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  • 1.
    Agrup, Måns
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Olsen, Karen
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    C-erbB-2 overexpression and survival in early onset breast cancer2000In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 63, no 1, p. 23-29Article in journal (Refereed)
    Abstract [en]

    Young breast cancer patients have a decreased survival rate and it has been demonstrated that young age is an independent predictor of adverse prognosis. Overexpression of c-erbB-2 protein (also known as HER-2/neu) has been shown to be a prognostic indicator in breast cancer in general and especially among patients with axillary nodal metastases. The present study was initiated to determine the prognostic significance of c-erbB-2 protein overexpression in early onset breast cancer.

    A population consisting of 110 young breast cancer patients, ≤ 36-year-old at diagnosis, was analyzed with immunohistochemical staining for c-erbB-2 protein.

    Thirty patients (27%) were found to overexpress the c-erbB-2 protein. C-erbB-2 positivity was significantly associated with poor survival when all patients were included in the analysis (P = 0.002) and for patients with axillary nodal metastases (P = 0.0007). No such association was found for node-negative patients. Furthermore, the difference in prognosis in relation to c-erbB-2 among node-positive patients was maintained, when these were stratified in groups treated or not treated with adjuvant chemotherapy.

    The study indicates that overexpression of c-erbB-2 protein is a strong prognostic factor in young breast cancer patients with axillary nodal metastases. Moreover, the adverse prognosis associated with c-erbB-2 overexpression in node-positive patients was observed whether or not the patients had received adjuvant chemotherapy.

  • 2.
    Ahnström Waltersson, Marie
    et al.
    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. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Rutqvist, Lars Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Skoog, Lambert
    Department of Cytology, Karolinska Hospital, Stockholm, Sweden.
    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.
    Role of cyclin D1 in ErbB2-positive breast cancer and tamoxifen resistance.2005In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 91, no 2, p. 145-151Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 plays an important role in the regulation of the G1 phase in the cell cycle. In mammary epithelial cells the expression of cyclin D1 is regulated through the oestrogen receptor and via ErbB2 signalling. Here we investigated the prognostic significance of cyclin D1 among 230 breast cancer patients randomised for tamoxifen, CMF chemotherapy and radiotherapy. The importance of combined cyclin D1 and ErbB2 overexpression was also analysed. Immunohistochemical analysis of the cyclin D1 expression resulted in 69 (29.8%) weakly positive, 107 (46.5%) moderately positive and 54 (23.7%) strongly positive cases. The prognostic importance of ErbB2 was significantly greater for patients whose tumours overexpressed cyclin D1 than for other patients (p = 0.026). In the former group, ErbB2 overexpression was strongly associated with increased risk of recurrence (RR = 4.7; 95% CI, 2.1-10.4) and breast cancer death (RR = 5.4; 95% CI, 2.3-12.6). This result is in accordance with experimental studies demonstrating a link between cyclin D1 and ErbB2 in oncogenesis. Among oestrogen receptor positive patients, those with moderate cyclin D1 expression significantly did benefit from tamoxifen treatment (RR = 0.42; 95% CI, 0.21-0.82) whereas those with weak or strong expression did not. Therefore cyclin D1 might be a predictive marker for tamoxifen resistance.

  • 3.
    Bjohle, J
    et al.
    Karolinska Institute, Sweden .
    Bergqvist, J
    Karolinska Institute, Sweden .
    Gronowitz, J S.
    Biov Int AB, Sweden .
    Johansson, H
    Karolinska Institute, Sweden .
    Carlsson, L
    Sundsvall Gen Hospital, Sweden .
    Einbeigi, Z
    Sahlgrens University Hospital, Sweden .
    Linderholm, B
    Sahlgrens University Hospital, Sweden .
    Loman, N
    Lund University, Sweden .
    Malmberg, M
    Helsingborg Gen Hospital, Sweden .
    Soderberg, M
    Lund University, Sweden .
    Sundquist, M
    Kalmar Gen Hospital, Sweden .
    Walz, Thomas
    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. Karolinska Institute, Sweden .
    Ferno, M
    Lund University, Sweden .
    Bergh, J
    Karolinska Institute, Sweden .
    Hatschek, T
    Karolinska Institute, Sweden .
    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 andlt; 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.

  • 4.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Alayev, Anya
    Yeshiva Univ, NY 10033 USA.
    Berman, Adi Y.
    Yeshiva Univ, NY 10033 USA.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, 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.
    Holz, Marina K.
    Yeshiva Univ, NY 10033 USA; Albert Einstein Coll Med, NY 10467 USA; Albert Einstein Coll Med, NY 10467 USA.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, 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.
    Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer2018In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, no 1, p. 17-27Article in journal (Refereed)
    Abstract [en]

    Deregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer. Raptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ER alpha-positive cell lines was compared with that in ER alpha-negative cell lines. Raptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ER alpha signaling, here shown by a coupled increase of ER alpha phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ER alpha-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ER alpha-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up. We present a connection between raptor localization to the nucleus and ER alpha-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.

  • 5.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. 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.
    Pandiyan, Muneeswaran J.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Westman, Hanna
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Stockholm S Gen Hospital, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 137, no 2, p. 397-406Article in journal (Refereed)
    Abstract [en]

    The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor alpha (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31-2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18-0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.

  • 6.
    Dabrosin, Charlotta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Increase of free insulin-like growth factor-1 in normal human breast in vivo late in the menstrual cycle2003In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 80, no 2, p. 193-198Article in journal (Refereed)
    Abstract [en]

    Prolonged exposure to endogenous and exogenous sex steroids increases the risk of breast cancer but the mechanisms are poorly understood. Increased levels of circulating insulin-like growth factor-1 (IGF-1) and low levels of IGF binding protein are associated with increased risk of breast cancer suggesting that IGF-1 has to be in its free form to be biologically active. Little is known about sex steroid regulation of IGF-1 locally in the breast. In this study microdialysis was used to determine the local levels of free IGF-1 in normal human breast tissue in healthy female volunteers during the menstrual cycle. The results showed that the extracellular levels of free IGF-1 locally in the breast were doubled in the luteal phase, when estradiol and progesterone levels were elevated, compared with the follicular phase. In plasma, free IGF-1 levels also exhibited a cyclic variation but to a less extent. The increased local levels of the tree form of IGF-1 may promote proliferation in the breast epithelium. This could be important in sex steroid dependent breast cancer development.

  • 7.
    Dabrosin, Charlotta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Johansson, Ann-Charlotte
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Öllinger, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen: Mediated by the mannose-6-phosphate/IGF-II receptor?2004In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 85, no 3, p. 229-238Article in journal (Refereed)
    Abstract [en]

    The lysosomal protease Catliepsin D (Cath D) is associated with increased invasiveness and metastasis in breast cancer. Both estrogen and tamoxifen have been reported to increase Cath D, which seems to contradict the efficacy of tamoxifen as an adjuvant for estrogen dependent breast cancer. Cath D is bioactive in the extracellular space but very little is known about hormonal regulation of secreted Cath D in vivo. In this study we used microdialysis to sample the extracellular fluid in estrogen receptor positive MCF-7 tumors in nude mice. We show that tamoxifen in combination with estradiol decreased secreted Cath D compared with estradiol treatment only in solid tumors in situ. Cell culture of MCF-7 cells revealed that estradiol and tamoxifen increased intracellular proteolytic activity of Cath D in a similar fashion whereas secretion of Cath D was increased by estradiol and inhibited by tamoxifen. Immunofluorescence showed that estradiol located Cath D to the cell surface, while tamoxifen accumulated Cath D to dense lysosomes in perinuclear regions. Moreover, tamoxifen increased the intracellular transporter of Cath D, the mannose 6-phosphate/IGF-II receptor (M6P/IGF2R). In contrast, estradiol decreased the levels of this receptor. Thus, secretion of Cath D is hormone dependent and may be mediated by altered expression of the M6P/IGF2R. Our results highlight the importance of measurements of proteins in all compartments where they are biological active and show that microdialysis is a viable technique for sampling of Cath D in vivo.

  • 8.
    Dabrosin, Charlotta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Palmer, Kay
    Muller, William J
    Gauldie, Jack
    Estradiol promotes growth and angiogenesis in polyoma middle T transgenic mouse mammary tumor explants2003In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 78Article in journal (Refereed)
  • 9.
    de Azambuja, Evandro
    et al.
    Inst Jules Bordet, B-1000 Brussels, Belgium.
    McCaskill-Stevens, Worta
    NCI, NIH, Bethesda, MD 20892 USA.
    Francis, Prudence
    Peter MacCallum Canc Ctr, Melbourne, Vic, Australia.
    Quinaux, Emmanuel
    Int Inst Drug Dev, Louvain, Belgium.
    Crown, John P A
    St Vincents Hosp, Dublin 4, Ireland.
    Vicente, Malou
    Br EAST Data Ctr, Brussels, Belgium.
    Giuliani, Rosa
    S Camillo Forlanini Hosp, Med Oncol Unit, Rome, Italy.
    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.
    Gutierez, Jorge
    Clin Las Condes, Santiago, Chile.
    Andersson, Michael
    Copenhagen Univ Hosp, Rigshosp, Finsen Ctr, Dept Oncol, Copenhagen, Denmark.
    Margeli Vila, Mireia
    Hosp Badalona Germans Trias and Pujol, Badalona, Spain.
    Jakesz, Raimund
    Univ Vienna, Gen Hosp, Vienna, Austria.
    Demol, Jan
    Heilig Hart Ziekenhuis, Roeselare, Belgium.
    Dewar, Joanna
    Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia.
    Santoro, Armando
    Ist Clin Humanitas, Rozzano, Italy.
    Lluch, Ana
    Hosp Clin Univ, Valencia, Spain.
    Olsen, Steven
    Sanofi Aventis, Paris, France.
    Gelber, Richard D
    Dana Farber Canc Inst, Dept Biostat and Computat Biol, Boston, MA 02115 USA.
    Di Leo, Angelo
    Hosp Prato, Sandro Pitigliani Med Oncol Unit, Prato, Italy.
    Piccart-Gebhart, Martine
    Inst Jules Bordet, B-1000 Brussels, Belgium.
    The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial2010In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 119, no 1, p. 145-153Article in journal (Refereed)
    Abstract [en]

    Background: Obesity has been shown to be an indicator of poor prognosis for patients with primary breast cancer (BC) regardless of the use of adjuvant systemic therapy. Patients and methods: This is a retrospective analysis of 2,887 node-positive BC patients enrolled in the BIG 02-98 adjuvant study, a randomised phase III trial whose primary objective was to evaluate disease-free survival (DFS) by adding docetaxel to doxorubicin-based chemotherapy. In the current analysis, the effect of body mass index (BMI) on DFS and overall survival (OS) was assessed. BMI was obtained before the first cycle of chemotherapy. Obesity was defined as a BMI a parts per thousand yen 30 kg/mA(2). Results: In total, 547 (19%) patients were obese at baseline, while 2,340 (81%) patients were non-obese. Estimated 5-year OS was 87.5% for non-obese and 82.9% for obese patients (HR 1.34; P = 0.013). Estimated 5-years DFS was 75.9% for non-obese and 70.0% for obese patients (HR 1.20; P = 0.041). In a multivariate model, obesity remained an independent prognostic factor for OS and DFS. Conclusions: In this study, obesity was associated with poorer outcome in node-positive BC patients. Given the increasing prevalence of obesity worldwide, more research on improving the treatment of obese BC patients is needed.

  • 10.
    Falck, Anna-Karin
    et al.
    Lund University, Sweden .
    Bendahl, Par-Ola
    Lund University, Sweden .
    Chebil, Gunilla
    Lund University, Sweden .
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ferno, Marten
    Lund University, Sweden .
    Ryden, Lisa
    Lund University, Sweden .
    Biomarker expression and St Gallen molecular subtype classification in primary tumours, synchronous lymph node metastases and asynchronous relapses in primary breast cancer patients with 10 years follow-up2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 140, no 1, p. 93-104Article in journal (Refereed)
    Abstract [en]

    Molecular profiles of asynchronous breast cancer metastases are of clinical relevance to individual patients treatment, whereas the role of profiles in synchronous lymph node metastases is not defined. The present study aimed to assess individual biomarkers and molecular subtypes according to the St Gallen classification in primary breast tumours, synchronous lymph node metastases and asynchronous relapses and relate the results to 10-year breast cancer mortality (BCM). Tissue microarrays were constructed from archived tissue blocks of primary tumours (N = 524), synchronous lymph node metastases (N = 147) and asynchronous relapses (N = 36). The samples were evaluated by two independent pathologists according to oestrogen receptor (ER), progesterone receptor (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and in situ hybridisation. The expression of biomarkers and molecular subtypes in the primary tumour was compared with that in the synchronous lymph node metastases and relapses, and related to 10-year BCM. Discordances were found between primary tumours and relapses (ER: p = 0.006, PR: p = 0.04, Ki67: p = 0.02, HER2: p = 0.02, St Gallen subtypes: p = 0.07) but not between primary tumours and metastatic lymph node. Prognostic information was gained by the molecular subtype classification in primary tumours and nodal metastases; triple negative subtype had the highest BCM compared with the luminal A subtype (primary tumours: HR 4.0; 95 % CI 2.0-8.2, p andlt; 0.001, lymph node metastases: HR 3.5; 95 % CI 1.3-9.7, p = 0.02). When a shift in subtype inherence between primary tumour and metastatic lymph node was identified, the prognosis seemed to follow the subtype of the lymph node. Molecular profiles are not stable throughout tumour progression in breast cancer. Prognostic information for individual patients appears to be available from the analysis of biomarker expression in synchronous metastatic lymph nodes. The study supports biomarker analysis also in asynchronous relapses.

  • 11.
    Fernö, Mårten
    et al.
    Department of Oncology, University Hospital, Lund.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Baldetorp, Bo
    Department of Oncology, University Hospital, Lund.
    Hatschek, Thomas
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Källström, Ann-Christine
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment.
    Malmström, Per
    Department of Oncology, University Hospital, Lund.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Rydén, Stefan
    Department of Surgery, Ängelholm, Sweden.
    Results of two or five years of adjuvant tamoxifen correlated to steroid receptor and S-phase levels2000In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 59, no 1, p. 69-76Article in journal (Refereed)
    Abstract [en]

    A Swedish cooperative trial demonstrated that 5 years of adjuvant tamoxifen was more beneficial than 2 years of tamoxifen in the treatment of postmenopausal women with estrogen receptor (ER) positive, early stage, invasive breast cancer. The main aim of the present study was to investigate the importance of progesterone receptor (PgR) and ER concentration levels for patients participating in the trial and still distant recurrence free two years after the primary operation. Subgroup analyses revealed that only patients with ER positive and PgR positive breast cancer had improved distant recurrence free survival (DRFS) by prolonged tamoxifen therapy (p=0.0016). Patients with ER negative and PgR negative as well as ER positive and PgR negative tumors showed no significant effect of prolonged tamoxifen (p=0.53 and p=0.80, respectively). The percentage of ER negative and PgR positive breast cancers was too small (2.2%) for any meaningful subgroup analysis. There was a significant positive trend that the concentration level of PgR (high positive vs. low positive vs. negative) decreased the recurrence rate for those with prolonged therapy. No corresponding pattern was found for the ER content. S-phase fraction did not correlate to the recurrence rate of PgR positive breast cancers. Patients recurring during tamoxifen therapy had receptor negative tumors to a greater extent than those recurring after tamoxifen treatment.

    In conclusion, prolonged tamoxifen therapy for 5 years instead of 2 years was found to be beneficial for patients with ER positive and PgR positive breast cancer, whereas three extra years of tamoxifen had little or no effect for patients with ER positive but PgR negative tumors as well as for steroid receptor negative patients.

  • 12.
    Gunnarsson, Cecilia
    et al.
    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.
    Jerevall, Piiha-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Hammar, Karl
    Linköping University, Department of Computer and Information Science. Linköping University, The Institute of Technology.
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Jansson, Agneta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology.
    Stål, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Amplification of HSD17B1 has prognostic significance in postmenopausal breast cancer2008In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 108, no 1, p. 35-41Article in journal (Refereed)
    Abstract [en]

    In situ synthesis of estrogens is believed to be of great importance for the progression of breast cancer. In postmenopausal women most estrogens are synthesized in peripheral hormone-target tissues from circulating precursor steroids, by the enzymes involved in formation of active estrogens. One of the enzymes involved in this process is 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1. This enzyme catalyzes the interconversion of estrone (E1) to the biologically more potent estradiol (E2). The gene coding for 17β-HSD type 1 (HSD17B1) is located at 17q12-21. The aim of this study was to investigate altered gene copy number of HSD17B1 in breast cancer. We used real-time PCR and examined 387 postmenopausal breast tumors for amplification of HSD17B1, and if an increased mRNA level of this enzyme is associated with amplification of the gene. We also investigated whether amplification of HSD17B1 has a prognostic value. There was a significant correlation between gene copy number of HSD17B1 and mRNA expression level (P = 0.00002). ER-positive patients with amplification of HSD17B1 showed lower breast cancer survival than patients without amplification (P = 0.025). Among ER-negative patients there was no significant correlation between increased gene copy number of HSD17B1 and prognosis. Furthermore, we found that amplification of the gene had prognostic significance in multivariate analysis adjusting for other clinicopathological variables. © 2007 Springer Science+Business Media, LLC.

  • 13.
    Hatschek, T
    et al.
    Karolinska Institute.
    Carlsson, L
    Sundsvall General Hospital.
    Einbeigi, Z
    Sahlgrens University Hospital.
    Lidbrink, E
    Karolinska Institute.
    Linderholm, B
    Sahlgrens University Hospital.
    Lindh, B
    Umeå University Hospital.
    Loman, N
    Skåne University Hospital Lund.
    Malmberg, M
    Helsingborg General Hospital.
    Rotstein, S
    Karolinska Institute.
    Soderberg, M
    Skåne University Hospital.
    Sundquist, M
    Kalmar General Hospital.
    Walz, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Hellstrom, M
    Karolinska University Hospital.
    Svensson, H
    Sahlgrens University Hospital.
    Astrom, G
    Karolinska Institute.
    Brandberg, Y
    Karolinska Institute.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Arts and Sciences.
    Ferno, M
    Lund University.
    Bergh, J
    Karolinska Institute.
    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.

  • 14.
    Hilborn, Erik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Sivik, Tove
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    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.
    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.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    C-X-C ligand 10 and C-X-C receptor 3 status can predict tamoxifen treatment response in breast cancer patients2014In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 145, no 1, p. 73-82Article in journal (Refereed)
    Abstract [en]

    To investigate the expression levels of CXCL10 and CXCR3 in tumors from breast cancer patients randomized to adjuvant tamoxifen treatment or no endocrine treatment, in order to further study the connection to prognosis and prediction of tamoxifen treatment outcome. Immunohistochemistry on tissue microarrays from 912 breast cancer patients randomized to tamoxifen or no endocrine treatment. CXCR3 status was found to be a prognostic tool in predicting distant recurrence, as well as reduced breast cancer-specific survival. In patients with estrogen receptor (ER)-positive tumors, tumors with strong CXCL10 levels had improved effect of tamoxifen treatment in terms of local recurrence-free survival [risk ratio (RR) 0.46 (95 % CI 0.25-0.85, P = 0.01)] compared with patients with tumors expressing weak CXCL10 expression. Further, patients with ER-positive tumors with strong CXCR3 expression had an improved effect of tamoxifen in terms of breast cancer-specific survival [RR 0.34 (95 % CI 0.19-0.62, P less than 0.001)] compared with the group with weak CXCR3 levels [RR 1.33 (95 % CI 0.38-4.79, P = 0.65)]. We show here for the first time that CXCL10 and CXCR3 expression are both predictors of favorable outcome in patients treated with tamoxifen.

  • 15.
    Jansson, Agneta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Carlsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Olsson, Anette
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Storm, Petter
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Margolin, Sara
    Department of Oncology, Karolinska University Hospital/ Södersjukhuset, Stockholm, Sweden.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Medical Genetics. Linköping University, Faculty of Health Sciences.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindblom, Annika
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer2007In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 106, no 1, p. 57-64Article in journal (Refereed)
    Abstract [en]

    In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17β-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.

  • 16.
    Jerevall, Piiha-Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Brommesson, Sara
    Lund University Hospital.
    Strand, Carina
    Lund University Hospital.
    Gruvberger-Saal, Sofia
    Lund University Hospital.
    Malmström, Per
    Lund 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.
    Wingren, Sten
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fernö, Mårten
    Lund University Hospital.
    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.
    Exploring the two-gene ratio in breast cancer – independent roles for HOXB13 and IL17BR in prediction of clinical outcome2008In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 107, no 2, p. 225-234Article in journal (Refereed)
    Abstract [en]

    Background: The two-gene expression ratio HOXB13:IL17BR has been proposed to predict the outcome of tamoxifen-treated breast cancer patients. We intended to examine whether this ratio can predict the benefit of 5 years vs. 2 years of tamoxifen treatment of postmenopausal patients. A further objective was to investigate any prognostic effects of the ratio in systemically untreated premenopausal patients. Based on the current knowledge of HOXB13 and IL17BR, we hypothesized that these genes may have individual prognostic or predictive power.

    Patients and methods: Expression of HOXB13 and IL17BR were quantified by real-time PCR in tumors from 264 randomized postmenopausal patients and 93 systemically untreated premenopausal patients.

    Results: A high HOXB13:IL17BR ratio was associated with aggressive tumor characteristics, as were low levels of IL17BR alone. The ratio and HOXB13 alone predicted recurrence-free survival after endocrine treatment, with a benefit of prolonged treatment in estrogen receptor-positive patients correlated to a low ratio (recurrence rate ratio: RR=0.39; p=0.030), or low expression of HOXB13 (RR=0.37; p=0.015). No difference in recurrence-free survival was seen for the high ratio or high HOXB13 subgroups. The predictive value of HOXB13 and HOXB13:IL17BR was significant in multivariate analysis. In the systemically untreated cohort, only IL17BR showed independent prognostic significance.

    Conclusion: We conclude that the ratio or HOXB13 alone can predict the benefit of endocrine therapy, with a high ratio or a high expression rendering patients less likely to respond. We have also shown that IL17BR might be an independent prognostic factor in breast cancer.

  • 17.
    Karakatsanis, Andreas
    et al.
    University of Uppsala Hospital, Sweden.
    Christiansen, Peer Michael
    Aarhus University Hospital, Denmark.
    Fischer, Lone
    Aarhus University Hospital, Denmark.
    Hedin, Christina
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Pistioli, Lida
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Sund, Malin
    Department Surg and Perioperat Science, Sweden.
    Ryegaard Rasmussen, Nils
    SVS, Denmark.
    Jornsgard, Hjordis
    SVS, Denmark.
    Tegnelius, Daniel
    University of Örebro, Sweden.
    Eriksson, Staffan
    Vastmanland County Hospital, Sweden.
    Daskalakis, Kosmas
    University of Uppsala Hospital, Sweden.
    Warnberg, Fredrik
    University of Uppsala Hospital, Sweden.
    Markopoulos, Christos J.
    University of Athens, Greece.
    Bergkvist, Leif
    Uppsala University, Sweden; Vastmanland County Hospital, 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 amp;lt; 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.

  • 18.
    Karlsson, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Veenstra, Cynthia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Emin, Shad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dutta, Chhanda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer2015In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 153, no 1, p. 31-40Article in journal (Refereed)
    Abstract [en]

    Breast cancer is a heterogeneous disease and new clinical markers are needed to individualise disease management and therapy further. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown frequently especially in the luminal breast cancer subtypes, suggesting a cross-talk between ER and PI3K/AKT. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies. In vitro studies have shown protein tyrosine phosphatase, non-receptor type 2 (PTPN2) as a previously unknown negative regulator of the PI3K/AKT pathway. Here, we evaluate possible genomic alterations in the PTPN2 gene and its potential as a new prognostic and treatment predictive marker for endocrine therapy benefit in breast cancer. PTPN2 gene copy number was assessed by real-time PCR in 215 tumour samples from a treatment randomised study consisting of postmenopausal patients diagnosed with stage II breast cancer 1976-1990. Corresponding mRNA expression levels of PTPN2 were evaluated in 86 available samples by the same methodology. Gene copy loss of PTPN2 was detected in 16 % (34/215) of the tumours and this was significantly correlated with lower levels of PTPN2 mRNA. PTPN2 gene loss and lower mRNA levels were associated with activation of AKT and a poor prognosis. Furthermore, PTPN2 gene loss was a significant predictive marker of poor benefit from tamoxifen treatment. In conclusion, genomic loss of PTPN2 may be a previously unknown mechanism of PI3K/AKT upregulation in breast cancer. PTPN2 status is a potential new clinical marker of endocrine treatment benefit which could guide further individualised therapies in breast cancer.

  • 19.
    Khoshnoud, Mahmoud R
    et al.
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Lofdahl, Britta
    Department of Pathology, Uppsala University Hospital, Sweden.
    Fohlin, Helena
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre. Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Bergh, Jonas
    Cancer Center, Karolinska Institute, Stockholm Sweden and Medical Breast Unit, Christie Hospital, Manchester, UK.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    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 ≤30 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 ≥0.05 fmol/μg DNA and 539 patients were ER-positive (79%) by IHC using the cutoff level at ≥10% 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.

  • 20.
    Kok, Marleen
    et al.
    Netherlands Cancer Institute.
    Zwart, Wilbert
    Netherlands Cancer Institute.
    Holm, Caroline
    Lund University.
    Fles, Renske
    Netherlands Cancer Institute.
    Hauptmann, Michael
    Netherlands Cancer Institute.
    Vant Veer, LauraJ.
    Netherlands Cancer Institute.
    Wessels, Lodewyk F. A.
    Netherlands Cancer Institute.
    Neefjes, Jacques
    Netherlands Cancer Institute.
    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.
    Linn, Sabine C.
    Netherlands Cancer Institute.
    Landberg, Goran
    Lund University.
    Michalides, Rob
    Netherlands Cancer Institute.
    PKA-induced phosphorylation of ER alpha at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer2011In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 125, no 1Article in journal (Refereed)
    Abstract [en]

    Phosphorylation of estrogen receptor alpha at serine 305 (ER alpha S305-P) by protein kinase A (PKA) or p21-activated kinase 1 (PAK1) has experimentally been associated with tamoxifen sensitivity. Here, we investigated the clinical application of this knowledge to predict tamoxifen resistance in ER-positive breast cancer patients. Using immunohistochemistry, a score including PAK1 and co-expression of PKA and ER alpha S305-P (PKA/ER alpha S305-P) was developed on a training set consisting of 103 patients treated with tamoxifen for metastatic disease, and validated on 231 patients randomized between adjuvant tamoxifen or no treatment. In the training set, PAK1 levels were associated with tumor progression after tamoxifen (HR 1.57, 95% CI 0.99-2.48), as was co-expression of PKA and ER alpha S305-P (HR 2.00, 95% CI 1.14-3.52). In the validation set, a significant tamoxifen benefit was found among the 73% patients negative for PAK1 and PKA/ER alpha S305-P (HR 0.54, 95% CI 0.34-0.87), while others (27%) were likely to have no benefit from tamoxifen (HR 0.88, 95% 0.42-1.82). The test for interaction showed a significant difference in recurrence-free survival between groups defined by PAK1 and PKA/ER alpha S305-P (P = 0.037). Elevated PAK1 and PKA/ER alpha S305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ER alpha S305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.

  • 21.
    Licznerska, Barbara E.
    et al.
    Institution of Clinical and Experimental Medicine Linköping University.
    Wegman, Pia P.
    Institution of Clinical and Experimental Medicine Linköping University.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Wingren, Sten
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients2008In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 112, no 1, p. 15-23Article in journal (Refereed)
    Abstract [en]

    Background: The risk of developing breast cancer is strongly correlated with the overall exposure to oestrogen and most tumours are more or less dependent on oestrogen for their growth. A great majority of breast cancers occur after menopause when the ovaries have ceased to be functional, yet breast tumours in postmenopausal women maintain high intratumoural oestrogen concentrations, primarily through enzymatic conversion of androgenic precursors. Patients with a hormone dependent tumour generally receive the anti-oestrogen tamoxifen that mediate its anti-tumour effect by competing with oestrogen for binding to the oestrogen-receptor (ER). We therefore propose that the levels of oestrogen producing enzymes may affect the prognosis in postmenopausal breast cancer patients treated with tamoxifen. Methods: We measured the mRNA and protein levels of aromatase and sulfatase by real-time PCR (n = 161) and immunohistochemistry (n = 131) in postmenopausal women with breast cancer. Results: A significant better recurrence-free survival was detected in patients with weak or high protein expression of stromal aromatase (P = 0.0008), as also demonstrated by a decreased relative risk (RR = 0.50, CI = 0.33-0.76, P = 0.003). When we combined patients with weak and high stromal aromatase and selected only ER-positive patients, the improved prognosis was even more evident (P = 0.0000) and was shown to be a significant prognostic factor in a multivariate Cox-model (HR = 0.15, CI = 0.06-0.39, P = 0.000). The mRNA expression of aromatase and sulfatase, as well as the protein expression of sulfatase revealed no prognostic significance. Conclusion: Protein expression of stromal aromatase may serve as a significant prognostic marker in ER-positive patients. © 2007 Springer Science+Business Media, LLC.

  • 22.
    Maguire, P.
    et al.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Margolin, S.
    Department of Oncology, Karolinska University Hospital, Södersjukhuset, Stockholm, Sweden.
    Skoglund, J.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gustafsson, J.-A.
    Gustafsson, J.-Å., Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge, Sweden.
    Borresen-Dale, A.-L.
    Børresen-Dale, A.-L., Department of Genetics, Norwegian Radium Hospital, University of Oslo, Montebello, Oslo, Norway.
    Lindblom, A.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, Department of Molecular Medicine, CMM L8:02, Karolinska Institute, S-171 76 Stockholm, Sweden.
    Estrogen receptor beta (ESR2) polymorphisms in familial and sporadic breast cancer2005In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 94, no 2, p. 145-152Article in journal (Refereed)
    Abstract [en]

    Estrogen is involved in both normal mammary development and in breast carcinogenesis. A family history of disease and exposure to estrogen are major risk factors for developing breast cancer. Estrogen exerts its biological effects through binding to the estrogen receptors, estrogen receptor alpha (ESR1) and the more recently discovered estrogen receptor beta (ESR2). Genetic variation in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to play a role in breast cancer risk. We therefore tested the hypothesis that common genetic variants of the ESR2 gene may be associated with increased risk for breast cancer and this risk may vary between breast cancer groups. We investigated three common ESR2 polymorphisms, rs1256049 (G1082A), rs4986938 (G1730A) and rs928554 (Cx+56 A?G) for association to breast cancer risk. A total of 723 breast cancer cases and 480 controls were included in the study. Of the breast cancer cases, 323 were sporadic and 400 were familial, the familial cases were further divided into familial high-risk and familial low-risk breast cancer cases. We found no overall statistically significant association for any of the single polymorphisms studied. Haplotype analysis suggested one haplotype associated with increased risk in sporadic breast cancer patients (OR = 3.0, p = 0.03). Further analysis is needed to elucidate the role of estrogen receptor beta in breast cancer susceptibility. © Springer 2005.

  • 23.
    Nordenskjold, Anna
    et al.
    Sahlgrens Acad, Sweden; Southern Alvsborg Hospital, Sweden.
    Fohlin, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden; Regional Cancer Centre Stockholm Gotland, Sweden.
    Lofdahl, Britta
    St Göran Hospital, Sweden.
    Skoog, Lambert
    Karolinska University Hospital, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer2016In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 160, no 2, p. 313-322Article in journal (Refereed)
    Abstract [en]

    The independent predictive information from progesterone receptor (PgR) positivity for breast cancer treated with tamoxifen has been questioned after an overview by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). However, the studies in the overview were to a large content performed before modern PgR immunohistochemistry (IHC) was developed. We therefore investigated the predictive value of PgR determined with IHC in estrogen receptor (ER)-positive tumors from patients participating in the Stockholm trial of adjuvant tamoxifen therapy. 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 618 patients with ER-positive "low-risk" breast cancer (size aecurrency sign 30 mm, lymph node-negative) for whom PgR was determined by IHC at one pathology laboratory. The median time of follow-up was 21 years. Patients with ER-positive tumors that were also PgR-positive by IHC did benefit from tamoxifen, while we could not show any long-term benefit for those with tumors positive for ER only (recurrence rate ratio 0.43, 95 % CI 0.29-0.62 and 0.87, 95 % CI 0.52-1.46, respectively). We further investigated the influence of different levels of PgR positivity on recurrence risk. The results show that at all receptor levels with aeyen10 % stained PgR-positive cells, the patients did benefit from tamoxifen. There was no clear linear trend in benefit with increasing proportion of stained cells. PgR positivity determined by IHC is a marker indicating long-term benefit from adjuvant tamoxifen in patients with ER-positive tumors.

  • 24.
    Perez-Tenorio, Gizeh
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology.
    Ahnström, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Holmlund, Birgitta
    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. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Fornander, Tommy
    Karolinska University Hospital, Department Oncol, S-11883 Stockholm, Sweden.
    Skoog, Lambert
    Karolinska University Hospital, Department Pathol and Cytol, S-17176 Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer2011In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 128, no 3, p. 713-723Article in journal (Refereed)
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.

  • 25.
    Petersson, Stina
    et al.
    Sahlgrens University Hospital.
    Shubbar, E.
    Sahlgrens University Hospital.
    Yhr, M.
    Sahlgrens University Hospital.
    Kovacs, A.
    Sahlgrens University Hospital.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Dermatology and Venerology in Östergötland. Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Loss of ICAM-1 signaling induces psoriasin (S100A7) and MUC1 in mammary epithelial cells2011In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 125, no 1, p. 13-25Article in journal (Refereed)
    Abstract [en]

    Psoriasin (S100A7), a member of the S100 gene family, is highly expressed in high-grade comedo ductal carcinoma in situ (DCIS), with a higher risk of local recurrence. Psoriasin is, therefore, a potential biomarker for DCIS with a poor prognosis. High-grade DCIS is characterized by a high proliferation rate and crowded cells, consequently, lose contact with the extracellular matrix. The aim of this study was, therefore, to elucidate the involvement of adhesion signals in the regulation of psoriasin. Protein expression was evaluated by Western blotting, flow cytometry, and immunohistochemistry, and using breast carcinoma SAGE databases available from the CGAP website. Intercellular adhesion molecule 1 (ICAM-1) was down-regulated in MCF10A cells using short hairpin RNA. We found a significant negative correlation between the expression of ICAM-1 and psoriasin, and a positive correlation between psoriasin and MUC1 in normal and DCIS SAGE libraries. In a cluster analysis of 34 adhesion molecules and 20 S100 proteins, we showed that SAGE libraries expressing the S100 proteins-psoriasin, calgranulin-A, and calgranulin-B-clustered together. Interestingly, the expression of all the three proteins correlated strongly to the oncogenic MUC1. We confirmed the negative correlation between ICAM-1 and psoriasin/MUC1, when normal and breast cancer cells were cultured in suspension and on collagen, respectively. The down-regulation of ICAM-1 by short hairpin RNA in MCF10A cells led to the induction of psoriasin, calgranulin-A, calgranulin-B, and MUC1, and we demonstrated that these up-regulations were not ROS dependent. By blocking the phospholipase C (PLC)-IP3 pathway in these cells, we showed that the induction of psoriasin diminished. The results suggest that psoriasin is an intracellular calcium-dependent target of the PLC pathway. Our findings suggest that the down-regulation of ICAM-1 in mammary epithelial cells may contribute both to the high expression of psoriasin seen in some high-grade DCIS tumors and to the induction of MUC1.

  • 26.
    Rosell, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bengtsson, Nils-Olof
    Umeå University Hospital, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Hatschek, Thomas
    Karolinska University Hospital, Sweden .
    Lindman, Henrik
    University of Uppsala Hospital, Sweden .
    Malmstrom, Per-Olof
    Skåne University Hospital, Sweden .
    Wallgren, Arne
    Sahlgrens University Hospital, Sweden .
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Health Sciences.
    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.

  • 27.
    Rydén, Lisa
    et al.
    Department of Surgery, Institution of Clinical Sciences, Lund University, Sweden.
    Landberg, Göran
    Division of Pathology, Institution of Laboratory Medicine, Malmö University Hospital, Sweden.
    Stål, Olle
    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.
    Fernö, Mårten
    Department of Oncology, Institition of Clinical Sciences, Lund University, Lund, Sweden.
    Bendahl, Pär-Ola
    Department of Oncology, Institition of Clinical Sciences, Lund University, Lund, Sweden.
    HER2 status in hormone receptor positive premenopausal primary breast cancer adds prognostic, but not tamoxifen treatment predictive, information2008In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 109, no 2, p. 351-357Article in journal (Refereed)
    Abstract [en]

    Background

    Overexpression of human epidermal growth factor receptor 2 (HER2) or amplification of its gene is a prognostic factor in primary breast cancer and a predictor for tamoxifen treatment efficacy in oestrogen receptor (ER) positive disease. In the present study we explored a defined cohort of breast cancer patients included in a randomised trial in order to assess prognostic and tamoxifen treatment information yielded by HER2 status.

    Methods

    Premenopausal breast cancer patients with stage II tumours (n = 564) were included and allocated to 2 years of adjuvant tamoxifen treatment versus no adjuvant treatment. ER, progesterone receptor (PR) status and HER2 status was determined by immunohistochemistry using a tissue microarray. HER2 amplification was analysed by fluorescent in situ hybridisation and tumours being amplified and/or HER2 3+ were considered HER2+. HER2 status was evaluable in 83% of the patients and 12.6% were HER2+. In untreated patients, HER2 was a negative prognostic factor in ER+ patients, HR 2.95; 95% CI: 1.61–5.38, p < 0.001, but not in ER- patients, HR 0.67; 95% CI: 0.28–1.61, p = 0.4, and a significant interaction between the two markers was found, p < 0.01. HER2 status was not related to tamoxifen treatment efficacy in ER+ patients (term of interaction p = 0.95). When stratifying for PR status, similar results were achieved.

    Discussion

    HER2+ and ER+ breast cancer constituted a subgroup of tumours with poor prognosis in premenopausal breast cancer, whereas no treatment interaction was found between HER2 status and tamoxifen in ER+ tumours. The poor prognosis in HER2+ and ER+ patients may interfere with the interpretation of HER2 data in non-randomised trials of adjuvant tamoxifen.

  • 28. Schüle, Jana
    et al.
    Bergkvist, Leif
    Håkansson, Leif
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Håkansson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Down-regulation of the CD3-? 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 ?-chain of the T-cell receptor. The degree of down-regulation of the ?-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 ?-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.

  • 29.
    Shubbar, Emman
    et al.
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Vegfors, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
    Carlström, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
    Petersson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
    Enerbäck, Charlotta
    Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Dermatology and Venerology in Östergötland. Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation2012In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 134, no 1, p. 71-80Article in journal (Refereed)
    Abstract [en]

    Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family. In high-grade ductal carcinoma in situ, psoriasin was identified as one of the most abundant transcripts. We have previously shown that psoriasin was induced by reactive oxygen species (ROS). Moreover, the downregulation of psoriasin by short hairpin RNA (shRNA) led to the reduced expression of vascular endothelial growth factor (VEGF) and inhibited tumor growth in vivo. The aim of the present study was to investigate whether psoriasin could have direct effects on endothelial cells. In this study we demonstrated that psoriasin increased VEGF expression in mammary epithelial cells. The treatment of endothelial cells with recombinant psoriasin increased proliferation comparable to that of recombinant VEGF protein. No change in proliferation was seen when endothelial cells were infected with psoriasin-expressing adenoviruses, suggesting that the proliferative effect of psoriasin was mediated by a specific receptor. Treatment with sRAGE, targeting the receptor for advanced glycation end products (RAGE), thus inhibited endothelial cell proliferation and tube formation enhanced by recombinant psoriasin. We showed that VEGF expression was not induced by hydrogen peroxide, when psoriasin was silenced by shRNA, which led to the hypothesis that psoriasin induces ROS. Indeed, psoriasin was shown to induce ROS in both endothelial and epithelial cells. Moreover, sRAGE inhibited the psoriasin-dependent generation of ROS in endothelial cells. Finally, treatment with antioxidant Bcl-2 protein abolished the effect of psoriasin on endothelial cell proliferation. Our data suggest that psoriasin expression in mammary epithelial cells leads to increased endothelial cell proliferation in a paracrine manner through RAGE. Psoriasin may therefore play a role in breast cancer progression by promoting oxidative stress response and angiogenesis.

  • 30.
    Sjostrom, Martin
    et al.
    Lund University, Sweden .
    Hartman, Linda
    Lund University, Sweden Regional Cancer Centre South, Sweden .
    Grabau, Dorthe
    Lund University, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Malmstrom, Per
    Lund University, Sweden Skåne University Hospital, Sweden .
    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.
    Sgroi, Dennis C.
    Massachusetts Gen Hospital, MA 02114 USA .
    Skoog, Lambert
    Karolinska University Hospital, Sweden .
    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.
    Fredrik Leeb-Lundberg, L.M.
    Lund University, Sweden .
    Ferno, Marten
    Lund University, Sweden .
    Lack of G protein-coupled estrogen receptor (GPER) in the plasma membrane is associated with excellent long-term prognosis in breast cancer2014In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 145, no 1, p. 61-71Article in journal (Refereed)
    Abstract [en]

    G protein-coupled estrogen receptor (GPER), or GPR30, is a membrane receptor reported to mediate non-genomic estrogen responses. Tamoxifen is a partial agonist at GPER in vitro. Here, we investigated if GPER expression is prognostic in primary breast cancer, if the receptor is treatment-predictive for adjuvant tamoxifen, and if receptor subcellular localization has any impact on the prognostic value. Total and plasma membrane (PM) GPER expression was analyzed by immunohistochemistry in breast tumors from 742 postmenopausal lymph node-negative patients subsequently randomized for tamoxifen treatment for 2-5 years versus no systemic treatment, regardless of estrogen receptor (ER) status, and with a median follow-up of 17 years for patients free of event. PM GPER expression was a strong independent prognostic factor for poor prognosis in breast cancer without treatment-predictive information for tamoxifen. In the tamoxifen-treated ER-positive and progesterone receptor (PgR)-positive patient subgroup, the absence of PM GPER (53 % of all ER-positive tumors) predicted 91 % 20-year distant disease-free survival, compared to 73 % in the presence of GPER (p = 0.001). Total GPER expression showed positive correlations with ER and PgR and negative correlation with histological grade, but the correlations were biphasic. On the other hand, PM GPER expression showed strong negative correlations with ER and PgR, and strong positive correlation with HER2 overexpression and high histological grade. GPER overexpression and PM localization are critical events in breast cancer progression, and lack of GPER in the PM is associated with excellent long-term prognosis in ER-positive and PgR-positive tamoxifen-treated primary breast cancer.

  • 31.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Brudin, Lars
    Department of Physiology, County Hospital, Kalmar, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Applying the Nottingham Prognostic Index to a Swedish breast cancer population1999In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 53, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to assess the applicability of histopathological grading according to the protocol of Elston/Ellis and the Nottingham Prognostic Index (NPI) to a defined breast cancer population. The NPI is the sum of the individual scores concerning grade, tumour size, and lymph node status, each weighted according to regression coefficients of a Cox proportional hazard analysis and calculated for each individual breast cancer patient. 630 consecutive patients with invasive breast cancer diagnosed 1988–91 were retrospectively followed up and their tumours reviewed and graded. A Cox proportional hazard analysis was performed. Grade, lymph node status, and tumour size were statistically significant predictors of survival within the follow up period (median 7.2 years). Similar to NPI, a temporary index (Kalmar Prognostic Index, KPI) was derived and normalised to NPI for comparison (KPI(norm)). NPI and KPI(norm) gave similar prognostic power in spite of the differences of the patient populations from which the 2 indices were derived. Patients with NPI 4 or less had 0.66% breast cancer specific mortality during the follow up time. 14% of the patients with NPI 4.1–5 and 32% of those with an index sum 5.1–6 died from breast cancer during this time. Younger patients tended to have higher grade tumours. We advocate the common use of grade and the NPI in order to increase the comparability of groups of patients receiving different therapies.

  • 32.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Brudin, Lars
    Department of Physiology, County Hospital, Kalmar, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    A comparison between flow cytometric assessment of S-phase fraction and Nottingham histologic grade as prognostic instruments in breast cancer2000In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 63, no 1, p. 11-15Article in journal (Refereed)
    Abstract [en]

    Flow cytometric DNA analysis with assessment of S-phase fraction and DNA ploidy was compared to Nottingham histologic grade. The study population consisted of 654 patients who presented between 1987 and 1996 with primary operable breast cancer and whose tumours had been analysed for S-phase fraction and DNA ploidy at the time of surgery. Grade, tumour size, node status, steroid receptor status, age, S-phase fraction and DNA ploidy were analysed univariately and multi-variately in a Cox proportional hazard analysis. In the univariate analyses all parameters were statistically significantly associated with breast cancer mortality during the follow-up period of 2–11 years. The most powerful predictor of death from breast cancer in the multiple regression analysis was grade. Patients with grade 1 tumours have excellent prognosis. We conclude that tumour grade is a strong prognostic indicator applicable to all breast cancer patients, regardless of size and nodal status, and advocate its general use.

  • 33.
    van t Veer, Laura J.
    et al.
    University of Calif San Francisco, CA 94115 USA.
    Yau, Christina
    University of Calif San Francisco, CA 94115 USA; Buck Institute Research Aging, CA 94945 USA.
    Yu, Nancy Y.
    Karolinska Institute, Sweden.
    Benz, Christopher C.
    Buck Institute Research Aging, USA; University of Calif San Francisco,USA.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, 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.
    Fornander, Tommy
    Karolinska Institute, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, 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.
    Esserman, Laura J.
    University of Calif San Francisco, CA 94115 USA.
    Sofie Lindstrom, Linda
    Karolinska Institute, Sweden.
    Tamoxifen therapy benefit for patients with 70-gene signature high and low risk2017In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 166, no 2, p. 593-601Article in journal (Refereed)
    Abstract [en]

    Breast cancer molecular prognostic tools that predict recurrence risk have mainly been established on endocrine-treated patients and thus are not optimal for the evaluation of benefit from endocrine therapy. The Stockholm tamoxifen (STO-3) trial which randomized postmenopausal node-negative patients to 2-year tamoxifen (followed by an optional randomization for an additional 3-year tamoxifen vs nil), versus no adjuvant treatment, provides a unique opportunity to evaluate long-term 20-year benefit of endocrine therapy within prognostic risk classes of the 70-gene prognosis signature that was developed on adjuvantly untreated patients. We assessed by Kaplan-Meier analysis 20-year breast cancer-specific survival (BCSS) and 10-year distant metastasis-free survival (DMFS) for 538 estrogen receptor (ER)-positive, STO-3 trial patients with retrospectively ascertained 70-gene prognosis classification. Multivariable analysis of long-term (20 years) BCSS by STO-3 trial arm in the 70-gene high-risk and low-risk subgroups was performed using Cox proportional hazard modeling adjusting for classical patient and tumor characteristics. Tamoxifen-treated, 70-gene low- and high-risk patients had 20-year BCSS of 90 and 83%, as compared to 80 and 65% for untreated patients, respectively (log-rank p amp;lt; 0.0001). Notably, there is equivalent tamoxifen benefit in both high (HR 0.42 (0.21-0.86), p = 0.018) and low (HR 0.46 (0.25-0.85), p = 0.013) 70-gene risk categories even after adjusting for clinico-pathological factors for BCSS. Limited tamoxifen exposure as given in the STO-3 trial provides persistent benefit for 10-15 years after diagnosis in a time-varying analysis. 10-year DMFS was 93 and 85% for low- and high-risk tamoxifen-treated, versus 83 and 70% for low- and high-risk untreated patients, respectively (log-rank p amp;lt; 0.0001). Patients with ER-positive breast cancer, regardless of high or low 70-gene risk classification, receive significant survival benefit lasting over 10 years from adjuvant tamoxifen therapy, even when given for a relatively short duration.

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