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  • 1.
    Aguilar, Helena
    et al.
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Urruticoechea, Ander
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Halonen, Pasi
    The Netherlands Cancer Institute, Amsterdam.
    Kiyotani, Kazuma
    Center for Genomic Medicine, RIKEN, Yokohama, Japan.
    Mushiroda, Taisei
    Center for Genomic Medicine, RIKEN, Yokohama, Japan.
    Barril, Xavier
    University of Barcelona, Catalonia, Spain.
    Serra-Musach, Jordi
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Islam, Abul
    University of Dhaka, Bangladesh.
    Caizzi, Livia
    Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.
    Di Croce, Luciano
    Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.
    Nevedomskaya, Ekaterina
    The Netherlands Cancer Institute, Amsterdam.
    Zwart, Wilbert
    The Netherlands Cancer Institute, Amsterdam.
    Bostner, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Karolinska University Hospital, Stockholm South General Hospital, Sweden.
    Sgroi, Dennis C
    Massachusetts General Hospital, Boston, USA.
    Garcia-Mata, Rafael
    University of North Carolina at Chapel Hill, USA.
    Jansen, Maurice Phm
    Cancer Institute, Rotterdam, The Netherlands.
    García, Nadia
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Bonifaci, Núria
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Climent, Fina
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Soler, María Teresa
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Rodríguez-Vida, Alejo
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Gil, Miguel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Brunet, Joan
    Hospital Josep Trueta, Girona, Catalonia, Spain.
    Martrat, Griselda
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Gómez-Baldó, Laia
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Extremera, Ana I
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Figueras, Agnes
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Balart, Josep
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Clarke, Robert
    Georgetown University Medical Center, Washington, DC, USA.
    Burnstein, Kerry L
    University of Miami, Miller School of Medicine, Miami, FL, USA.
    Carlson, Kathryn E
    University of Illinois, Urbana, USA.
    Katzenellenbogen, John A
    University of Illinois, Urbana, USA.
    Vizoso, Miguel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Esteller, Manel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain .
    Villanueva, Alberto
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    Rodríguez-Peña, Ana B
    CSIC-University of Salamanca, Spain.
    Bustelo, Xosé R
    CSIC-University of Salamanca, Spain.
    Nakamura, Yusuke
    University of Tokyo, Japan.
    Zembutsu, Hitoshi
    University of Tokyo, Japan.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Beijersbergen, Roderick L
    The Netherlands Cancer Institute, Amsterdam .
    Pujana, Miguel Angel
    L’Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
    VAV3 mediates resistance to breast cancer endocrine therapy2014In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 16, no 3, p. R53-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.

    METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.

    RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.

    CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

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  • 2.
    Campbell, Diahnn
    et al.
    University of Calif San Diego, CA 92093 USA.
    Saenz, Rebecca
    University of Calif San Diego, CA 92093 USA.
    Bharati, Ila S.
    University of Calif San Diego, CA 92093 USA.
    Seible, Daniel
    University of Calif San Diego, CA 92093 USA.
    Zhang, Liangfang
    University of Calif San Diego, CA 92093 USA.
    Esener, Sadik
    University of Calif San Diego, CA 92093 USA.
    Messmer, Bradley
    University of Calif San Diego, CA 92093 USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of Calif San Diego, CA 92093 USA.
    Enhanced anti-tumor immune responses and delay of tumor development in human epidermal growth factor receptor 2 mice immunized with an immunostimulatory peptide in poly(D, L-lactic-co-glycolic) acid nanoparticles nanoparticles2015In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, no 48Article in journal (Refereed)
    Abstract [en]

    Introduction Cancer vaccines have the potential to induce curative anti-tumor immune responses and better adjuvants may improve vaccine efficacy. We have previously shown that Hp91, a peptide derived from the B box domain in high-mobility group box protein 1 (HMGB1), acts as potent immune adjuvant. Method In this study, Hp91 was tested as part of a therapeutic vaccine against human epidermal growth factor receptor 2 (HER2) positive breast cancer. Results Free peptide did not significantly augment immune responses but, when delivered in poly(D, L-lactic-co-glycolic) acid nanoparticles (PLGA-NPs), robust activation of dendritic cells (DCs) and increased activation of HER2 specific T cells was observed in vitro. Vaccination of HER2NEU transgenic mice, a mouse breast cancer model that closely mimics the immune modulation and tolerance in some breast cancer patients, with Hp91 loaded PLGA-NPs enhanced the activation of HER2 specific cytotoxic T lymphocyte (CTL) responses, delayed tumor development, and prolonged survival. Conclusion Taken together these findings demonstrate that the delivery of the immunostimulatory peptide Hp91 inside PLGA-NPs enhances the potency of the peptide and efficacy of a breast cancer vaccine.

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  • 3. Duffy, S
    et al.
    Agbaje, O
    Tabar, L
    Bedrich, Vitak
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Medical Radiology. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology UHL.
    Bjurstam, N
    Björneld, L
    Myles, J
    Warwick, J
    Estimates of overdiagnosis from two trials of mammographic screening for breast cancer2005In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 7, no 6, p. 258-265Article in journal (Refereed)
    Abstract [en]

    Randomised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality. This has often been accompanied, however, by an increase in breast cancer incidence, particularly during the early years of a screening programme, which has led to concerns about overdiagnosis, that is to say, the diagnosis of disease that, if left undetected and therefore untreated, would not become symptomatic. We used incidence data from two randomised controlled trials of mammographic screening, the Swedish Two-county Trial and the Gothenburg Trial, to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ (DCIS) in the study groups, to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of 'real' and non-progressive 'overdiagnosed' tumours from the study groups of the trials. We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters. After taking into account the effect of lead time, we estimated that less than 5% of cases diagnosed at prevalence screen and less than 1 % of cases diagnosed at incidence screens are being overdiagnosed. Overall, we estimate overdiagnosis to be around 1 % of all cases diagnosed in screened populations. These estimates are, however, subject to considerable uncertainty. Our results suggest that overdiagnosis in mammography screening is a minor phenomenon, but further studies with very large numbers are required for more precise estimation. © 2005 BioMed Central Ltd.

  • 4.
    Jerevall, Piiha-Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital.
    Skoog, Lambert
    Department of Clinical Pathology and Cytology, Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Predictive relevance of HOXB13 protein expression for tamoxifen benefit in breast cancer2010In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 12, no 4Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: INTRODUCTION: The HOXB13:IL17BR index has been identified to predict clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer. Further studies have shown that HOXB13 in particular can indicate benefit of prolonged tamoxifen treatment. Patients with high-expressing tumors did not benefit from prolonged treatment, suggesting that HOXB13 might be involved in tamoxifen resistance. No studies have been made regarding the HOXB13 protein levels in breast cancer. The aim of our study was to investigate whether tamoxifen benefit can be correlated to different levels of HOXB13 protein expression. METHODS: We used immunohistochemistry to analyze protein levels of HOXB13 in tumor samples from 912 postmenopausal node-negative breast cancer patients randomized to adjuvant tamoxifen therapy or no endocrine treatment. RESULTS: Tamoxifen-treated patients with estrogen receptor-positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (DRFS) (hazard ratio = 0.38, 95% confidence interval = 0.23 to 0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared with the untreated patients (hazard ratio = 0.88, 95% confidence interval = 0.47 to 1.65, P = 0.69). Interaction between HOXB13 expression and benefit from tamoxifen was statistically significant for DRFS (P = 0.035). No prognostic value could be ascribed to HOXB13 among systemically untreated patients. CONCLUSIONS: A high HOXB13 expression was associated with decreased benefit from tamoxifen, which indicates that HOXB13 protein level may be used as a predictive marker for tamoxifen treatment.

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  • 5.
    Johansson, Ida
    et al.
    Lund University, Sweden.
    Nilsson, Cecilia
    Central Hospital Vasteres, Sweden Uppsala University, Sweden .
    Berglund, Pontus
    Lund University, Sweden .
    Lauss, Martin
    Lund University, Sweden.
    Ringner, Markus
    Lund University, Sweden.
    Olsson, Hakan
    Lund University, Sweden .
    Luts, Lena
    Lund University, Sweden .
    Sim, Edith
    University of Oxford, England .
    Thorstensson, Sten
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Fjallskog, Marie-Louise
    Uppsala University, Sweden .
    Hedenfalk, Ingrid
    Lund University, Sweden .
    Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1Article in journal (Refereed)
    Abstract [en]

    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). less thanbrgreater than less thanbrgreater thanMethods: 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. less thanbrgreater than less thanbrgreater thanResults: 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. less thanbrgreater than less thanbrgreater thanConclusions: 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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  • 6.
    Karlsson, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Pérez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Amin, Risul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bostner, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Skoog, Lambert
    Department of Pathology and Cytology, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm South General Hospital, Stockholm, Sweden .
    Sgroi, Dennis C
    Department of Pathology, Molecular Pathology Research Unit, Massachusetts General Hospital, Boston, USA.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Hallbeck, Anna-Lotta
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials.2013In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, no 5, p. R96-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with oestrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.

    METHODS: The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomised Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.

    RESULTS: S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signalling may be involved and the results further support a combination of ER and mTOR signalling targeted therapies.

    CONCLUSION: This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signalling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.

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  • 7.
    Lundberg, Peter
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Abrahamsson, Annelie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Kihlberg, Johan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Tellman, Jens
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Tomkeviciene, Ieva
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Karlsson, Anette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Kristoffersen Wiberg, Maria
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Warntjes, Marcel Jan Bertus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dabrosin, Charlotta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Low-dose acetylsalicylic acid reduces local inflammation and tissue perfusion in dense breast tissue in postmenopausal women2024In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 26, no 1, article id 22Article in journal (Refereed)
    Abstract [en]

    Purpose One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to similar to 30% of all breast cancer. Prevention targeting dense breast tissue has the potential to improve breast cancer mortality and morbidity. Anti-estrogens, which may be associated with severe side-effects, can be used for prevention of breast cancer in women with high risk of the disease per se. However, no preventive therapy targeting dense breasts is currently available. Inflammation is a hallmark of cancer. Although the biological mechanisms involved in the increased risk of cancer in dense breasts is not yet fully understood, high mammographic density has been associated with increased inflammation. We investigated whether low-dose acetylsalicylic acid (ASA) affects local breast tissue inflammation and/or structural and dynamic changes in dense breasts. Methods Postmenopausal women with mammographic dense breasts on their regular mammography screen were identified. A total of 53 women were randomized to receive ASA 160 mg/day or no treatment for 6 months. Magnetic resonance imaging (MRI) was performed before and after 6 months for a sophisticated and continuous measure breast density by calculating lean tissue fraction (LTF). Additionally, dynamic quantifications including tissue perfusion were performed. Microdialysis for sampling of proteins in vivo from breasts and abdominal subcutaneous fat, as a measure of systemic effects, before and after 6 months were performed. A panel of 92 inflammatory proteins were quantified in the microdialysates using proximity extension assay. Results After correction for false discovery rate, 20 of the 92 inflammatory proteins were significantly decreased in breast tissue after ASA treatment, whereas no systemic effects were detected. In the no-treatment group, protein levels were unaffected. Breast density, measured by LTF on MRI, were unaffected in both groups. ASA significantly decreased the perfusion rate. The perfusion rate correlated positively with local breast tissue concentration of VEGF. Conclusions ASA may shape the local breast tissue microenvironment into an anti-tumorigenic state. Trials investigating the effects of low-dose ASA and risk of primary breast cancer among postmenopausal women with maintained high mammographic density are warranted.hic density are warranted.

  • 8.
    Lundgren, Christine
    et al.
    Reg Jonkoping Cty, Sweden; Lund Univ, Sweden.
    Bendahl, Par-Ola
    Lund Univ, Sweden.
    Ekholm, Maria
    Reg Jonkoping Cty, Sweden; Lund Univ, Sweden.
    Ferno, Marten
    Lund Univ, Sweden.
    Forsare, Carina
    Lund Univ, Sweden.
    Kruger, Ute
    Lund Univ, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ryden, Lisa
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Tumour-infiltrating lymphocytes as a prognostic and tamoxifen predictive marker in premenopausal breast cancer: data from a randomised trial with long-term follow-up2020In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 22, no 1, article id 140Article in journal (Refereed)
    Abstract [en]

    Background: Tumour-infiltrating lymphocytes (TILs) are of important prognostic and predictive value in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) and triple-negative breast cancer (TNBC), but their clinical relevance in oestrogen receptor-positive/HER2-negative (ER+/HER2-) remains unknown. The primary study aim was to analyse the prognostic effect of TILs on the BC-free interval (BCFi) in premenopausal patients stratified by BC subtypes. The secondary aim was to investigate if TILs are predictive of tamoxifen (TAM) benefit. Methods: Archival tissues from primary breast tumours were collected from patients from the SBII:2pre trial, in which 564 premenopausal women were randomised to 2 years of adjuvant TAM or no systemic treatment, regardless of hormone receptor status. TILs were scored on whole tissue sections from 447 patients with available ER status. Tumours were divided into ER+/HER2-, HER2+ and TNBC subtypes by immunohistochemistry and in situ hybridisation. The prognostic value of TILs was analysed in systemically untreated patients (n = 221); the predictive information was investigated in the ER+ subgroup (n = 321) by cumulative incidence curves and Cox regression analyses. The median follow-up was 28 years. Results: High (>= 50%) infiltration of TILs was a favourable prognostic factor in terms of BCFi (univariable analysis: hazard ratio(BCFi) (HRBCFi) 0.40; 95% confidence interval (CI) 0.22-0.71; P = 0.002). Similar effects were observed across all BC subtypes. The effect of adjuvant TAM was stronger in patients with ER+ tumours and TILs < 50% (HRBCFi 0.63; 95% CI 0.47-0.84; P = 0.002) than in patients with high immune infiltration (>= 50%) (HRBCFi 0.84; 95% CI (0.24-2.86); P = 0.77). However, evidence for differential effects of TAM in categories of TILs, i.e. interaction, was weak. Conclusions: We demonstrate a long-term favourable prognostic value of high infiltration of TILs in a cohort of premenopausal BC patients and the positive prognostic effect was extended to the ER+/HER2- subgroup. A beneficial effect of TAM in ER+ patients was observed in patients with tumours of low TIL infiltration, but evidence for a treatment predictive effect was weak.

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  • 9.
    Lundgren, Christine
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden; Lund Univ, Sweden.
    Tutzauer, Julia
    Lund Univ, Sweden.
    Church, Sarah E.
    NanoString Technol Inc, WA USA.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ekholm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Forsare, Carina
    Lund Univ, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ferno, Marten
    Lund Univ, Sweden.
    Bendahl, Par-Ola
    Lund Univ, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer: data from the randomized SBII:2 trial2023In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 25, no 1, article id 110Article in journal (Refereed)
    Abstract [en]

    <bold>Background: </bold>Gene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer.<bold>Methods: </bold>RNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling (n = 437, NanoString Breast Cancer 360 (TM) panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX signatures and tamoxifen effect were assessed in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+ /HER2-) tumors using Kaplan-Meier estimates and Cox regression. The prognostic effects of GEX signatures were studied in the entire cohort. False discovery rate adjustments (q-values) were applied to account for multiple hypothesis testing.<bold>Results: </bold>In patients with ER+/HER2- tumors, FOXA1 expression below the median was associated with an improved effect of tamoxifen after 10 years with regard to RFi (hazard ratio [HR](FOXA1(high)) = 1.04, 95% CI = 0.61-1.76, HRFOXA1(low) = 0.30, 95% CI = 0.14-0.67, q(interaction) = 0.0013), and a resembling trend was observed for AR (HRAR(high) = 1.15, 95% CI = 0.60-2.20, HRAR(low) = 0.42, 95% CI = 0.24-0.75, q(interaction) = 0.87). Similar patterns were observed for OS. Tamoxifen was in the same subgroup most beneficial for RFi in patients with low ESR1 expression (HRRFi ESR1(high) = 0.76, 95% CI = 0.43-1.35, HRRFi, ESR1(low) = 0.56, 95% CI = 0.29-1.06, q(interaction) = 0.37). Irrespective of molecular subtype, higher levels of ESR1, Mast cells, and PGR on a continuous scale were correlated with improved 10 years RFi (HRESR1 = 0.80, 95% CI = 0.69-0.92, q = 0.005; HRMast cells = 0.74, 95% CI = 0.65-0.85, q < 0.0001; and HRPGR = 0.78, 95% CI = 0.68-0.89, q = 0.002). For BC proliferation and Hypoxia, higher scores associated with worse outcomes (HRBCproliferation = 1.54, 95% CI = 1.33-1.79, q < 0.0001; HRHypoxia = 1.38, 95% CI = 1.20-1.58, q < 0.0001). The results were similar for OS.<bold>Conclusions: </bold>Expression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2- premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR, ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors.

  • 10.
    Martrat, Griselda
    et al.
    IDIBELL.
    Maxwell, Christopher A.
    IDIBELL.
    Tominaga, Emiko
    University of Texas Health Science Centre San Antonio.
    Porta-de-la-Riva, Montserrat
    Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, IDIBELL, Spain.
    Bonifaci, Nuria
    IDIBELL.
    Gomez-Baldo, Laia
    IDIBELL.
    Bogliolo, Massimo
    Autonomous University Barcelona.
    Lazaro, Conxi
    IDIBELL.
    Blanco, Ignacio
    IDIBELL.
    Brunet, Joan
    Hospital Josep Trueta.
    Aguilar, Helena
    Bellvitge Institute Biomed Research IDIBELL.
    Fernandez-Rodriguez, Juana
    IDIBELL.
    Seal, Sheila
    Institute Canc Research.
    Renwick, Anthony
    Institute Canc Research.
    Rahman, Nazneen
    Institute Canc Research.
    Küehl, Julia
    Department of Human Genetics, University of Würzburg, Biozentrum, Am Hubland, Würzburg, Germany .
    Neveling, Kornelia
    University Wurzburg.
    Schindler, Detlev
    University Wurzbur.
    J. Ramirez, Maria
    Autonomous University Barcelona.
    Castella, Maria
    Autonomous University Barcelon.
    Hernandez, Gonzalo
    Autonomous University Barcelona.
    F. Easton, Douglas
    University Cambridge.
    Peock, Susan
    University Cambridge.
    Cook, Margaret
    University Cambridge.
    T. Oliver, Clare
    University Cambridge.
    Frost, Debra
    University Cambridge.
    Platte, Radka
    University Cambridge.
    Gareth Evans, D.
    Cent Manchester University Hospital NHS Fdn Trust.
    Lalloo, Fiona
    Cent Manchester University Hospital NHS Fdn Trust.
    Eeles, Rosalind
    Institute Canc Research, Oncogenet Team.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust.
    Chu, Carol
    St James Hospital.
    Davidson, Rosemarie
    Ferguson Smith Centre Clin Genet.
    Ong, Kai-Ren
    Birmingham Womens Hospital Healthcare NHS Trust.
    Cook, Jackie
    Sheffield Childrens Hospital.
    Douglas, Fiona
    Newcastle Upon Tyne Hospital NHS Trust.
    Hodgson, Shirley
    University London.
    Brewer, Carole
    Royal Devon and Exeter Hospital.
    J. Morrison, Patrick
    Belfast City Hospital.
    Porteous, Mary
    Western Gen Hospital.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Manoukian, Siranoush
    Fdn IRCCS INT.
    Peissel, Bernard
    Fdn IRCCS INT.
    Zaffaroni, Daniela
    Fdn IRCCS INT.
    Roversi, Gaia
    Fdn IRCCS INT.
    Barile, Monica
    Ist Europeo Oncol IEO.
    Viel, Alessandra
    IRCCS.
    Pasini, Barbara
    University Turin.
    Ottini, Laura
    University Roma La Sapienza.
    Laura Putignano, Anna
    Fiorgen Fdn Pharmacogen.
    Savarese, Antonella
    Regina Elena Institute Canc Research.
    Bernard, Loris
    IEO.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Healey, Sue
    Queensland Institute Med Research.
    Spurdle, Amanda
    Queensland Institute Med Research.
    Chen, Xiaoqing
    Queensland Institute Med Research.
    Beesley, Jonathan
    Queensland Institute Med Research.
    A. Rookus, Matti
    Netherlands Canc Institute.
    Verhoef, Senno
    Netherlands Canc Institute.
    A. Tilanus-Linthorst, Madeleine
    Erasmus MC Daniel den Hoed Canc Centre.
    P. Vreeswijk, Maaike
    Leiden University.
    J. Asperen, Christi
    Leiden University.
    Bodmer, Danielle
    Radboud University Nijmegen.
    G. E. M. Ausems, Margreet
    University Med Centre Utrecht.
    A. van Os, Theo
    University Amsterdam.
    J. Blok, Marinus
    University Hospital Maastricht.
    E. J. Meijers-Heijboer, Hanne
    Vrije University Amsterdam Med Centre.
    B. L. Hogervorst, Frans
    Netherlands Canc Institute.
    E. Goldgar, David
    University Utah.
    Buys, Saundra
    Huntsman Canc Institute.
    M. John, Esther
    Canc Prevent Institute Calif.
    Miron, Alexander
    Harvard University.
    Southey, Melissa
    University Melbourne.
    B. Daly, Mary
    Fox Chase Canc Centre.
    Harbst, Katja
    Skane University Hospital.
    Borg, Ake
    Skane University Hospital.
    Rantala, Johanna
    Karolinska University Hospital.
    Barbany-Bustinza, Gisela
    Karolinska University Hospital.
    Ehrencrona, Hans
    Uppsala University.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Kaufman, Bella
    The Institute of Oncology, Chaim Sheba Medical Center, Israel .
    Laitman, Yael
    Chaim Sheba Med Centre.
    Milgrom, Roni
    Chaim Sheba Med Centre.
    Friedman, Eitan
    Chaim Sheba Med Centre.
    M. Domchek, Susan
    University Penn.
    L. Nathanson, Katherine
    University Penn.
    R. Rebbeck, Timothy
    University Penn.
    Thor Johannsson, Oskar
    Department of Oncology, 20A Landspitali-LSH v/Hringbraut, Reykjavik, Iceland.
    J. Couch, Fergus
    Mayo Clin.
    Wang, Xianshu
    Mayo Clin.
    Fredericksen, Zachary
    Mayo Clin.
    Cuadras, Daniel
    IDIBELL.
    Moreno, Vctor
    IDIBELL.
    K. Pientka, Friederike
    University Lubeck.
    Depping, Reinhard
    University Lubeck.
    Caldes, Trinidad
    Hospital Clin San Carlos.
    Osorio, Ana
    Spanish Natl Canc Research Centre.
    Benitez, Javier
    Spanish Natl Canc Research Centre.
    Bueren, Juan
    Centre Invest Energet Medioambientales and Tecnol CIEM,.
    Heikkinen, Tuomas
    University Helsinki.
    Nevanlinna, Heli
    University Helsinki.
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ.
    Torres, Diana
    Pontificia University Javeriana.
    Adelaide Caligo, Maria
    University Hospital Pisa.
    K. Godwin, Andrew
    University Kansas.
    N. Imyanitov, Evgeny
    NN Petrov Oncol Research Institute.
    Janavicius, Ramunas
    Vilnius University Hospital.
    M. Sinilnikova, Olga
    University Lyon 1.
    Stoppa-Lyonnet, Dominique
    Institute Curie.
    Mazoyer, Sylvie
    University Lyon 1.
    Verny-Pierre, Carole
    University Lyon 1.
    Castera, Laurent
    Institute Curie.
    de Pauw, Antoine
    Institute Curie.
    Bignon, Yves-Jean
    University Clermont Ferrand.
    Uhrhammer, Nancy
    University Clermont Ferrand.
    Peyrat, Jean-Philippe
    Centre Oscar Lambret.
    Vennin, Philippe
    Consultation d'Oncogénétique, Centre Oscar Lambret, Lille, France .
    Fert Ferrer, Sandra
    Hotel Dieu Centre Hospital.
    Collonge-Rame, Marie-Agnes
    CHU Besancon.
    Mortemousque, Isabelle
    CHU Bretonneau.
    McGuffog, Lesley
    University Cambridge.
    Chenevix-Trench, Georgia
    Queensland Institute Med Research.
    M. Pereira-Smith, Olivia
    University Texas Hlth Science Centre San Antonio.
    C. Antoniou, Antonis
    University Cambridge.
    Ceron, Julian
    IDIBELL.
    Tominaga, Kaoru
    University Texas Hlth Science Centre San Antonio.
    Surralles, Jordi
    Autonomous University Barcelona.
    Angel Pujana, Miguel
    Catalan Institute of Oncology, IDIBELL, Spain.
    Exploring the link between MORF4L1 and risk of breast cancer2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 2Article in journal (Refereed)
    Abstract [en]

    Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

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  • 11.
    Mulligan, Anna Marie
    et al.
    University of Toronto.
    Couch, Fergus J
    Rochester.
    Barrowdale, Daniel
    University of Cambridge.
    Domchek, Susan M
    University of Penn.
    Eccles, Diana
    University of Southampton.
    Nevanlinna, Heli
    University of Helsinki.
    Ramus, Susan J
    University of So Calif.
    Robson, Mark
    Mem Sloan Kettering Cancer Centre.
    Sherman, Mark
    NCI.
    Spurdle, Amanda B
    Queensland Institute Medical Research.
    Wappenschmidt, Barbara
    University Hospital Cologne.
    Lee, Andrew
    University of Cambridge.
    McGuffog, Lesley
    University of Cambridge.
    Healey, Sue
    Queensland Institute Medical Research.
    Sinilnikova, Olga M
    Centre Hospital University of Lyon Centre Leon Berard.
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin.
    Hansen, Thomas V O
    Copenhagen University Hospital.
    Nielsen, Finn C
    Copenhagen University Hospital.
    Ejlertsen, Bent
    Copenhagen University Hospital, Rigshosp.
    Osorio, Ana
    Spanish National Cancer Research Centre.
    Munoz-Repeto, Ivan
    Spanish National Cancer Research Centre.
    Duran, Mercedes
    University of Valladolid.
    Godino, Javier
    Hospital Clin University of Lozano Blesa.
    Pertesi, Maroulio
    National Centre Science Research Demokritos.
    Benitez, Javier
    Spanish National Cancer Research Centre.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumouri INT.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumouri INT.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumouri INT.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumouri INT.
    Cattaneo, Elisa
    Fdn IRCCS Ist Nazl Tumouri INT.
    Bonanni, Bernardo
    Ist Europeo Oncol, Div Cancer Prevent and Genet.
    Viel, Alessandra
    IRCCS.
    Pasini, Barbara
    University of Turin.
    Papi, Laura
    University of Florence.
    Ottini, Laura
    University of Roma La Sapienza.
    Savarese, Antonella
    Regina Elena Institute Cancer Research.
    Bernard, Loris
    Ist Europeo Oncol.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumouri INT.
    Hamann, Ute
    DKFZ.
    Verheus, Martijn
    Netherlands Cancer Institute.
    Meijers-Heijboer, Hanne E J
    Vrije University of Amsterdam Medical Centre.
    Wijnen, Juul
    Leiden University.
    Gomez Garcia, EncarnaB
    MUMC.
    Nelen, Marcel R
    Radboud University of Nijmegen.
    Kets, C Marleen
    Radboud University of Nijmegen.
    Seynaeve, Caroline
    Erasmus University.
    Tilanus-Linthorst, Madeleine M A
    Erasmus University.
    van der Luijt, Rob B
    University of Medical Centre Utrecht.
    van Os, Theo
    University of Amsterdam.
    Rookus, Matti
    Netherlands Cancer Institute.
    Frost, Debra
    University of Cambridge.
    Jones, J Louise
    Queen Mary University of London.
    Evans, D Gareth
    Central Manchester University Hospital NHS Fdn Trust.
    Lalloo, Fiona
    Central Manchester University Hospital NHS Fdn Trust.
    Eeles, Ros
    Institute Cancer Research, Oncogenet Team, London.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust.
    Adlard, Julian
    Yorkshire Regional Genet Serv.
    Davidson, Rosemarie
    Yorkhill Hospital.
    Cook, Jackie
    Sheffield Childrens Hospital.
    Donaldson, Alan
    St Michaels Hospital.
    Dorkins, Huw
    Kennedy Galton Centre.
    Gregory, Helen
    NHS Grampian.
    Eason, Jacqueline
    Nottingham University Hospital NHS Trust.
    Houghton, Catherine
    Liverpool Womens NHS Fdn Trust.
    Barwell, Julian
    University Hospital Leicester NHS Trust.
    E Side, Lucy
    Great Ormond St Hospital Sick Children.
    McCann, Emma
    Glan Clwyd Gen Hospital.
    Murray, Alex
    Singleton Hospital.
    Peock, Susan
    University of Cambridge.
    K Godwin, Andrew
    University of Kansas.
    K Schmutzler, Rita
    University Hospital Cologne.
    Rhiem, Kerstin
    University Hospital Cologne.
    Engel, Christoph
    University of Leipzig.
    Meindl, Alfons
    Technical University of Munich.
    Ruehl, Ina
    University of Munich.
    Arnold, Norbert
    University of Kiel.
    Niederacher, Dieter
    University of Dusseldorf.
    Sutter, Christian
    University of Heidelberg Hospital.
    Deissler, Helmut
    University Hospital.
    Gadzicki, Dorothea
    Hannover Medical Sch.
    Kast, Karin
    Technical University of Dresden.
    Preisler-Adams, Sabine
    University of Munster.
    Varon-Mateeva, Raymonda
    Charite, Campus Virchov Klinikum.
    Schoenbuchner, Ines
    University of Wurzburg.
    Fiebig, Britta
    University of Regensburg.
    Heinritz, Wolfram
    University of Leipzig.
    Schaefer, Dieter
    University Hospital, Frankfurt.
    Gevensleben, Heidrun
    Institute Cancer Research,London.
    Caux-Moncoutier, Virginie
    Institute Curie .
    Fassy-Colcombet, Marion
    Institute Curie.
    Cornelis, Francois
    Avicenne Hospital.
    Mazoyer, Sylvie
    University of Lyon 1.
    Leone, Melanie
    Centre Hospital University of Lyon Centre Leon Berard.
    Boutry-Kryza, Nadia
    Centre Hospital University of Lyon Centre Leon Berard.
    Hardouin, Agnes
    Centre Francois Baclesse.
    Berthet, Pascaline
    Centre Francois Baclesse.
    Muller, Daniele
    CLCC Paul Strauss.
    Fricker, Jean-Pierre
    CLCC Paul Strauss.
    Mortemousque, Isabelle
    CHU Bretonneau.
    Pujol, Pascal
    CHU Amaud de Villeneuve.
    Coupier, Isabelle
    CHU Amaud de Villeneuve.
    Lebrun, Marine
    Centre Hospital University of St Etienne.
    Kientz, Caroline
    Centre Hospital University of St Etienne.
    Longy, Michel
    University of Bordeaux.
    Sevenet, Nicolas
    University of Bordeaux.
    Stoppa-Lyonnet, Dominique
    Institute Curie.
    Isaacs, Claudine
    Georgetown University.
    Caldes, Trinidad
    Hospital Clin San Carlos.
    de la Hoya, Miguel
    Hospital Clin San Carlos.
    Heikkinen, Tuomas
    University of Helsinki.
    Aittomaki, Kristiina
    University of Helsinki.
    Blanco, Ignacio
    Hospital Duran i Reynals Bellvitge Biomed Research Institute ID.
    Lazaro, Conxi
    Hospital Duran i Reynals Bellvitge Biomed Research Institute ID.
    B Barkardottir, Rosa
    Landspitali University Hospital.
    Soucy, Penny
    CHU Quebec.
    Dumont, Martine
    CHU Quebec.
    Simard, Jacques
    CHU Quebec.
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS.
    Tognazzo, Silvia
    Ist Oncology Veneto IOV IRCCS.
    DAndrea, Emma
    University of Padua.
    Fox, Stephen
    Peter MacCallum Cancer Centre.
    Yan, Max
    Prince Wales Hospital.
    Rebbeck, Tim
    Abramson Cancer Centre.
    I Olopade, Olufunmilayo
    University of Chicago.
    N Weitzel, Jeffrey
    City Hope National Medical Centre.
    T Lynch, Henry
    Creighton University.
    A Ganz, Patricia
    University of Calif Los Angeles.
    E Tomlinson, Gail
    University of Texas SW Medical Centre Dallas.
    Wang, Xianshu
    Mayo Clin.
    Fredericksen, Zachary
    Mayo Clin.
    S Pankratz, Vernon
    Mayo Clin.
    M Lindor, Noralane
    Mayo Clin.
    Szabo, Csilla
    University of Delaware.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre.
    Sakr, Rita
    Mem Sloan Kettering Cancer Centre.
    Gaudet, Mia
    Amer Cancer Soc.
    Bhatia, Jasmine
    Mem Sloan Kettering Cancer Centre.
    Kauff, Noah
    Mem Sloan Kettering Cancer Centre.
    F Singer, Christian
    Medical University of Vienna.
    Tea, Muy-Kheng
    Medical University of Vienna.
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna.
    Fink-Retter, Anneliese
    Medical University of Vienna.
    L Mai, Phuong
    US National Cancer Institute.
    H Greene, Mark
    US National Cancer Institute.
    Imyanitov, Evgeny
    NN Petrov Institute Oncol.
    P OMalley, Frances
    St Michaels Hospital.
    Ozcelik, Hilmi
    Mt Sinai Hospital.
    Glendon, Gordon
    Ohio State University.
    Gerdes, Anne-Marie
    University of Copenhagen.
    Thomassen, Mads
    Odense University Hospital.
    A Kruse, Torben
    Odense University Hospital.
    Birk Jensen, Uffe
    Aarhus University Hospital.
    Skytte, Anne-Bine
    Vejle Hospital.
    A Caligo, Maria
    University of Pisa.
    Soller, Maria
    University of Lund Hospital.
    Henriksson, Karin
    University of Lund Hospital.
    Anna Wachenfeldt, von
    Karolinska University Hospital.
    Arver, Brita
    Karolinska University Hospital.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Karlsson, Per
    Sahlgrens University Hospital.
    Chun Ding, Yuan
    City Hope National Medical Centre.
    L Neuhausen, Susan
    City Hope National Medical Centre.
    Beattie, Mary
    University of Calif San Francisco.
    D P Pharoah, Paul
    University of Cambridge.
    B Moysich, Kirsten
    Roswell Pk Cancer Institute.
    L Nathanson, Katherine
    University of Penn.
    Y Karlan, Beth
    Cedars Sinai Medical Centre.
    Gross, Jenny
    Cedars Sinai Medical Centre.
    M John, Esther
    Cancer Prevent Institute Calif.
    B Daly, Mary
    Fox Chase Cancer Centre.
    M Buys, Saundra
    University of Utah.
    C Southey, Melissa
    University of Melbourne.
    L Hopper, John
    University of Melbourne.
    Beth Terry, Mary
    Columbia University.
    Chung, Wendy
    Columbia University.
    F Miron, Alexander
    Dana Farber Cancer Institute.
    Goldgar, David
    University of Utah.
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research.
    F Easton, Douglas
    University of Cambridge.
    L Andrulis, Irene
    University of Toronto.
    C Antoniou, Antonis
    University of Cambridge.
    Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/22011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 6Article in journal (Refereed)
    Abstract [en]

    Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. less thanbrgreater than less thanbrgreater thanMethods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. less thanbrgreater than less thanbrgreater thanResults: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. less thanbrgreater than less thanbrgreater thanConclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

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  • 12.
    Niméus-Malmström, Emma
    et al.
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Krogh, Morten
    Computational Biology and Biological Physics, Department of Theoretical Physics, Lund University, Lund, Sweden .
    Malmström, Per
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Strand, Carina
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Fredriksson, Irma
    Department of Surgery, Karolinska University Hospital in Solna, Stockholm, Sweden .
    Karlsson, Per
    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Östberg, Görel
    Department of Pathology, Halmstad Hospital, Halmstad, Sweden .
    Peterson, Carsten
    Computational Biology and Biological Physics, Department of Theoretical Physics, Lund University, Lund, Sweden .
    Ferno, Marten
    Institute of Clinical Sciences, Department of Oncology, University Hospital, Lund, Sweden.
    Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy2008In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 10, no 2Article in journal (Refereed)
    Abstract [en]

    Introduction

    Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.

    Methods

    We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.

    Results

    Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-).

    Conclusion

    A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.

  • 13.
    Ogony, Joshua
    et al.
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    de Bel, Thomas
    Radboud Univ Nijmegen, Netherlands; Radboud Univ Nijmegen, Netherlands.
    Radisky, Derek C.
    Mayo Clin, FL 32224 USA.
    Kachergus, Jennifer
    Mayo Clin, FL 32224 USA.
    Thompson, E. Aubrey
    Mayo Clin, FL 32224 USA.
    Degnim, Amy C.
    Mayo Clin, MN USA.
    Ruddy, Kathryn J.
    Mayo Clin, MN USA.
    Hilton, Tracy
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    Stallings-Mann, Melody
    Mayo Clin, FL 32224 USA.
    Vachon, Celine
    Mayo Clin, MN USA.
    Hoskin, Tanya L.
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    Heckman, Michael G.
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    Vierkant, Robert A.
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    White, Launia J.
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    Moore, Raymond M.
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    Carter, Jodi
    Mayo Clin, MN USA.
    Jensen, Matthew
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    Pacheco-Spann, Laura
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    Henry, Jill E.
    Indiana Univ Sch Med, IN 46202 USA.
    Storniolo, Anna Maria
    Indiana Univ Sch Med, IN 46202 USA.
    Winham, Stacey J.
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA.
    van der Laak, Jeroen
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Radboud Univ Nijmegen, Netherlands.
    Sherman, Mark E.
    Mayo Clin, MN 55905 USA; Mayo Clin, FL 32224 USA; Mayo Clin, FL 32224 USA.
    Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence2022In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 24, no 1, article id 45Article in journal (Refereed)
    Abstract [en]

    Background Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. Methods Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors <= 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fishers exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: <= 5 years versus remote birth: > 5 years]) using multivariable regression models. Results Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked <= 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. Conclusions Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

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  • 14.
    Palmebäck Wegman, Pia
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Wingren, Sten
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    CYP2D6 variants and the prediction of tamoxifen response in randomized patients: authors' response2005In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 7, no 6, p. 234-234Article in journal (Refereed)
  • 15.
    Stål, Olle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Åkerberg, Lind
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden .
    Rutqvist, Lars
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden .
    Akt kinases in breast cancer and the results of adjuvant therapy2003In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 5, no 2, p. R37-R44Article in journal (Refereed)
    Abstract [en]

    Background

    The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase.

    Methods

    We analysed the expression of the isoforms Akt1 and Akt2 as well as phosphorylated Akt (pAkt) by immunohistochemistry in frozen tumour samples from 280 postmenopausal patients who participated in a randomised trial comparing cyclophosphamide–methotrexate–5-fluorouracil chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or to no endocrine treatment.

    Results

    Marked staining was found in 24% of the tumours for Akt1, but in only 4% for Akt2. A low frequency of Akt2-positive cells (1–10%) was observed in another 26% of the tumours. pAkt was significantly associated with both Akt1 and Akt2 expression. Overexpression of erbB2 correlated significantly with pAkt (P = 0.0028). The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients. Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen. The relative rate of distant recurrence, with versus without tamoxifen, was 0.44 (95% confidence interval [CI], 0.25–0.79) for ER+/Akt1- patients, while it was 0.72 (95% CI, 0.34–1.53) for ER+/Akt1+ patients. The difference in rate ratio did not reach statistical significance. The rate of locoregional recurrence was significantly decreased with radiotherapy versus chemotherapy for Akt-negative patients (rate ratio, 0.23; 95% CI, 0.08–0.67; P = 0.0074), while no benefit was evident for the Akt-positive subgroup (rate ratio, 0.77; 95% CI, 0.31–1.9; P = 0.58). The interaction between Akt and the efficacy of radiotherapy was significant in multivariate analysis (P = 0.042).

    Conclusion

    Activation of the Akt pathway is correlated with erbB2 overexpression in breast cancer. The results suggest that Akt may predict the local control benefit from radiotherapy.

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