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  • 101.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sgroi, Dennis C.
    Massachusetts Gen Hospital, MA 02114 USA .
    Skoog, Lambert
    Karolinska University Hospital, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    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 cancer2014Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 145, nr 1, s. 61-71Artikel i tidskrift (Refereegranskat)
    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.

  • 102.
    Stendahl, Maria
    et al.
    Lund University.
    Nilsson, Sofie
    University of Manchester.
    Wigerup, Caroline
    Lund University.
    Jirstrom, Karin
    Lund University.
    Jonsson, Per Ebbe
    Helsingborgs Lasarett.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Landberg, Goran
    University of Manchester.
    p27(Kip1) is a predictive factor for tamoxifen treatment response but not a prognostic marker in premenopausal breast cancer patients2010Ingår i: INTERNATIONAL JOURNAL OF CANCER, ISSN 0020-7136, Vol. 127, nr 12, s. 2851-2858Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cell-cycle regulating protein p27(Kip1) (p27) has dual roles by acting as both a cdk inhibitor and as an assembly factor for different cdk complexes. Loss of p27 has been linked to malignant features in tumours; however, the exact role of p27 deregulation in breast cancer regarding prognostic and treatment predictive information has not been fully clarified. We have evaluated p27 expression in 328 primary, Stage II breast cancers from premenopausal patients who had been randomised to either tamoxifen treatment or no adjuvant treatment after surgery. p27 was associated with the oestrogen receptor and cyclin D1, and p27 downregulation was associated with high proliferation. There was no association between recurrence-free survival (RFS) and p27 (HR = 0.800, 95% CI 0.523-1.222, p = 0.300), indicating that p27 is not a prognostic marker. The predictive value of p27 was analysed by comparing RFS in tamoxifen-treated and untreated patients in subgroups of low and high p27 expression (HR = 0.747, 95% CI 0.335-1.664, p = 0.474 and HR = 0.401, 95% CI 0.240-0.670, p andlt; 0.001, respectively). Only patients with p27-high tumours benefited from tamoxifen (multivariate interaction analysis p = 0.034). Our study suggests that p27 downregulation is associated with tamoxifen resistance in premenopausal breast cancer but is not linked to impaired prognosis.

  • 103. Stenmark Askmalm, Marie
    et al.
    Carstensen, John
    Linköpings universitet, Institutionen för hälsa och samhälle.
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Olsson, Birgit
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi.
    Rutqvist, Lars Erik
    Skoog, Lambert
    Stål, Olle
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients2004Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 43, nr 3, s. 235-244Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    p53 protein accumulation and gene mutation have been implicated in resistance to cytotoxic treatment. This study was performed to further assess the predictive value of p53 in breast cancer. Postmenopausal patients were randomized to adjuvant chemotherapy with cyclophosphamide, metothrexate, or 5-fluorouracil (CMF) vs. Postoperative radiotherapy. The patients were also randomized to adjuvant tamoxifen vs. No endocrine treatment. Immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP), followed by direct sequencing, was performed. The p53 altered group, regarded as positive for p53 gene mutation and/or p53 protein accumulation, tended to benefit more from CMF than from radiotherapy as compared with others regarding distant recurrences. In the group lacking p53 alteration there was a significantly decreased local recurrence rate in the radiotherapy group as compared with the CMF group (RR = 0.24, 95% CI = 0.083-0.62), whereas no benefit from radiotherapy was found for patients snowing p53 alterations. Tamoxifen significantly decreased the rate of distant recurrence for estrogen receptor-positive patients with no apparent difference in relation to p53 alteration. It is suggested that p53 alteration indicates benefit from CMF compared with radiotherapy regarding distant recurrence-free survival and the best local control with radiotherapy is achieved in the absence of p53 alteration. Finally, altered p53 status is probably not a marker of resistance to tamoxifen.

  • 104.
    Stenmark-Askmalm, Askmalm Marie
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gentile, Massimiliano
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Wingren, Sten
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Arnesson, Lars-Gunnar
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Protein accumulation and gene mutation of p53 in bilateral breast cancer2001Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 40, nr 1, s. 56-62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to investigate the frequency of p53 alterations in bilateral breast cancer and to evaluate a possible clonal relationship between the paired tumours regarding p53 alteration and other pathobiological variables. Tumours from 34 patients were investigated with immunohistochemistry, single strand conformation polymorphism analysis and DNA-sequence analysis applied to exons 5-8. Fifteen percent of the 68 tumours showed positive immunoreaction and/or presence of mutation. The occurrence of p53 accumulation was 9% and the prevalence of gene mutation 10%. No significant concordance was found between the tumours in the same patient for p53 alterations, progesterone receptor status or DNA ploidy. S-phase fraction showed a weak correlation, not statistically significant. Oestrogen receptor status was the only variable that exhibited a significant concordance. No convincing evidence was found for other associations between the paired tumours or for a high prevalence of p53 alterations in bilateral breast cancer.

  • 105.
    Strand, Carina
    et al.
    Lund University, Skåne University Hospital, Lund, Sweden.
    Bak, Martin
    Odense University Hospital, Denmark.
    Borgquist, Signe
    Lund University, Skåne University Hospital, Lund, Sweden.
    Chebil, Gunilla
    Unilabs, Mammography, Helsingborg, Sweden.
    Falck, Anna-Karin
    Helsingborg Hospital, Sweden.
    Fjällskog, Marie-Louise
    Uppsala University, Sweden.
    Grabau, Dorthe
    Lund University, Skåne University Hospital, Lund, Sweden.
    Hedenfalk, Ingrid
    Lund University, Skåne University Hospital, Lund, Sweden.
    Jirström, Karin
    Lund University, Sweden.
    Klintman, Marie
    Lund University, Skåne University Hospital, Lund, Sweden.
    Malmström, Per
    Lund University, Skåne University Hospital, Lund, Sweden.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Ryden, Lisa
    Lund University, Skåne University Hospital, Lund, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bendahl, Pär-Ola
    Lund University, Skåne University Hospital, Lund, Sweden.
    Fernö, Mårten
    Lund University, Skåne University Hospital, Lund, Sweden.
    The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naïve women with N0/N1 primary breast cancer2013Ingår i: SpringerPlus, E-ISSN 2193-1801, Vol. 2, nr 111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

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

    METHODSDESIGN:

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

    DISCUSSION:

    We have confirmed a prognostic index based on a proliferation marker (Ki67), histological grade, and ER for identification of a low-risk group of patients with N0/N1 primary breast cancer. For this low-risk group constituting 57% of the patients, with a five-year distant disease-free survival of 92%, adjuvant chemotherapy will have limited effect and may be avoided.

  • 106.
    Stål, Olle
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Static and flow cytometry for tumor DNA analysis1989Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The analysis of cellular DNA content in human tumors has shown to be of prognostic importance. The techniques used involve measurements in slide preparations by absorption cytophotometry and static cytofluorometry as well as the analysis of cell suspensions by flow cytometry. The aim of this work has been to improve these techniques by the development of computer aided systems in order to facilitate the use in a larger scale for clinical purposes. Another aim has been to study the prognostic significance of DNA analysis in breast cancer.

    Software for determination of DNA content and nuclear area by scanning absorption cytophotometry was developed. The system, HISTOSCAN, is insensitive to light scattering and may therefore be used in tissue sections. Thus, measurements in morphologically well-defined areas may be performed, but the method is less suitable for extensive use due to the slow procedure of the mechanical scanning.

    More rapid analyses are achieved by the system developed for static cytofluorometry in cytocentrifuged specimens. Cells to be measured are not positioned in the ordinary way, but are just passed through the excitation light beam as the specimen is visually scanned. DNA content and nuclear size are estimated simultaneously from the fluorescence recorded. For estimation of proliferative activity a sufficient number of cells may be analysed within a reasonable time.

    Similar results were obtained by static cytofluorometry and flow cytometry in a series of primary breast cancers. A close correlation was found for DNA index and, if 200 cells or more were measured, the same was true for S-phase fraction.

    Tumors from 472 women with primary breast cancer were analysed by flow cytometry. DNA ploidy showed significant association with disease recurrence and mortality but did not show a prognostic value in addition to that of traditional factors. The prognostic significance of S-phase fraction was independent of nodal status, tumor size and estrogen receptor content concerning early relapse and mortality. The survival of 116 women with recurrent breast cancer was correlated with both DNA ploidy and S-phase fraction in a multivariate analysis including nodal status, tumor size, ER content and site of recurrence.

  • 107.
    Stål, Olle
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Borg, Å
    Department of Oncology, University Hospital Lund, Sweden.
    Fernö, M
    Department of Oncology, University Hospital Lund, Sweden.
    Källström, Ann-Christine
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Malmström, P
    Department of Oncology, University Hospital Lund, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer2000Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, nr 12, s. 1545-1550Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim:We aimed to study the importance of erbB2 status in early stage postmenopausal breast cancer for patients who participated in a trial of five vs. two years of adjuvant tamoxifen.

    Patients and methods: We analysed the erbB2 status of the tumours from 577 patients participating in the trial, either by a DNA amplification assay (n=181) or by measurement of the protein level with flow cytometry (n=396).

    Results: ErbB2 was overexpressed or gene amplified in 102 of the patients (18%). Overall, erbB2-positive patients had a significantly lower recurrence-free probability than others, 62% at five years as compared to 83%, and showed a significantly decreased breast cancer survival rate (P=0.0007). ErbB2 status was significantly associated with recurrence and death in Cox multivariate analysis, adjusting for nodal status, tumour size and estrogen receptor status. The relative risk of recurrence (RR) for five vs. two years of tamoxifen was analysed in relation to erbB2 status for patients still disease-free two years after surgery. Whereas erbB2-negative patients showed significant benefit from prolonged treatment (RR=0.62, 95% confidence interval (95% CI): 0.42–0.93), no benefit was evident for erbB2-positive patients (RR=1.1, 95% CI: 0.41–3.2). When the same analysis was restricted to ER-positive patients a similar difference in relative hazard was obtained but the difference was not strictly significant (P=0.065).

    Conclusions: For early stage breast cancer patients treated with adjuvant tamoxifen, overexpression of erbB2 is an independent marker of poor prognosis. The results suggest that overexpression decreases the benefit from prolonged tamoxifen treatment.

  • 108.
    Stål, Olle
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Jerevall, Piiha-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Ma, Xiai-Jun
    bioTheranostics, San Diego, CA, USA.
    Li, Hongying
    bioTheranostics, San Diego, CA, USA.
    Salunga, Ranelle
    Massachusetts General Hospital, USA.
    Erlander, Mark
    Karolinska Institute, Stockholm, Sweden.
    Sgroi, Dennis
    Harvard Medical School, Boston, MA, USA.
    Holmlund, Birgitta
    Karolinska Institute, Stockholm, Sweden.
    Skoog, Lambert
    Karolinska Institute, Stockholm, Sweden.
    Fornander, Tommy
    Karolinska Institute, Stockholm, Sweden.
    Validation of Prognostic Utility of HOXB13:IL17BR and Molecular Grade Index in Early Stage Breast Cancer: in CANCER RESEARCH, vol 69, issue 24, pp 504S-504S2009Konferensbidrag (Refereegranskat)
    Abstract [en]

    Background. HOXB13:IL17BR (H:I) is a two gene expression index, which has been shown to be an independent prognostic factor in estrogen receptor (ER)-positive lymph node-negative (N0) breast cancer. A molecular grade index (MGI) measures the expression of five proliferation-related genes. An algorithm based on dichotomized H:I and MGI stratifying patients into three risk groups has been shown to be superior to either alone in predicting risk of distant metastasis in ER+/N0 patients. Further validation in larger cohorts is needed to establish its clinical performance. A continuous predictor combining H:I and MGI is desirable for making individualized risk assessment in the clinical setting.

    Methods. During 1976 through 1990 the Stockholm Breast Cancer Group conducted a randomized clinical trial comparing adjuvant tamoxifen with control in 1780 postmenopausal women considered to be at low risk of recurrence (N0 and tumor size < 3 cm). We measured H:I and MGI using a real time PCR assay in 769 patients from this trial based on sample availability. Correlation of gene expression indices with distant metastasis and death due to breast cancer was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. Modeling was also used to develop a continuous risk index as a function of both H:I and MGI.

    Results. Using pre-specified cutoff points and combination algorithm, H:I, MGI and their combination each was significantly associated with both distant metastasis-free survival and breast cancer-specific survival (Table 1). Furthermore, we used the ER+ tamoxifen-treated subset (n=314) to develop a continuous risk model (Breast Cancer Index or BCI) combining both H:I and MGI. The prognostic utility of BCI was then successfully validated in the untreated subset in this trial and three additional previously published cohorts. BCI consistently identified ∼50% patients with a very low 10-year recurrence risk (< 5%). Discussion. This large retrospective analysis of a randomized clinical trial cohort validated the prognostic utility of H:I, MGI, and their combination. With the continuous risk model, this RT-PCR-based assay allows prediction of risk of recurrence at the individual level, which may help tailor personalized treatment strategy.

  • 109.
    Stål, Olle
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Åkerberg, Lind
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden .
    Rutqvist, Lars
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden .
    Akt kinases in breast cancer and the results of adjuvant therapy2003Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 5, nr 2, s. R37-R44Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

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

    Methods

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

    Results

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

    Conclusion

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

  • 110.
    Sundquist, M
    et al.
    County Hospital Kalmar.
    Holmberg, E
    ROC, Gothenburg.
    Holmberg, S
    Sahlgrenska University Hospital.
    Kovacs, A
    Sahlgrenska University Hospital.
    Mathe, G
    Sahlgrenska University Hospital.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Tejler, Göran
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Assessments of Proliferation in Breast Cancer in EUROPEAN JOURNAL OF CANCER, vol 47, issue , pp S333-S3332011Ingår i: EUROPEAN JOURNAL OF CANCER, Elsevier , 2011, Vol. 47, s. S333-S333Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 111.
    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
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    A comparison between flow cytometric assessment of S-phase fraction and Nottingham histologic grade as prognostic instruments in breast cancer2000Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 63, nr 1, s. 11-15Artikel i tidskrift (Refereegranskat)
    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.

  • 112.
    Söderlund Leifler, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    ¨, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Rutqvist, Lars Erik
    Department of Medicine/Huddinge, Karolinska Institute, Stockholm,Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer2007Ingår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 68, nr 1, s. 50-58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: Post-operative radiotherapy is offered to a majority of breast cancer patients, since it significantly reduces the risk of local recurrence. However, some patients still develop recurrences. Owing to their vital roles in the repair of radiation-induced double-strand breaks, the Mre11/Rad50/Nbs1 (MRN) complex and the ATM protein might be implicated in tumour cell resistance to radiotherapy. The aim of this study was to investigate the expression and predictive role of these DNA repair proteins for the outcome of radiotherapy in breast cancer patients.

    Patients and Methods: The protein expression of ATM and the proteins in the MRN complex were investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (CMF).

    Results: Compared to normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1 and ATM was reduced in a majority of the tumours. Weak expression of the MRN complex was correlated to high histological grade and ER negativity (p=0.01 and p=0.0001). Radiotherapy significantly reduced the risk of local recurrence as compared to chemotherapy (p=0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (RR=0.27, 95% C.I. 0.098-0.72, p=0.009), whereas patients with negative/weak MRN had no benefit of radiotherapy compared to CMF. These results suggest that an intact MRN complex is important for the tumour cell eradicating effect of radiotherapy.

  • 113.
    Söderlund Leifler, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells2005Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 26, nr 1, s. 25-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Radiotherapy is widely used in the treatment of breast cancer and reduces the risk of loco-regional recurrence. Overexpression of the erbB2 receptor occurs in 20-30% of all breast cancers, and seems to be involved in chemotherapeutic resistance of breast cancer cells and radioresistance of lung cancer cells. The hypothesis of this study was that erbB2 confers resistance to radiation-induced apoptosis in breast cancer cells through the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway. Two human breast cancer cell lines were used, BT-474 and MCF-7. BT-474 cells overexpress erbB2 and have mutated p53, while MCF-7 have normal expression of erbB2 and functional p53. The cells were treated with the PI3-K inhibitor wortmannin or the erbB receptor ligand heregulin-ß1, which is expressed by both malignant and stromal cells in vivo. After pharmacological treatment, the cells were irradiated with 10 Gy gamma-radiation. Consistent with the p53 status in the cell lines, gamma-radiation caused G1 arrest in MCF-7 cells, but not in BT-474 cells. 10 Gy gamma-radiation increased apoptosis by on an average 76% (95% CI, 44-109%) in MCF-7. Treatment of MCF-7 with heregulin-ß1 decreased apoptosis by 66% (95% CI, 48-84%) compared to the untreated controls. In BT-474 cells, wortmannin in combination with radiation resulted in 119% (95% CI, 76-161%) more apoptosis compared to wortmannin alone, whereas radiation alone resulted in 45% (95% CI, 15-75%) increased apoptosis. This radiosensitising effect was not seen in MCF-7. Furthermore, transfection of MCF-7 cells with constitutively active Akt made the cells more resistant against apoptosis. Taken together, our results support the hypothesis that the erbB2/PI3-K/Akt signalling pathway is involved in resistance to radiation-induced apoptosis in breast cancer cells in which this signalling pathway is overstimulated.

  • 114.
    Veenstra, Cynthia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Stelling, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Elin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Mirwani Mirwani, Sanam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Met and its ligand HGF are associated with clinical outcome in breast cancer2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 24, s. 37145-37159Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo-or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre-and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the premenopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.

  • 115.
    Vitak, B
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Radiologi. Linköpings universitet, Hälsouniversitetet.
    Olsen, K E
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och cytologi. Linköpings universitet, Hälsouniversitetet.
    Månson, Jan-Christer
    Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och cytologi. Linköpings universitet, Hälsouniversitetet.
    Arnesson, Lars-Gunnar
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Tumour characteristics and survival in patients with invasive interval breast cancer classified according to mammographic findings at the latest screening: a comparison of true interval and missed interval cancers1999Ingår i: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 9, nr 3, s. 460-469Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to investigate whether different mammographic categories of interval cancer classified according to findings at the latest screening are associated with different distributions of prognostic factors or with different survival rates. The series consisted of all patients with invasive interval cancer detected from May 1978 to August 1995 (n = 544). The tumours were evaluated with regard to age, radiological category, interval between the latest screen and diagnosis and tumour characteristics at the time of diagnosis. We investigated possible relationships between the survival rate of patients with interval cancer and the interval between the latest screen and diagnosis, tumour characteristics and radiological category of the interval tumours. The study focused on comparison of patients with true interval and missed interval cancer. Women with mammographically occult tumours were younger than those in the other radiological categories. Comparisons of true interval cancers with overlooked or misinterpreted tumours showed equal distributions of age, tumour size, TNM stage and lymph node status. The overlooked or misinterpreted tumours showed significantly higher proportions of grade-I tumours (22 vs 11 %), tumours with low S-phase fraction (SPF; 44 vs 24 %) and oestrogen receptor (ER) positive tumours (72 vs 57 %). However, analyses of survival rates disclosed no clear differences between the two radiological categories. Radiological category and interval between the latest screen and diagnosis were not genuine predictors of the prognosis in patients with invasive interval breast cancer. No certain prognostic difference existed between true interval cancers and overlooked or misinterpreted interval breast cancers, despite higher proportions of grade-I tumours, ER positive tumours and tumours with low SPF in the latter group.

  • 116.
    Waltersson, MA
    et al.
    Karolinska University Hospital.
    Karlsson, E
    Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Fornander, T
    Karolinska University Hospital.
    Skoog, L
    Karolinska University Hospital.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    miR-206 Expression Is Downregulated in Cyclin D1 Amplified Breast Tumours. in CANCER RESEARCH, vol 69, issue 24, pp 579S-579S2009Ingår i: CANCER RESEARCH, 2009, Vol. 69, nr 24, s. 579S-579SKonferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 117.
    Wegman Palmebäck, Pia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Elingarami, Sauli
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Wingren, Sten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients2007Ingår i: Breast Cancer Research, ISSN 1465-5411, Vol. 9, nr 1, s. R7-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction

    Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer.

    Methods

    In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography.

    Results

    The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15.

    Conclusion

    The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.

  • 118.
    Wegman (Palmebäck), Pia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Rutqvist, Lars-Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Wingren, Sten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients2006Ingår i: Pharmacogenetics and Genomics, ISSN 1744-6872, Vol. 16, nr 5, s. 347-351Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress.

     

    Methods: In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen.

     

    Results: Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12–0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088).

     

    Conclusion: The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.

  • 119.
    Wegman (Palmebäck), Pia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Vainikka, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden.
    Rutqvist, Lars-Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Wingren, Sten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients2005Ingår i: Breast Cancer Research, ISSN 1465-5411, Vol. 7, nr 3, s. R284-R290Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy.

    Methods

    The patients were genotyped using PCR followed by cleavage with restriction enzymes.

    Results

    Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).

    Conclusion

    The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.

  • 120.
    Wegman, Pia
    et al.
    University Orebro, Sch Hlth and Med Science, Department Clin Med, S-70185 Orebro, Sweden .
    Gothlin Eremo, Anna
    University Orebro, Sch Hlth and Med Science, Department Clin Med, S-70185 Orebro, Sweden .
    Lindlof, Angelica
    Skovde University, Sch Life Science, Syst Biol Research Centre, S-54145 Skovde, Sweden .
    Karlsson, Mats
    Orebro University Hospital, Sch Hlth and Med Science, Department Pathol, S-70185 Orebro, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Wingren, Sten
    University Orebro, Sch Hlth and Med Science, Department Clin Med, S-70185 Orebro, Sweden .
    Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen2011Ingår i: INTERNATIONAL JOURNAL OF ONCOLOGY, ISSN 1019-6439, Vol. 38, nr 4, s. 1145-1151Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter 11 in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 postmenopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear FOXL2 was a significant prognostic factor in ER-positive patients treated with tamoxifen (HR=0.18, 95% confidence interval (CI)=0.04-0.81, P=0.03). Tumours expressing nuclear FOXL2 were also more likely positive for stromal and/or cytoplasmic aromatase (P=0.03 and P=0.008, respectively). In silico analyses revealed binding elements of FOXL2 in promoters 1.3, 11 and 17 of the aromatase gene of which promoter 1.7 was most significant. In conclusion, this is the first study to report that FOXL2 is expressed in breast cancer and correlates with aromatase as well as with clinical outcome. The results further strengthen a possible binding of FOXL2 to aromatase promoter 1.7. Nevertheless, whether FOXL2 is a direct activator of aromatase requires further investigation.

  • 121.
    Weiner, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Skoog, L
    Karolinska Institute, Sweden.
    Fornander, T
    Karolinska Institute, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Sgroi, D C.
    Massachusetts General Hospital, Boston, USA.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Oestrogen receptor co-activator AIB1 is a marker of tamoxifen benefit in postmenopausal breast cancer2013Ingår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, nr 8, s. 1994-1999Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The oestrogen receptor (ER) co-activator amplified in breast cancer 1 (AIB1) has been suggested as a treatment predictive and prognostic marker in breast cancer. Studies have however not been unanimous.

    Patients and methods AIB1 protein expression was analysed by immunohistochemistry on tissue micro-arrays with tumour samples from 910 postmenopausal women randomised to tamoxifen treatment or no adjuvant treatment. Associations between AIB1 expression, clinical outcome in the two arms and other clinicopathological variables were examined.

    Results In patients with ER-positive breast cancer expressing low tumour levels of AIB1 (<75%), we found no significant difference in recurrence-free survival (RFS) or breast cancer-specific survival (BCS) between tamoxifen treated and untreated patients. In patients with high AIB1 expression (>75%), there was a significant decrease in recurrence rate (HR 0.40, 95% CI 0.26–0.61, P < 0.001) and breast cancer mortality rate (HR 0.38, 95% CI 0.21–0.69, P = 0.0015) with tamoxifen treatment. In the untreated arm, we found high expression of AIB1 to be significantly associated with lower RFS (HR 1.74, 95% CI 1.20–2.53, P = 0.0038).

    Conclusion Our results suggest that high AIB1 is a predictive marker of good response to tamoxifen treatment in postmenopausal women and a prognostic marker of decreased RFS in systemically untreated patients.

  • 122.
    Yu, Qunyan
    et al.
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Sicinska, Ewa
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Geng, Yan
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Ahnström, Marie
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Zagozdzon, Agnieszka
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Kong, Yinxin
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Gardner, Humphrey
    Department of Research Pathology, Biogen Idec, Cambridge, Massachusetts.
    Kiyokawa, Hiroaki
    Department of Molecular Pharmacology and Biochemical Chemistry, Northwestern University, Chicago, Illinois.
    Harris, Lyndsay N
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts and Department of Medical Oncology, Dana-Farber Cancer Institute, and Brigham and Women's Hospital, Boston, Massachusetts.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sicinski, Piotr
    Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts.
    Requirement for CDK4 kinase function in breast cancer2006Ingår i: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 9, nr 1, s. 23-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclin D1 is overexpressed in the majority of human breast cancers. We previously found that mice lacking cyclin D1 are resistant to mammary carcinomas triggered by the ErbB-2 oncogene. In this study, we investigated which function of cyclin D1 is required for ErbB-2-driven mammary oncogenesis. We report that the ability of cyclin D1 to activate cyclin-dependent kinase CDK4 underlies the critical role for cyclin D1 in breast cancer formation. We also found that the continued presence of CDK4-associated kinase activity is required to maintain breast tumorigenesis. We analyzed primary human breast cancers and found high cyclin D1 levels in a subset (∼25%) of ErbB-2-overexpressing tumors. We propose that this subset of breast cancer patients might benefit from inhibiting CDK4 kinase.

  • 123.
    Zhang, Yi
    et al.
    BioTheranostics Inc, CA USA .
    Schnabel, Catherine A.
    BioTheranostics Inc, CA USA .
    Schroeder, Brock E.
    BioTheranostics Inc, CA USA .
    Jerevall, Piiha-Lotta
    Massachusetts Gen Hospital, MA USA .
    Jankowitz, Rachel C.
    University of Pittsburgh, PA USA .
    Fornander, Tommy
    Karolinska Institute, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Brufsky, Adam M.
    University of Pittsburgh, PA USA .
    Sgroi, Dennis
    Massachusetts Gen Hospital, MA USA .
    Erlander, Mark G.
    BioTheranostics Inc, CA USA .
    Breast Cancer Index Identifies Early-Stage Estrogen Receptor-Positive Breast Cancer Patients at Risk for Early- and Late-Distant Recurrence2013Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, nr 15, s. 4196-4205Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: Residual risk of relapse remains a substantial concern for patients with hormone receptor-positive breast cancer, with approximately half of all disease recurrences occurring after five years of adjuvant antiestrogen therapy. less thanbrgreater than less thanbrgreater thanExperimental Design: The objective of this study was to examine the prognostic performance of an optimized model of Breast Cancer Index (BCI), an algorithmic gene expression-based signature, for prediction of early (0-5 years) and late (andgt;5 years) risk of distant recurrence in patients with estrogen receptor-positive (ER+), lymph node-negative (LN-) tumors. The BCI model was validated by retrospective analyses of tumor samples from tamoxifen-treated patients from a randomized prospective trial (Stockholm TAM, n = 317) and a multi-institutional cohort (n = 358). less thanbrgreater than less thanbrgreater thanResults: Within the Stockholm TAM cohort, BCI risk groups stratified the majority (similar to 65%) of patients as low risk with less than 3% distant recurrence rate for 0 to 5 years and 5 to 10 years. In the multi-institutional cohort, which had larger tumors, 55% of patients were classified as BCI low risk with less than 5% distant recurrence rate for 0 to 5 years and 5 to 10 years. For both cohorts, continuous BCI was the most significant prognostic factor beyond standard clinicopathologic factors for 0 to 5 years and more than five years. less thanbrgreater than less thanbrgreater thanConclusions: The prognostic sustainability of BCI to assess early- and late-distant recurrence risk at diagnosis has clinical use for decisions of chemotherapy at diagnosis and for decisions for extended adjuvant endocrine therapy beyond five years.

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