit, DK-8000 Aarhus, Denmark..
    Fischer, Lone
    Aarhus Univ Hosp, Randers Reg Hosp, Dept Surg, Breast Unit, DK-8000 Aarhus, Denmark..
    Hedin, Christina
    Linkoping Univ Hosp, Dept Surg, Breast Unit, S-58185 Linkoping, Sweden..
    Pistioli, Lida
    Linkoping Univ Hosp, Dept Surg, Breast Unit, S-58185 Linkoping, Sweden..
    Sund, Malin
    Dept Surg & Perioperat Sci, Umea, Sweden..
    Rasmussen, Nils Ryegaard
    SVS, Dept Surg, Breast Unit, Esbjerg, Denmark..
    Jornsgard, Hjordis
    SVS, Dept Surg, Breast Unit, Esbjerg, Denmark..
    Tegnelius, Daniel
    Univ Orebro, Dept Surg, Breast Unit, SE-70182 Orebro, Sweden..
    Eriksson, Staffan
    Vastmanland Cty Hosp, Dept Surg, Vasteras, Sweden..
    Daskalakis, Kosmas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Markopoulos, Christos J.
    Univ Athens, Sch Med, Athens 11528, Greece..
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Vastmanland Cty Hosp, Dept Surg, Vasteras, Sweden..
    The Nordic SentiMag trial: a comparison of super paramagnetic iron oxide (SPIO) nanoparticles versus Tc-99 and patent blue in the detection of sentinel node (SN) in patients with breast cancer and a meta-analysis of earlier studies2016In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 157, no 2, p. 281-294Article in journal (Refereed)
    Abstract [en]

    The aim of the study is to compare the efficacy of SPIO as a tracer in sentinel node biopsy (SNB) in breast cancer with Tc and patent blue in a multicentre prospective study and perform a meta-analysis of all published studies. It also aims to follow skin discoloration after SPIO injection and describe when and how it resolves. Totally 206 patients with early breast cancer were recruited. Tc and patent blue were administered in standard fashion. Patients were injected with SPIO (Sienna+) preoperatively. SNB was performed and detection rates were recorded for both methods. Skin discoloration was followed and documented postoperatively. Data extraction and subsequent meta-analysis of all previous studies were also performed. SN detection rates were similar between standard technique succeeded and SPIO both per patient (97.1 vs. 97.6 %, p = 0.76) as well as per node (91.3 vs. 93.3 %, p = 0.34), something which was not affected by the presence of malignancy. Concordance rates were also consistently high (98.0 % per patient and 95.9 % per node). Discoloring was present in 35.5 % of patients postoperatively, almost exclusively in breast conservation. It fades slowly and is still detectable in 8.6 % of patients after 15 months. Meta-analysis depicted similar detection rates (p = 0.71) and concordance rates (p = 0.82) per patient. However, it seems that SPIO is characterized by higher nodal retrieval (p < 0.001). SPIO is an effective method for the detection of SN in patients with breast cancer. It is comparable to the standard technique and seems to simplify logistics. Potential skin discoloration is something of consideration in patients planned for breast conservation.

  • 15. Khoshnoud, Mahmoud R.
    et al.
    Löfdahl, Britta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fohlin, Helena
    Fornander, Tommy
    Stål, Olle
    Skoog, Lambert
    Bergh, Jonas
    Nordenskjöld, Bo
    Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen2011In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 126, no 2, p. 421-430Article in journal (Refereed)
    Abstract [en]

    The purpose of this study is to compare immunohistochemistry (IHC) and cytosol-based assays for determination of estrogen receptor (ER) and prediction of response to adjuvant tamoxifen treatment in postmenopausal women with early-stage invasive breast cancer. The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. The patients were stratified according to tumor size and lymph node status in high-risk and low-risk groups. In this study we evaluated 683 patients with "low risk" breast cancer (size a parts per thousand currency sign30 mm, lymph node-negative) for whom ER status had been determined by both the cytosol assays and IHC at one pathology laboratory. The median follow-up was 17 years. Six hundred eighty-three patients had tumors with ER determined by both methods, 536 (78.5%) were ER-positive by cytosol assays using the cutoff level at a parts per thousand yen0.05 fmol/mu g DNA and 539 patients were ER-positive (79%) by IHC using the cutoff level at a parts per thousand yen10% cell stained. Thirty-nine tumors (5.7%) were ER-positive by cytosol but not by IHC, whereas the opposite pattern was found for 42 cases (6.1%). Only seven tumors had stained cells between 0 and 9% by IHC. The concordance between IHC and cytosol assays was high (88%). The kappa statistic was 0.65, 95% CI 0.58-0.72. Among patients classified as ER-negative no therapeutic benefit from tamoxifen was observed. Among patients with ER-expressing tumors, tamoxifen resulted in significantly better recurrence-free survival irrespective of the method (IHC: HR, 0.53, P < 0.001; cytosol: HR, 0.53, P < 0.001). The effect on overall survival was not statistically significant probably due to the limited sample size. Both IHC and cytosol assay accurately predict long-term response to adjuvant tamoxifen.

  • 16.
    Lambe, Mats
    et al.
    Regional Oncologic Centre, Uppsala Sweden .
    Wigertz, Annette
    Regional Oncologic Centre, Uppsala Sweden .
    Holmqvist, Marit
    Regional Oncologic Centre, Uppsala Sweden .
    Adolfsson, Jan
    Bardage, Carola
    Fornander, Tommy
    Karlsson, Per
    Odlind, Viveca
    Persson, Ingemar
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Reductions in use of hormone replacement therapy: effects on Swedish breast cancer incidence trends only seen after several years2010In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 121, no 3, p. 679-683Article in journal (Refereed)
    Abstract [en]

    Studies from Western countries have found evidence of a recent decline in breast cancer incidence rates in postmenopausal women, findings which have been hypothesized to reflect a reduced use of hormonal replacement therapy (HRT). We examined breast cancer incidence trends in Sweden between 1997 and 2007, a period characterized by a drop in the use of HRT. Incidence trends were assessed using data from three population-based Regional Clinical Registries on breast cancer covering 2/3 of the Swedish population. Information on HRT sales was obtained from national pharmacy data. The prevalence of HRT use in age group 50-59 years decreased from a peak of 36% in 1999 to 27% in 2002 and further to 9% in 2007. Incidence rates of breast cancer in women 50 years and older increased between 1997 and 2003. A significant decrease in incidence between 2003 and 2007 was confined to women 50-59 years of age, the group in which the prevalence of HRT use has been highest and the decrease in use most pronounced. As opposed to the immediate effects reported from the United States and other regions, there was a time lag between the drop in HRT use and clear reductions in breast cancer incidence. This may reflect between country differences with regard to types of HRT used, and the rate, magnitude and pattern of change in use. The present findings give further support to the notion that HRT use is a driver of breast cancer incidence trends on the population level.

  • 17. Liu, Yanhong
    et al.
    Zhou, Renke
    Baumbusch, Lars O
    Tsavachidis, Spyros
    Brewster, Abenaa M
    Do, Kim-Anh
    Sahin, Aysegul
    Hortobagyi, Gabriel N
    Taube, Joseph H
    Mani, Sendurai A
    Aarøe, Jørgen
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Børresen-Dale, Anne-Lise
    Mills, Gordon B
    Thompson, Patricia A
    Bondy, Melissa L
    Genomic copy number imbalances associated with bone and non-bone metastasis of early-stage breast cancer2014In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 143, no 1, p. 189-201Article in journal (Refereed)
    Abstract [en]

    The aim of this study is to identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis. Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model. Gains at 1q41 and 1q42.12 and losses at 1p13.3, 8p22, and Xp11.3 were significantly associated with bone metastasis. Gains at 2p11.2, 3q21.3-22.2, 3q27.1, 10q23.1, and 14q13.2-3 and loss at 7q21.11 were associated with non-bone metastasis. To examine the joint effect of CNIs and clinical predictors, patients were stratified into three risk groups (low, intermediate, and high) based on the sum of predicted linear hazard ratios. For bone metastasis, the hazard (95 % confidence interval) for the low-risk group was 0.32 (0.11-0.92) compared to the intermediate-risk group and 2.99 (1.74-5.11) for the high-risk group. For non-bone metastasis, the hazard for the low-risk group was 0.34 (0.17-0.66) and 2.33 (1.59-3.43) for the high-risk group. The prognostic value of loss at 8p22 for bone metastasis and gains at 10q23.1 for non-bone metastasis, and gain at 11q13.5 for both bone and non-bone metastases were externally validated in 335 breast tumors pooled from four independent cohorts. Distinct CNIs are independently associated with bone and non-bone metastasis for early-stage breast cancer patients across cohorts. These data warrant consideration for tailoring surveillance and management of metastasis risk.

  • 18.
    Matikas, Alexios
    et al.
    Karolinska Univ Hosp, Radiumhemmet, Dept Oncol, Stockholm, Sweden..
    Margolin, Sara
    Stockholm South Gen Hosp, Dept Oncol, Stockholm, Sweden..
    Hellström, Mats
    Karolinska Univ Hosp, Radiumhemmet, Dept Oncol, Stockholm, Sweden..
    Johansson, Hemming
    Karolinska Univ Hosp, Radiumhemmet, Dept Oncol, Stockholm, Sweden..
    Bengtsson, Nils-Olof
    Norrland Univ Hosp, Umea, Sweden..
    Karlsson, Lena
    Cty Hosp, Sundsvall, Sweden..
    Edlund, Per
    Gavle Cent Hosp, Gavle, Sweden..
    Karlsson, Per
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Dept Oncol,Inst Clin Sci, Gothenburg, Sweden..
    Lidbrink, Elisabet
    Karolinska Univ Hosp, Radiumhemmet, Dept Oncol, Stockholm, Sweden..
    Linderholm, Barbro
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Dept Oncol,Inst Clin Sci, Gothenburg, Sweden..
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Malmstrom, Per
    Skane Univ Hosp, Dept Oncol & Radiat Phys, Lund, Sweden..
    Villman, Kenneth
    Orebro Univ Hosp, Orebro, Sweden..
    Foukakis, Theodoros
    Karolinska Univ Hosp, Radiumhemmet, Dept Oncol, Stockholm, Sweden..
    Bergh, Jonas
    Karolinska Univ Hosp, Radiumhemmet, Dept Oncol, Stockholm, Sweden..
    Long-term safety and survival outcomes from the Scandinavian Breast Group 2004-1 randomized phase II trial of tailored dose-dense adjuvant chemotherapy for early breast cancer2018In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, no 2, p. 349-355Article in journal (Refereed)
    Abstract [en]

    Although adjuvant polychemotherapy improves outcomes for early breast cancer, the significant variability in terms of pharmacokinetics results in differences in efficacy and both short and long-term toxicities. Retrospective studies support the use of dose tailoring according to the hematologic nadirs. The SBG 2004-1 trial was a randomized feasibility phase II study which assessed tailored dose-dense epirubicin and cyclophosphamide (EC) followed by docetaxel (T) (group A), the same regimen with fixed doses (group B) and the TAC regimen (group C). Women aged 18-65 years, ECOG PS 0-1 with at least one positive axillary lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term toxicity have been previously published. Here, we report safety and efficacy data after 10 years of follow-up. A total of 124 patients were included in the study. After a median follow-up of 10.3 years, the probability for 10-year survival was 78.5, 75.1, and 63.4% and for relapse free survival 64.1, 71.0, and 59.5% for groups A, B, and C, respectively. There were no cases of clinically diagnosed cardiotoxicity or hematologic malignancies. No patient was lost to follow-up. In this randomized phase II trial, tailored dose adjuvant chemotherapy was feasible, without an increased risk for long-term adverse events after a median follow-up of 10 years.

  • 19. Mohammad Hossein, Hajiebrahimi
    et al.
    Bahmanyar, Shahram
    Lambe, Mats
    Adolfsson, Jan
    Fornander, Tommy
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Cnattingius, Sven
    Placental weight and mortality in premenopausal breast cancer by tumor characteristics2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 137, no 1, p. 297-305Article in journal (Refereed)
    Abstract [en]

    Placental weight may be regarded as an indirect marker of hormone exposures during pregnancy. There is epidemiological evidence that breast cancer mortality in premenopausal women increases with placental weight in the most recent pregnancy. We investigated if this association differs by tumor characteristics, including expression of estrogen and progesterone receptors. In a Swedish population-based cohort, we followed 1,067 women with premenopausal breast cancer diagnosed from 1992 to 2006. Using Cox regression models, we estimated hazard ratios for the association between placental weight and risk of premenopausal breast cancer mortality. In stratified analyses, we estimated mortality risks in subjects with different tumor stages, estrogen receptor (ER) or progesterone receptor (PR) status. Compared with women with placental weight less than 600 g, women with a placental weight between 600 and 699 g were at a 50 % increased risk of mortality, however, not significant change in risk was observed for women with placental weight ≥700 g. Mortality risks associated with higher placental weight were more pronounced among ER and PR breast cancer tumors, where both a placental weight 600–699 g and ≥700 g were associated with a more than doubled mortality risks compared with tumors among women with placental weight less than 600 g. Moreover, stratified analyses for joint receptor status revealed that a consistent increased mortality risk by placental weight was only apparent in women with ER/PR breast cancer. The increased mortality risk in premenopausal breast cancer associated with higher placental weight was most pronounced among ER and PR tumors.

  • 20. Rosell, Johan
    et al.
    Nordenskjold, Bo
    Bengtsson, Nils-Olof
    Fornander, Tommy
    Hatschek, Thomas
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Malmstrom, Per-Olof
    Wallgren, Arne
    Stal, Olle
    Carstensen, John
    Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 138, no 2, p. 467-473Article in journal (Refereed)
    Abstract [en]

    Tamoxifen is associated with a reduced risk of coronary heart disease (CHD). However, there are few reports on long-term effects. Using data from a large Swedish randomized trial of 5 and 2 years of adjuvant tamoxifen in women with early breast cancer, we here present results on morbidity and mortality from cardiac diseases during treatment and long-term after treatment. A total of 4,150 patients were breast cancer recurrence-free after 2 years. Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry were used to define events of disease. Hazard ratios were estimated using Cox regression. Patients assigned to 5 years in comparison with 2 years of postoperative tamoxifen experienced a reduced incidence of CHD [hazard ratio (HR), 0.83; 95 % CI 0.70-1.00], especially apparent during the active treatment period (HR 0.65; 95 % CI 0.43-1.00). The mortality from CHD was significantly reduced (HR 0.72; 95 % CI 0.53-0.97). During the active treatment, the morbidity of other heart diseases was also significantly reduced (HR 0.40; 95 % CI 0.25-0.64) but not after treatment stopped (HR 1.06; 95 % CI 0.87-1.30). Similar results were seen for both heart failure and atrial fibrillation/flutter. As compared to 2 years of therapy, 5 years of postoperative tamoxifen therapy prevents CHD as well as other heart diseases. The risk reduction is most apparent during the active treatment period, and later tends to diminish.

  • 21. Schüle, Jana
    et al.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Håkansson, Leif
    Gustafsson, Bertil
    Håkansson, Annika
    Down-regulation of the CD3-ζ chain in sentinel node biopsies from breast cancer patients2002In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 74, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Background. In several neoplastic diseases, immunosuppression has been shown to correlate with disease stage, progression, and outcome. As the prognosis for metastatic breast cancer is still pessimistic, additional strategies are being sought to improve survival. Local immunosuppression in sentinel node biopsies from 24 evaluable breast cancer patients was studied as a possible way of selecting patients for immunotherapy.

    Method. Sentinel node biopsy was performed in 24 out of 25 women operated on for primary breast cancer (one was not evaluable). Specimens were snap-frozen and double-stained for the zeta-chain of the T-cell receptor. The degree of down-regulation of the zeta-chain was evaluated in three different lymph-node areas: primary follicles, secondary follicles, and paracortex.

    Results. Down-regulation of varying degrees was noted in all 24 sentinel node biopsies. A high degree of down-regulation (more than 50% of T-cells not expressing zeta-chain) was seen in the primary follicles in six patients (25%), in the secondary follicles in 13 patients (72%), and in the paracortex in 19 patients (79%).

    Conclusion. Local down-regulation of an immune function parameter was seen in sentinel node biopsies from breast cancer patients. In addition to possible prognostic implications, the sentinel node might be an appropriate location for detecting early-stage immunological down-regulation, which might open a possibility of selecting patients who could benefit from immunotherapy.

  • 22. Strand, Carina
    et al.
    Ahlin, Cecilia
    Bendahl, Pär-Ola
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hedenfalk, Ingrid
    Malmström, Per
    Ferno, Marten
    Combination of the proliferation marker cyclin A, histological grade, and estrogen receptor status in a new variable with high prognostic impact in breast cancer2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 131, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    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.

  • 23.
    Valachis, Antonis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Garmo, Hans
    Kings Coll London, Sch Med, Div Canc Studies, Canc Epidemiol Unit, London, England..
    Weinman, John
    Kings Coll London, Inst Pharmaceut Sci, London SE1 9NH, England..
    Fredriksson, Irma
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Stockholm, Sweden..
    Ahlgren, Johan
    Univ Orebro, Fac Med & Hlth, Dept Oncol, Orebro, Sweden..
    Sund, Malin
    Umea Univ, Dept Surg & Perioperat Sci, S-90185 Umea, Sweden..
    Holmberg, Lars
    Kings Coll London, Sch Med, Div Canc Studies, Canc Epidemiol Unit, London, England..
    Effect of selective serotonin reuptake inhibitors use on endocrine therapy adherence and breast cancer mortality: a population-based study2016In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 159, no 2, p. 293-303Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to investigate whether the concomitant use of selective serotonin reuptake inhibitors (SSRI) with tamoxifen influences the risk of death due to breast cancer, and we also investigated the association between SSRI use and adherence to oral endocrine therapy (ET). We analyzed data from BCBaSe Sweden, which is a database created by the data linkage of Registries from three different regions of Sweden. To investigate the association between ET adherence and SSRI use, we included all women who were diagnosed with non-distant metastatic ER-positive invasive breast cancer from July 2007 to July 2011 and had at least one dispensed prescription of oral tamoxifen or aromatase inhibitor. To investigate the role of concurrent administration of SSRI and tamoxifen on breast cancer prognosis, we performed a nested case-control study. In the adherence cohort, 9104 women were included in the analyses. Women who received SSRI, either before or after breast cancer diagnosis, were at higher risk for low adherence to ET. However, when the overlapping period between SSRI use and ET was > 50 %, no excess risk for low adherence was observed. Non-adherence (< 80 %) to ET was significantly associated with worse breast cancer survival (OR 4.07; 95 % CI 3.27-5.06). In the case-control study, 445 cases and 11125 controls were included. The concomitant administration of SSRI and tamoxifen did not influence breast cancer survival, neither in short-term (OR 1.41; 95 % CI 0.74-2.68) nor in long-term SSRI users (OR 0.85; 95 % CI 0.35-2.08). Concomitant SSRI and tamoxifen use does not seem to increase risk for death due to breast cancer. Given the positive association between continuing antidepressive pharmacotherapy for a longer period of time and adherence to ET, it is essential to capture and treat depression in breast cancer patients to secure adherence to ET.

  • 24.
    Valachis, Antonis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Nearchou, Andreas D.
    Lind, Pehr
    Surgical management of breast cancer in BRCA-mutation carriers: a systematic review and meta-analysis2014In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 144, no 3, p. 443-455Article, review/survey (Refereed)
    Abstract [en]

    This meta-analysis investigates the oncological safety of breast-conserving therapy BCT in BRCA-mutation carriers and the risk for contralateral breast cancer (CBC) compared with non-carriers, potential risk factors for ipsilateral breast recurrence (IBR) or CBC and grades these factors based on the level of evidence. A PubMed search was conducted through April 2013 to identify studies that described the risk for IBR and CBC after BCT in BRCA-mutation carriers versus non-carriers as well as studies that investigated risk factors for IBR and CBC in BRCA-mutation carriers. Results were summarized using meta-analysis when sufficient studies were available. Ten studies investigated the oncological safety of BCT in BRCA-mutation carriers versus non-carriers. There was no significant difference in IBR between carriers and controls (RR 1.45, 95 % CI 0.98-2.14). However, a significant higher risk for IBR in BRCA-mutation carriers was observed in studies with a median follow-up a parts per thousand yen7 years (RR 1.51, 95 % CI 1.15-1.98). CBCs were significantly greater in carriers versus controls (RR 3.56, 95 % CI 2.50-5.08). Use of adjuvant chemotherapy and oophorectomy were associated with a significantly lower risk for IBR in BRCA-mutation carriers. Three factors were associated with a lower risk for CBC in BRCA-mutation carriers: oophorectomy, use of tamoxifen, and age at first breast cancer. Based on current evidence, the use of BCT in BRCA-mutation carriers can be considered a reasonable option since it does not seem to increase the risk for IBR. However, several aspects should be taken into account before the final decision-making.

  • 25.
    Valachis, Antonis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nearchou, Andreas
    Lind, Pehr
    Mauri, Davide
    Lapatinib, trastuzumab or the combination added to preoperative chemotherapy for breast cancer: a meta-analysis of randomized evidence2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 135, no 3, p. 655-662Article, review/survey (Refereed)
    Abstract [en]

    We compared the efficacy and safety of the addition of lapatinib versus trastuzumab or their combination to neoadjuvant chemotherapy in HER2-positive breast cancer. Potentially eligible trials were located through PubMed and Cochrane Library searches and abstracts of major international conferences. The endpoints that we assessed were pathologic complete response (pCR) rate, and toxicity. Pooled risk ratios (RR) were estimated for each endpoint with fixed or random effects models, depending on between studies heterogeneity. Six trials were identified with 1,494 eligible patients. The probability to achieve pCR was higher for the trastuzumab plus chemotherapy arm versus lapatinib plus chemotherapy (RR 1.25, 95 % confidence interval [CI] 1.08-1.43; p = 0.003) (6 trials; 1,494 patients). Probability to pCR was significantly higher in the group receiving lapatinib and trastuzumab than in the group with trastuzumab alone (RR 1.39, 95 % CI 1.20-1.63; p < 0.001) (4 trials; 779 patients). Grade III-IV diarrhea and dermatologic toxicities were statistically more frequent in patients receiving lapatinib. No differences were observed regarding cardiac adverse events among patients receiving trastuzumab, lapatinib, or their combination. These data supports the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer in the neoadjuvant setting. The direct comparison of trastuzumab and lapatinib showed that lapatinib is inferior in terms of pCR and associated with a higher risk for toxicity.

  • 26. Vichapat, Voralak
    et al.
    Garmo, Hans
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Fentiman, Ian S
    Tutt, Andrew
    Gillett, Cheryl
    Lüchtenborg, Margreet
    Prognosis of metachronous contralateral breast cancer: importance of stage, age and interval time between the two diagnoses2011In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 130, no 2, p. 609-618Article in journal (Refereed)
    Abstract [en]

    Studies comparing the prognosis after contralateral breast cancer (CBC) with that after unilateral breast cancer (UBC) shows conflicting results. We assessed the risk of breast cancer-specific death for women with metachronous CBC compared to those with a UBC in 8,478 women with invasive primary breast cancer registered in the Guy's and St. Thomas' Breast Cancer Tissue and Data Bank. Risk factors associated with breast cancer-specific death for women with CBC were estimated using Cox proportional hazards modelling. Prognoses after UBC and CBC were compared, with survival time for women with CBC calculated: (i) from CBC, (ii) from the initial cancer with CBC as a time-dependent covariate. Women diagnosed with CBC within 5 years after the initial primary breast cancer had a worse prognosis than those with CBC after 5 years and those with UBC. Women with CBC who had positive lymph nodes at the initial breast cancer diagnosis were at an increased risk of dying from breast cancer compared to those without [HR 2.5 (95% CI 1.5-4.0)]. For all stages of the initial breast cancer, a worse prognosis was observed after CBC. CBC increased the hazard originating from the initial cancer at any follow-up time, but the highest hazards were associated with a short interval to CBC. Metachronous CBC adds to the risk of dying from breast cancer. The risk increases substantially when it occurs shortly after the initial cancer, indicating a CBC in some instances may be an indicator of active distant disease. The occurrence of CBC implies a new surveillance and therapeutic situation.

  • 27.
    Wensman, Helena
    et al.
    Institutionen för anatomi, fysiologi och biokemi, Sveriges Lantbruksuniversitet.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Leuchowius, Karl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Strömberg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rutteman, Gerard
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pejler, Gunnar
    Institutionen för anatomi, fysiologi och biokemi, Sveriges Lantbruksuniversitet.
    Hellmén, Eva
    Institutionen för anatomi, fysiologi och biokemi, Sveriges Lantbruksuniversitet.
    Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas2009In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 118, no 2, p. 333-343Article in journal (Refereed)
    Abstract [en]

    The global gene expression in three types of canine mammary tumors: carcinoma, fibrosarcoma and osteosarcoma were investigated by Affymetrix gene array technology. Unsupervised clustering analysis revealed a close clustering of the respective tumor types, with fibrosarcomas clustering close to the osteosarcomas and the carcinomas clustering closer to non-malignant mammary tissues (NMTs). A number of epithelial markers were expressed in both carcinomas and NMTs, whereas the sarcomas expressed genes related to mesenchymal differentiation. A comparison of the gene expression profile of the sarcomas versus carcinoma/NMTs revealed that the sarcomas, in particular the osteosarcomas, showed a striking upregulation of a panel of homeobox genes previously linked to craniofacial bone formation. In line with this finding, osteosarcomas showed an upregulation of bone morphogenetic proteins (BMPs) and of genes associated with retinoic acid signaling. Increased homeobox gene expression in sarcomas was also confirmed at the protein level by immunohistochemical analysis of tumor tissue, and in an osteosarcoma cell line after stimulation by BMP-2. These findings suggest that the development of mammary sarcomas specifically involves triggering of a set of homeobox genes related to neural crest and craniofacial bone development.

  • 28.
    Wiercinska, Eliza
    et al.
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
    Naber, Hildegonda P H
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
    Pardali, Evangelia
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
    van der Pluijm, Gabri
    Department of Urology and Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
    van Dam, Hans
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system2011In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 128, no 3, p. 657-666Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-β (TGF-β) has opposing roles in breast cancer progression by acting as a tumor suppressor in the initial phase, but stimulating invasion and metastasis at later stages. In contrast to the mechanisms by which TGF-β induces growth arrest, the pathways that mediate tumor invasion are not well understood. Here, we describe a TGF-β-dependent invasion assay system consisting of spheroids of MCF10A1 normal breast epithelial cells (M1) and RAS-transformed (pre-)malignant derivatives (M2 and M4) embedded in collagen gels. Both basal and TGF-β-induced invasion of these cell lines was found to correlate with their tumorigenic potential; M4 showing the most aggressive behavior and M1 showing the least. Basal invasion was strongly inhibited by the TGF-β receptor kinase inhibitor SB-431542, indicating the involvement of autocrine TGF-β or TGF-β-like activity. TGF-β-induced invasion in premalignant M2 and highly malignant M4 cells was also inhibited upon specific knockdown of Smad3 or Smad4. Interestingly, both a broad spectrum matrix metalloproteinase (MMP) inhibitor and a selective MMP2 and MMP9 inhibitor mitigated TGF-β-induced invasion of M4 cells, while leaving basal invasion intact. In line with this, TGF-β was found to strongly induce MMP2 and MMP9 expression in a Smad3- and Smad4-dependent manner. This collagen-embedded spheroid system therefore offers a valuable screening model for TGF-β/Smad- and MMP2- and MMP9-dependent breast cancer invasion.

  • 29. Wigertz, Annette
    et al.
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Holmqvist, Marit
    Fornander, Tommy
    Adolfsson, Jan
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Lambe, Mats
    Adherence and discontinuation of adjuvant hormonal therapy in breast cancer patients: a population-based study2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 133, no 1, p. 367-373Article in journal (Refereed)
    Abstract [en]

    Adherence to long-term pharmacological treatment for chronic conditions is often less than optimal. Till date, a limited number of population-based studies have assessed adherence to adjuvant hormonal therapy in breast cancer, a therapy with proven benefits in terms of reductions of recurrence and mortality. We aimed to examine rates of adherence and early discontinuation in Sweden where prescribed medications are subsidized for all residents and made available at reduced out-of-pocket costs. Individual-level data were obtained from Regional Clinical Quality Breast Cancer Registers, the Swedish Prescribed Drug Register, and several other population-based registers. Multivariate logistic regression was used to analyze factors associated with adherence to prescribed medication for a period of 3 years. Between January 1 and December 31, 2005, 1,741 patients in central Sweden were identified with estrogen receptor positive breast cancer, and at least one prescription dispensation of either tamoxifen or an aromatase inhibitor. Of these women, 1,193 (69%) were fully adherent to therapy for 3 years (medication possession ratio of 80% or higher and a maximum of 180 days between refills). During the 3-year follow-up, 215 women (12%) had prematurely discontinued therapy. Adherence was positively associated with younger age, large tumor size, being married, and being born in the Nordic countries, while no clear association was observed with education or income. During the 3 years of follow-up, 31% of women were non-adherent to therapy. Further efforts must be undertaken to promote adherence over the entire recommended treatment period.

1 - 29 of 29
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