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  • 51.
    Nordenskjöld, Bo
    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.
    Rosell, Johan
    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.
    Rutqvist, Lars-Erik
    Department of Oncology, Södersjukhuset Hospital, Stockholm, Sweden.
    Malmström, Per-Olof
    Department of Oncology, Lund University Hospital, Lund, Sweden.
    Bergh, Jonas
    Department of Oncology, Karolinska Hospital, Stockholm, Sweden.
    Bengtsson, Nils-Olof
    Department of Oncology, Umeå University Hospital, Umeå, Sweden.
    Hatschek, Thomas
    Department of Oncology, Karolinska Hospital, Stockholm, Sweden.
    Wallgren, Arne
    Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Carstensen, John
    Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Department of Health and Society, Tema Health and Society.
    Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy: Results from a randomized trial2005In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 97, no 21, p. 1609-1610Article in journal (Refereed)
    Abstract [en]

    From January 1, 1983, through December 31, 1992, a total of 4610 patients entered a randomized trial that compared mortality among patients receiving 2 years of adjuvant tamoxifen therapy with that in patients receiving 5 years of adjuvant tamoxifen therapy, 4175 of whom were recurrence free after 2 years of tamoxifen therapy. Among the 2046 patients randomly assigned to the 5-year group all-cause mortality, breast cancer-specific mortality, and the incidence of contralateral breast cancer were reduced, compared with those among 2129 patients randomized in the 2-year group, but the incidence of endometrial cancer was increased. In addition, mortality from coronary heart disease was statistically significantly reduced in the 5-year group, compared with that in the 2-year group (hazard ratio = 0.67, 95% confidence interval = 0.47 to 0.94, P = .022 [two-sided Wald test]). Ten years after surgery, 2.1% of the patients in the 5-year group and 3.5% of those in the 2-year group had died from coronary heart disease. No statistically significant increases in mortality from other heart diseases, cerebrovascular diseases, or other vascular diseases were observed. © The Author 2005. Published by Oxford University Press. All rights reserved.

  • 52. Nyström, Lennarth
    et al.
    Andersson, Ingvar
    Bjurstam, Nils
    Frisell, Jan
    Nordenskjöld, Bo
    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.
    Rutqvist, Lars Erik
    Long-term effects of mammography screening: Updated overview of the Swedish randomised trials2002In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 359, no 9310, p. 909-919Article in journal (Refereed)
    Abstract [en]

    Background: There has been much debate about the value of screening mammography. Here we update the overview of the Swedish randomised controlled trials on mammography screening up to and including 1996. The Kopparberg part of the Two-County trial was not available for the overview, but the continuation of the Malm÷ trial (MMST II) has been added. The article also contains basic data from the trials that have not been presented before. Methods: The trials (n=247 010, invited group 129 750, control group 117 260) have been followed up by record linkage to the Swedish Cancer and Cause of Death Registers. The relative risks (RR) for breast cancer death and mortality were calculated for the invited and the control groups. The trial-specific as well as the age-specific effects were analysed. RRs were calculated by the density method, with total person-time experience of the cohort by time interval of follow-up as a basis for estimating mortality rates. We calculated weighted RRs and 95% CI with the Mantel-Haenszel procedure. Findings: The median trial time - the time from randomisation until the first round was completed for the control group or if the control group was not invited, until end of follow-up - was 6.5 years (range 3.0-18.1). The median follow-up time, the time from randomisation, to the end of follow-up, was 15.8 years (5.8-20.2). There were 511 breast cancer deaths in 1 864 770 women-years in the invited groups and 584 breast cancer deaths in 1 688 440 women-years in the control groups, a significant 21% reduction in breast cancer mortality (RR=0.79, 95% CI 0.70-0.89). The reduction was greatest in the age group 60-69 years at entry (33%). Looking at 5-year age groups, there were statistically significant effects in the age groups 55-59, 60-64, and 65-69 years (RR=0.76, 0.68, and 0.69, respectively). There was a small effect in women 50-54 years at randomisation (RR=0.95). The benefit in terms of cumulative breast cancer mortality started to emerge at about 4 years after randomisation and continued to increase to about 10 years. Thereafter the benefit in absolute terms was maintained throughout the period of observation. The age-adjusted relative risk for the total mortality was 0.98 (0.96-1.00). Interpretation: The advantageous effect of breast screening on breast cancer mortality persists after long-term follow-up. The recent criticism against the Swedish randomised controlled trials is misleading and scientifically unfounded.

  • 53.
    Oakman, C
    et al.
    Hospital Prato, Italy .
    Francis, P A.
    Peter MacCallum Cancer Centre, Australia .
    Crown, J
    Irish Clin Oncology Research Grp, Ireland .
    Quinaux, E
    Int Institute Drug Dev, Belgium .
    Buyse, M
    Int Institute Drug Dev, Belgium .
    De Azambuja, E
    University of Libre Brussels, Belgium .
    Margeli Vila, M
    Hospital Badalona Germans Trias and Pujol, Spain .
    Andersson, M
    Danish Breast Cancer Cooperat Grp, Denmark .
    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.
    Jakesz, R
    Vienna Medical Sch, Austria .
    Thuerlimann, B
    Kantonsspital, Switzerland .
    Gutierrez, J
    Clin Las Condes, Chile .
    Harvey, V
    Auckland City Hospital, New Zealand .
    Punzalan, L
    University of Libre Brussels, Belgium .
    DellOrto, P
    University of Milan, Italy .
    Larsimont, D
    University of Libre Brussels, Belgium .
    Steinberg, I
    Sanofi Oncol, England .
    Gelber, R D.
    IBCSG, MA USA .
    Piccart-Gebhart, M
    University of Libre Brussels, Belgium .
    Viale, G
    University of Milan, Italy .
    Di Leo, A
    Hospital Prato, Italy .
    Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer-8-year results of the Breast International Group 02-98 phase III trial2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 5, p. 1203-1211Article in journal (Refereed)
    Abstract [en]

    Background: In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. less thanbrgreater than less thanbrgreater thanMethods: Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) x 4 -andgt; classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) x 4 -andgt; CMF; (iii) sequential docetaxel: A (75 mg/m(2)) x3 -andgt; docetaxel (T) (100 mg/m(2)) x3. CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) x 4 -andgt; CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. less thanbrgreater than less thanbrgreater thanResults: Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. less thanbrgreater than less thanbrgreater thanConclusion: With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.

  • 54.
    Perez-Tenorio, Gizeh
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Berglund, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Esguerra Merca, Anna
    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.
    Rutqvist, Lars Erik
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Institutionen för cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål , Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer2006In: International Journal of Oncology, ISSN 1019-6439, Vol. 28, no 5, p. 1031-1042Article in journal (Refereed)
    Abstract [en]

    P21WAF1/Cip1 (p21) translocates to the cytoplasm inducing cell cycle progression and survival upon Akt/PKB activation. We studied whether heregulin beta1 (HRGbeta1), that activates the PI3K/Akt and MAPK pathways, also misallocates p21. We also explored whether HRGbeta1 interferes with the effects of tamoxifen. The clinical material studied helped us to clarify whether p21 was associated with phosphorylated Akt, recurrence-free survival and response to tamoxifen. MCF-7 cells treated with HRGbeta1 -/+ E2 were analyzed by flow cytometry to observe how the different compounds affected tamoxifen-induced cell cycle arrest and apoptosis. Total cell lysate and nuclear and cytoplasmic fractions were used to detect p21, phospho-Akt and other proteins by Western blotting. Immunofluorescence was used to visualize p21+ cells upon HRGbeta1 and E2 stimulation. The localization of p21 in breast cancer was studied by immunohistochemistry in frozen tumor sections from 280 patients. In MCF-7 we found that HRGbeta1 counteracted the inhibition of p21 expression by tamoxifen and caused p21 cytoplasmic accumulation. HRGbeta1 partially counteracted the cytostatic effect of tamoxifen but abrogated its cytotoxic effect. The clinical material revealed that nuclear p21 (P=0.022) and cytoplasmic p21 (P=0.00001) were associated with phospho-Akt. Based on p21 cell location, we identified 3 subgroups of ER+ patients: the p21N+/C- group for whom tamoxifen was needed otherwise the survival was poor (P=0.0082), the p21N+/C+ or p21N-/C- group, that responded to tamoxifen (P=0.034), and the p21C+/N- group, that might not benefit from this treatment (P=0.7). In conclusion, HRGbeta1 inhibits tamoxifen-induced apoptosis, contributes to p21 cytoplasmic expression while the cellular localization of p21 interacts with the benefit from tamoxifen treatment.

  • 55.
    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.

  • 56.
    Perez-Tenorio, Gizeh
    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. Linköping University, Faculty of Health Sciences.
    Ahnström Waltersson, 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. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Department of Cytology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer2008Article in journal (Refereed)
    Abstract [en]

    The mammalian target of rapamycin (mTOR) and its substrates the ribosomal S6 kinases (S6K)1 and 2 integrate nutrient and hormonal/growth factor mediated signals and are implicated indiabetes, obesity and cancer. The genes encoding S6K1 (RPS6KB1) and S6K2 (RPS6KB2) aresituated close to well known amplicons but information regarding its expression and clinicalvalue is scarce. In this study we quantified RPS6KB1/2 gene copy number, establishedassociations with other clinical factors and explored their clinical value in breast cancer. RPS6KB1/2 copy number was determined by fast real-time PCR in 207 breast tumors.RPS6KB1 was amplified (≥ 4 copies) in 10.7% (22/206) and RPS6KB2 in 4.3% (9/207) of thetumors. Amplification of RPS6KB1 was associated with HER2 gene amplification (P=0.025)and protein expression (P=0.014) while RPS6KB2 correlated with ER+ status (P=0.046) and CCND1 amplification (P<0.00001). In a multivariate analysis, both genes were independentprognostic factors indicating higher risk to develop recurrences. In terms of loco regionalcontrol, amplification of the RPS6KB1 gene predicted less response to radiotherapy (P=0.035) while RPS6KB2 gene copy gain (≥ 3 copies) indicated increased benefit from tamoxifen (P=0.03) among ER+ patients. S6K1/2 gene amplification could be used as an indicator oftherapy response among postmenopausal breast cancer patients.

  • 57. Pestalozzi, B. C.
    et al.
    Francis, P.
    Quinaux, E.
    Dolci, S.
    Azambuja, E.
    Gelber, R. D.
    Viale, G.
    Balil, A.
    Andersson, M.
    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.
    Gnant, M.
    Gutierrez, J.
    Láng, I.
    Crown, J. P. A.
    Piccart-Gebhart, M.
    Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup phase III BIG 02-98 trial2008In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 19, no 11, p. 1837-1841Article in journal (Refereed)
    Abstract [en]

    Background: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. Patients and methods: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. Results: CNS relapse occurred in 4.0% of control patients and3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. Conclusion: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

  • 58.
    Pérez-Tenorio, Gizeh
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Alkhori, Liza
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Ahnstro Waltersson, Marie
    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 Oncology UHL.
    Rutqvist, Lars Erik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Institutionen för 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.
    PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 12, p. 3577-3584Article in journal (Refereed)
    Abstract [en]

    Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.

    Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.

    Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.

    Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

  • 59.
    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.

  • 60.
    Rosell, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Regional Cancer Center South East 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.
    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, Division of Clinical Sciences. 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, Division of Health Care Analysis. Linköping University, Faculty of Health Sciences.
    Effects of adjuvant tamoxifen therapy on the incidence of secondary cancer: results from a randomized trial with long term follow-up2014Manuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND

    Tamoxifen is a well-established endocrine treatment for breast cancer. We here present results with respect to second primary cancer from a large randomized trial of 5 and 2 years of adjuvant tamoxifen. Breast cancer distant recurrence and mortality are also reported.

    METHODS

    Our study included 4128 postmenopausal patients with early stage breast cancer who were alive and free of breast cancer recurrence after 2 years of tamoxifen therapy. They were randomized to receive three more years of therapy or stop tamoxifen. In the comparison of 5 years versus 2 years of postoperative tamoxifen treatment hazard ratios were estimated using Cox regression for different follow-up periods defined as: During treatment (2-5 years) and after treatment (5-10 years, 10-15 years, > 5 years, > 10 years and > 15 years).

    RESULTS

    In the five years group the incidence of lung cancer was halved (hazard ratio [HR], 0.45, 95% confidence interval [95% CI], 0.27-0.77 [P = .0038]), and lung cancer mortality was decreased. An increased risk was observed for endometrial cancer (HR, 1.83; 95% CI, 1.19-2.81 [P = .0059]), but this risk appeared to decrease over time. The risk of contralateral breast cancer was decreased (HR, 0.73; 95% CI, 0.56-0.96 [P = .022]), also in the period after treatment stopped. In the five years group, the risk of distant recurrence was decreased, and statistically significant reductions were observed both during treatment and in the five year period after treatment stopped. The breast cancer mortality was reduced, especially during the post-treatment phase.

    CONCLUSIONS

    In this randomized study, tamoxifen substantially reduces the risk of new cancer both in contralateral breast and in lung up to 10 years after treatment stopped.

  • 61.
    Rosell, Johan
    et al.
    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.
    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.
    Bengtsson, N-O
    Department of Oncolog, Umea University Hospital, Sweden.
    Fornander, T
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Hatschek, T
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Lindman, H
    Department of Oncology, Uppsala University Hospital, Uppsala, Sweden.
    Malmstrom, P-O
    Department of Oncology, Lund University Hospital, Lund, Sweden.
    Wallgren, A
    Department of Oncology, Sahlgrenska University Hospital, Göteborg, 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.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Health Sciences.
    Time dependent effects of adjuvant tamoxifen therapy on cerebrovascular disease: results from a randomised trial2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 6, p. 899-902Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tamoxifen has been associated with an increased risk of stroke. There is, however, little information on the effect in the post-treatment period. Using data from the Swedish Breast Cancer Group adjuvant trial of 5 vs 2 years of tamoxifen treatment, we now report both short-term and long-term effects on morbidity as well as mortality because of cerebrovascular disease. METHODS: Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry was used to define events of disease. Hazard ratios (HRs) were estimated using Cox regression. RESULTS: Comparing patients randomised to 5 years of tamoxifen with patients randomised to 2 years of tamoxifen, the incidence of cerebrovascular diseases was increased (HR 1.70, 95% CI 1.05-2.75) during the active treatment phase and reduced after the active treatment period (HR 0.78, 95% CI 0.63-0.96), and the difference in HR between the two time-periods was significant (P 0.0033). The mortality from cerebrovascular diseases was increased during the treatment period (HR 3.18, 95% CI 1.03-9.87) and decreased during the post-treatment period (HR 0.60, 95% CI 0.40-0.90) with a significant difference in HR between the two periods of follow-up (P=0.0066). Similar results were seen for subgroups of cerebrovascular diseases, such as stroke and ischaemic stroke. CONCLUSION: In an adjuvant setting, tamoxifen was associated with an increased risk of cerebrovascular disease during treatment, but a decreased risk in the post-treatment period.

  • 62. Ryden, L
    et al.
    Jirstrom, K
    Bendahl, PA
    Ferno, M
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Thorstenson, Sten
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Jonsson, PE
    Landberg, G
    Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer2005In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 23, no 21, p. 4695-4704Article in journal (Refereed)
    Abstract [en]

    Purpose Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance.

    Patients and Methods Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors.

    Results VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER–positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor–positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status.

    Conclusion Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor–positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.

  • 63.
    Rydén, Lisa
    et al.
    Department of Surgery, Helsingborgs Lasarett, Helsingborg, Sweden and Department of Laboratory Medicine, div of Pathology, University Hospital, Malmö.
    Jönsson, Per-Ebbe
    Department of Surgery, Helsingborgs Lasarett, Helsingborg, Sweden.
    Chebil, Gunilla
    Department of Pathology, Helsingborgs Lasarett, Helsingborg.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Fernö, Mårten
    Department of Oncology, University Hospital, Lund.
    Jirström, Karin
    Department of Laboratory Medicine, div of Pathology, University Hospital, Malmö.
    Källström, Ann-Christine
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Landberg, Göran
    Department of Laboratory Medicine, div of Pathology, University Hospital, Malmö.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Thorstenson, Sten
    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.
    Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up2005In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 41, no 2, p. 256-264Article in journal (Refereed)
    Abstract [en]

    Adjuvant tamoxifen treatment increases recurrence-free survival (RFS) and overall survival (OS) in early breast cancer, although in premenopausal patients the number of studies comparing tamoxifen vs no treatment are limited. We report herein the effect on RFS of adjuvant tamoxifen treatment in a multicentre trial of premenopausal patients with stage II breast cancer patients randomised between 1986 and 1991 to 2 years of tamoxifen treatment (n = 276) or no treatment (n = 288). The receptor status of the tumour was known for 541 (96%) of the patients included. Tamoxifen treatment significantly increased RFS in patients with hormone receptor-positive (oestrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)) tumours (Relative Risk (RR) 0.65; 95% Confidence Interval (CI): 0.48–0.89, P = 0.006), and the beneficial effect of tamoxifen was extended to patients with indicators of poor prognosis, such as young age and nodal-positivity. PR status was a significant predictor of response to tamoxifen in multivariate models with testing of interactions of hormone receptor status and adjuvant therapy.

  • 64.
    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.

  • 65.
    Sanchez, B. C.
    et al.
    Karolinska Institute.
    Sundqvist, M.
    Kalmar Hospital.
    Fohlin, Helena
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Spyratos, F.
    Ctr Rene Huguenin, Lab Oncogenet, St Cloud, France.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Linderholm, B. K,
    Karolinska Institute.
    Prolonged tamoxifen treatment increases relapse-free survival for patients with primary breast cancer expressing high levels of VEGF2010In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 46, no 9, p. 1580-1587Article in journal (Refereed)
    Abstract [en]

    Previous retrospective studies have shown that high intratumoural levels of vascular endothelial growth factor (VEGF) correlate with an inferior outcome for patients treated with adjuvant tamoxifen. Our objectives were to validate the impact of VEGF on survival after adjuvant tamoxifen and to investigate the interaction between VEGF and treatment duration. For this purpose tumour homogenates from 402 patients with operable oestrogen receptor positive breast cancer (BC), treated with tamoxifen for 2 (n = 149) or 5 years (n = 253) as the only systemic adjuvant therapy were included. The median follow-up time for surviving patients was 9.8 years (range 0.5-14.8 years). Expression of VEGF was assessed by an enzyme-linked immunosorbent assay and investigated in relation to the standard BC parameters and survival. In the total population, higher VEGF was significantly correlated with shorter recurrence-free survival (RFS) (HR = 1.63, 95%CI = 1.11-2.39, p = 0.010), breast cancer corrected survival (BCCS) (HR = 1.82, 95%CI = 1.13-2.93, p = 0.014) and overall survival (OS) (HR = 1.51, 95%CI = 1.11-2.05, p = 0.009). High VEGF was significantly associated with reduced RFS (HR = 2.61, 95%CI = 1.45-4.70, p = 0.001) after two years of tamoxifen, whilst no difference was seen in patients treated for five years (HR = 1.09, 95%CI = 0.64-1.84, p = 0.760). A statistically significant interaction was observed between high VEGF expression and improved RFS after 5-year tamoxifen (p = 0.034). In concordance with previous studies, high VEGF was significantly correlated with shorter survival. We present data not reported previously revealing that patients expressing high levels of VEGF display a better outcome provided that tamoxifen is given for five years. Further studies on the impact of VEGF on a 5-year regimen are motivated.

  • 66.
    Sivik, Tove
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Medical Genetics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Fornander, Tommy
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, 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.
    Skoog, Lambert
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, 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.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e40568-Article in journal (Refereed)
    Abstract [en]

    Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours.

    Methods: An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry.

    Results: Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19–0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54–2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients.

    Conclusions: Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.

  • 67.
    Sivik, Tove
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, T
    Karolinska Institute.
    Skoog, L
    Karolinska Institute.
    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.
    Jansson, Agneta
    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.
    Significance of 17bHSD Type 14 as a Predictive Factor for Adjuvant Tamoxifen Treatment Response in Breast Cancer in CANCER RESEARCH, vol 69, issue 24, pp 596S-597S2009In: CANCER RESEARCH, 2009, Vol. 69, no 24, p. 596S-597SConference paper (Refereed)
    Abstract [en]

    n/a

  • 68.
    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.

  • 69.
    Sonnenblick, Amir
    et al.
    University of Libre Bruxelles, Belgium.
    Francis, Prudence A.
    Peter MacCallum Cancer Centre, Australia; Australia and New Zealand Breast Cancer Trials Grp, Australia; Int Breast Cancer Study Grp, Switzerland.
    Azim, Hatem A. Jr.
    University of Libre Bruxelles, Belgium.
    de Azambuja, Evandro
    University of Libre Bruxelles, Belgium.
    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.
    Gutierez, Jorge
    Clin Las Condes, Chile.
    Quinaux, Emmanuel
    Int Institute Drug Dev, Belgium.
    Mastropasqua, Mauro G.
    University of Milan, Italy; University of Milan, Italy.
    Ameye, Lieveke
    University of Libre Bruxelles, Belgium.
    Anderson, Michael
    Copenhagen University Hospital, Denmark; Danish Breast Cancer Cooperat Grp, Denmark.
    Lluch, Ana
    University of Valencia, Spain.
    Gnant, Michael
    Medical University of Vienna, Austria; Medical University of Vienna, Austria.
    Goldhirsch, Aron
    European Institute Oncol, Italy; Int Breast Cancer Study Grp, Switzerland.
    Di Leo, Angelo
    Hospital Prato, Italy.
    Barnadas, Agusti
    University of Autonoma Barcelona, Spain.
    Cortes-Funes, Hernan
    University Hospital 12 Octubre, Spain.
    Piccart, Martine
    University of Libre Bruxelles, Belgium.
    Crown, John
    St Vincets University Hospital, Ireland.
    Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer2015In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 51, no 12, p. 1481-1489Article in journal (Refereed)
    Abstract [en]

    Aim: Breast International Group (BIG) 2-98 is a randomised phase III trial that tested the effect of adding docetaxel, either in sequence to or in combination with anthracycline-based adjuvant chemotherapy, in women with node-positive breast cancer (BC). Here, we present the 10-year final trial safety and efficacy analyses. We also report an exploratory analysis on the predictive value of Ki67 for docetaxel efficacy, in the BIG 2-98 and using a pooled analysis of three other randomised trials. Patients and methods: 2887 patients were randomly assigned in a 2 x 2 trial design to one of four treatments. The primary objective was to evaluate the overall efficacy of docetaxel on disease free survival (DFS). Secondary objectives included comparisons of sequential docetaxel versus sequential control arm, safety and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry. Results: After a median follow-up of 10.1 years, the addition of docetaxel did not significantly improve DFS or OS (hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.81-1.04; P = 0.16 and HR = 0.88, 95% CI = 0.76-1.03; P = 0.11, respectively). Sequential docetaxel did not improve DFS compared to the sequential control arm (HR = 0.86, 95% CI = 0.721.03; P = 0.10). In oestrogen receptor (ER)-positive tumours with Ki67 greater than= 14%, the addition of docetaxel resulted in 5.4% improvement in 10-year OS (P = 0.03, test for interaction = 0.1). In a multivariate model, there was a trend for improved DFS and OS in ER-positive patients with high Ki67 and treated with docetaxel (HR = 0.79, 95% CI = 0.63-1.01; P = 0.05 and HR = 0.76, 95% CI = 0.57-1.01; P = 0.06, respectively). A pooled analysis of four randomised trials showed a benefit of taxanes in highly proliferative ER-positive disease but not in low proliferating tumours (interaction test P = 0.01). Conclusion: The DFS benefit previously demonstrated with sequential docetaxel is no longer observed at 10 years. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly proliferative ER-positive BC.

  • 70.
    Stendahl, M.
    et al.
    Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden, Department of Medicine, Ryhov Regional Hospital, Jönköping, Sweden.
    Ryden, L.
    Rydén, L., Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden.
    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.
    Jonsson, P.E.
    Jönsson, P.E., Department of Surgery, Helsingborg Hospital, Helsingborg, Sweden.
    Landberg, G.
    Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden.
    Jirstrom, K.
    Jirström, K., Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden.
    High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients2006In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 12, no 15, p. 4614-4618Article in journal (Refereed)
    Abstract [en]

    Purpose: Tamoxifen has long been the drug of choice in adjuvant endocrine therapy of steroid hormone receptor-positive breast cancer, and it still remains important due to its well-documented beneficial effect. Hormone receptor status is often reported as "positive" or "negative" using 10% positive nuclei as a cutoff. In this study, we aimed to assess whether a further subclassification of hormone receptor status could enhance the treatment predictive value. Experimental Design: The immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) was quantified in tissue microarrays with tumors from 500 premenopausal breast cancer patients previously included in a randomized trial of adjuvant tamoxifen compared with an untreated control group. Results: Our findings show a gradually increasing tamoxifen effect in tumors with >10% ER-positive nuclei. However, when analyzing tamoxifen response according to various PR fractions, we found that it was primarily patients with tumors showing >75% PR-positive nuclei that responded to tamoxifen treatment, with an improved recurrence-free [relative risk, 0.42 (0.25-0.70), P = 0.001] as well as overall [relative risk, 0.49 (0.28-0.84), P = 0.010] survival. Conclusions: Adjuvant tamoxifen improved recurrence-free and overall survival for premenopausal patients with tumors showing >75% PR-positive nuclei. No effect could be shown in tumors with fewer PR-positive nuclei. The PR was a stronger predictor of treatment response than the ER. Based on these findings, we suggest the implementation of a fractioned rather than dichotomized immunohistochemical evaluation of hormone receptors in clinical practice, possibly with greater emphasis on the PR than the ER. © 2006 American Association for Cancer Research.

  • 71. Stenmark Askmalm, Marie
    et al.
    Carstensen, John
    Linköping University, Department of Department of Health and Society.
    Nordenskjöld, Bo
    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.
    Olsson, Birgit
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Rutqvist, Lars Erik
    Skoog, Lambert
    Stål, Olle
    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.
    Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients2004In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 43, no 3, p. 235-244Article in journal (Refereed)
    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.

  • 72.
    Stål, Olle
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Borg, Å
    Department of Oncology, University Hospital Lund, Sweden.
    Fernö, M
    Department of Oncology, University Hospital Lund, Sweden.
    Källström, Ann-Christine
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Malmström, P
    Department of Oncology, University Hospital Lund, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer2000In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 11, no 12, p. 1545-1550Article in journal (Refereed)
    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.

  • 73.
    Stål, Olle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Åkerberg, Lind
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden .
    Rutqvist, Lars
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden .
    Akt kinases in breast cancer and the results of adjuvant therapy2003In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 5, no 2, p. R37-R44Article in journal (Refereed)
    Abstract [en]

    Background

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

    Methods

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

    Results

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

    Conclusion

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

  • 74.
    Sun, Xiao-Feng
    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.
    Ekberg, Hanna
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology.
    Carstensen, John
    Linköping University, Faculty of Arts and Sciences. Linköping University, The Tema Institute.
    Nordenskjöld, Bo
    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.
    Overexpression of ras is an independent prognostic factor in colorectal adenocarcinoma1998In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 106, no 6, p. 657-664Article in journal (Refereed)
  • 75.
    Sun, Xiao-Feng
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Rütten, Sabine
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Nordenskjöld, Bo
    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.
    Expression of the deleted in colorectal cancer gene is related to prognosis in DNA diploid and low proliferative colorectal adenocarcinoma.1999In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 17, p. 1745-1750Article in journal (Refereed)
  • 76.
    Sun, Xiao-Feng
    et al.
    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.
    Zhang, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
    Carstensen, John
    Linköping University, Department of Medicine and Health Sciences, Health and Society. Linköping University, Faculty of Arts and Sciences.
    Jansson, Agneta
    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 Oncology UHL.
    Heat shock protein 72/73 in relation to cytoplasmic p53 expression and prognosis in colorectal adenocarcinomas1997In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 74, no 6, p. 600-604Article in journal (Refereed)
    Abstract [en]

    Heat shock proteins (hsp) are molecular chaperones that are increased by various environmental and patho-physiological stimuli. Hsp can bind to mutant/wild-type p53 in tumors and, consequently, could not only regulate p53 accumulation or localization but also modulate its biological effects on cells. However, there is little information available on the significance of hsp expression in colorectal cancer. The aim of our study was to investigate the relationship of hsp to p53 expression, clinico-pathological factors and prognosis in a series of 256 patients with colorectal adenocarcinomas, using immuno-histochemistry. Seventy-five cases exhibited hsp expression in the cytoplasm, with 11 presenting both cytoplasmic and nuclear staining. Hsp expression was related positively to cytoplasmic p53 expression but not to nuclear p53 expression. In the subgroup of rectal tumors, hsp over-expression appeared to predict unfavorable survival, though its prognostic value diminished using multivariate analysis. There were no significant relationships of hsp with patient sex or age, tumor site, Duke's stage, growth pattern or differentiation.

  • 77.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Nilsson, I.
    Department of Clinical Chemistry, 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.
    Disease free interval and survival after dissemination of breast cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Tumour and patients characteristics were analysed and correlated to disease development in 184 women who were consecutively diagnosed with systemic breast cancer. Nottingham histologic grade (NHG) and steroid receptor content were significantly associated with disease-free interval and survival after dissemination. In the multiple regression analysis, NHG was the strongest predictor. Patients with tumours of grade 1 had median disease-free interval of 8,9 years; tumours of grade 2 4,4 years and patients with grade 3 tumours 1,8 years. Grade 2 patients had a median survival after dissemination of 2,6 years and patients with grade 3 tumours 1,2 years. Only 1 of the 12 grade 1 patients are so far diseased. 85 patients participated in a prospective trial assessing the value of serum cerbb-2 as prognostic indicator. Patients with high serum-cerbb-2 levels when distant disease was diagnosed had a more rapid disease development.

    Tumour grade was associated with disease-free interval and post-recurrence survival. Follow up progranunes could be differentiated according to tumour grade.

  • 78.
    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.

  • 79.
    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.

  • 80.
    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 Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Wingren, Sten
    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.
    Incidence and prognosis in early onset breast cancer2002In: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 11, no 1, p. 30-35Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to assess the incidence and prognosis in early onset breast cancer. Age-adjusted incidence and death rate for the 5394 Swedish women diagnosed with breast cancer under the age of 40 between 1960 and 1996 was studied using data from the Swedish Cancer Registry and Swedish Death Cause Registry. A total of 107 consecutive young patients with invasive breast cancer undergoing surgery during 1980–1993 in the Southeast Swedish health care region were retrospectively followed up and their cancers reviewed and graded blindly. The median follow-up time was 11.2 years. The applicability of the Nottingham Prognostic Index (NPI) as a prognostic tool was investigated. Grade, age, node status, tumour size, S-phase fraction and steroid receptor content were related to survival univariately and multivariately in a Cox proportional hazard analysis.

    The incidence of early onset breast cancer has increased moderately and the survival rate has not improved during the last 35 years. When young women are diagnosed with breast cancer their tumours are larger, their lymph nodes more often involved, and the median grade higher than in older with 64% having grade 3 tumours. Lymph node status was the strongest sole prognostic indicator but the use of NPI gave more accurate prognostic information than node status alone.

  • 81.
    Sundquist, Marie
    et al.
    Department of Surgery, County Hospital, Kalmar, Sweden.
    Thorstenson, Sten
    Department of Cytology and Pathology, County Hospital, Kalmar, Sweden.
    Klintenberg, Claes
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    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.
    Indicators of loco-regional recurrence in breast cancer2000In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 26, no 4, p. 357-362Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of the investigation was to contribute to the identification of patients who have increased or decreased risk of loco-regional recurrence.

    Methods: Six hundred and twenty-nine consecutive patients with primary breast cancer diagnosed between 1988 and 1990 were studied. Two-thirds of the patients underwent mastectomy. Radiotherapy was administered if patients were node positive or breast conserved. The Nottingham histological grading protocol was used and presence of lymphovascular invasion was assessed. Investigated parameters were: age, size, grade, steroid receptor content, surgical radicality, vascular invasion and nodal status. Statistically significant risk factors for loco-regional recurrence using univariate or Cox proportional hazard analysis were grade and lymphovascular invasion.

    Results: Women with grade 1-2, node-negative tumours without vascular invasion had a very low loco-regional recurrence rate - 3.1%. Seventeen percent of patients with grade 3 tumours and vessel invasion had loco-regional recurrence.

    Conclusions: Our findings, and those of others, indicate that the use of adjuvant radiotherapy should be influenced to a greater extent by grade and lymphovascular invasion.

  • 82.
    Söderlund Leifler, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    ¨, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    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
    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.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer2007In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 68, no 1, p. 50-58Article in journal (Refereed)
    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.

  • 83. Tejler, G
    et al.
    Norberg, B
    Dufmats, Monika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Nordenskjöld, Bo
    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.
    Arnesson, Lars-Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Survival after treatment for breast cancer in a geographically defined population2004In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 91, no 10, p. 1307-1312Article in journal (Refereed)
    Abstract [en]

    Background: South East Sweden with 976000 inhabitants is served by nine hospitals with specialized breast surgeons. Population-based mammographic screening was introduced in 1986 for women aged 40-74 years. Patients with primary breast cancer were treated according to a joint management programme. Methods: All patients were reported to a regional cancer registry from which breast cancer incidence, treatment and survival in this defined population were reported. Results: A total of 7892 women had their first invasive breast cancer diagnosed between 1986 and 1999. The median tumour size was 17 mm and 29.9 per cent had axillary metastases. Some 49.8 per cent of these women had a modified radical mastectomy and 31.9 per cent had a segmental resection with axillary clearance. Postoperative radiotherapy was given to 40.3 per cent of the women after mastectomy and to 87.1 per cent after breast-conserving surgery. Tamoxifen and chemotherapy were used as adjuvant treatment except in low-risk patients. Breast cancer-specific survival rate for all stages was 83.5 per cent at 5 years and 74.0 per cent at 10 years. Respective values were 95.8 and 90.9 per cent for patients with stage T1 N0 M0 tumours, and 77.7 and 62.4 per cent for those with T1-2 N1 M0 tumours. Conclusion: Breast specialists treating women with breast cancer according to a joint management programme have achieved very good survival rates.

  • 84.
    Veenstra, Cynthia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Stelling, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Mirwani Mirwani, Sanam
    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.
    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. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Met and its ligand HGF are associated with clinical outcome in breast cancer2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 37145-37159Article in journal (Refereed)
    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.

  • 85.
    Waltersson, MA
    et al.
    Karolinska University Hospital.
    Karlsson, E
    Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, T
    Karolinska University Hospital.
    Skoog, L
    Karolinska 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.
    miR-206 Expression Is Downregulated in Cyclin D1 Amplified Breast Tumours. in CANCER RESEARCH, vol 69, issue 24, pp 579S-579S2009In: CANCER RESEARCH, 2009, Vol. 69, no 24, p. 579S-579SConference paper (Refereed)
    Abstract [en]

    n/a

  • 86.
    Wegman Palmebäck, Pia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elingarami, Sauli
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Arts and Sciences.
    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.
    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.
    Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients2007In: Breast Cancer Research, ISSN 1465-5411, Vol. 9, no 1, p. R7-Article in journal (Refereed)
    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.

  • 87.
    Wegman (Palmebäck), Pia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. 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, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Rutqvist, Lars-Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Wingren, Sten
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients2006In: Pharmacogenetics and Genomics, ISSN 1744-6872, Vol. 16, no 5, p. 347-351Article in journal (Refereed)
    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.

  • 88.
    Wegman (Palmebäck), Pia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vainikka, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    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.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden.
    Rutqvist, Lars-Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Wingren, Sten
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients2005In: Breast Cancer Research, ISSN 1465-5411, Vol. 7, no 3, p. R284-R290Article in journal (Refereed)
    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.

  • 89.
    Weiner, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Skoog, L
    Karolinska Institute, Sweden.
    Fornander, T
    Karolinska Institute, 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.
    Sgroi, D C.
    Massachusetts General Hospital, Boston, USA.
    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.
    Oestrogen receptor co-activator AIB1 is a marker of tamoxifen benefit in postmenopausal breast cancer2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 8, p. 1994-1999Article in journal (Refereed)
    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.

  • 90.
    Zhang, Hong
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Ahmadi, Ahmad
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Arbman, G
    Zdolsek, J
    Carstensen, J
    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.
    Nordenskjöld, Bo
    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.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Glutathione S-transferase T1 and M1 genotypes in normal mucosa, transitional mucosa and colorectal adenocarcinom.1999In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 84, p. 135-138Article in journal (Refereed)
  • 91.
    Zhang, Hong
    et al.
    Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    K-ras mutations in colorectal adenocarcinomas and neighbouring transitional mucosa.1998In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 34, no 13, p. 2053-2057Article in journal (Refereed)
    Abstract [en]

    The K-ras gene in codons 12 and 13 was investigated using allele-specific polymerase chain reaction in matched normal mucosa (n = 106), transitional mucosa (n = 69) and tumours (n = 149) from 149 patients with colorectal adenocarcinomas. K-ras mutations in codon 12 were detected in 41/149 (28%) of tumours and 4/69 (6%) of transitional mucosa samples, but not in the normal mucosa. Further, mutation rates were increased in younger patients (P = 0.001) and in mucinous carcinomas (50%) compared with well differentiated (17%), moderately differentiated (26%) or poorly differentiated (24%) tumours. Our findings indicate that mucinous carcinoma may represent a distinct genetic entity.

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