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  • 1.
    Engstrom, Terese
    et al.
    Lund Univ, Sweden.
    Ekholm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hosp, Sweden.
    Ferno, Marten
    Lund Univ, Sweden.
    Lundgren, Christine
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden; Ryhov Hosp, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bendahla, Paer-Ola
    Lund Univ, Sweden.
    Tutzauer, Julia
    Lund Univ, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Hormone receptor mRNA and protein levels as predictors of premenopausal tamoxifen benefit2024In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 63, no 1, p. 125-136Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Tamoxifen remains an important adjuvant treatment in premenopausal patients with hormone receptor-positive breast cancer. Thus, determination of hormone receptors is important. Here, we compare cytosol-based methods, immunohistochemistry (IHC), and gene expression (GEX) analysis for determining hormone receptor status in premenopausal breast cancer patients from a randomised tamoxifen trial, to evaluate their performance in identifying patients that benefit from tamoxifen. Patients and Methods: Premenopausal patients (n=564) were randomised to 2 years of tamoxifen or no measured by cytosol-based methods and IHC, and mRNA by GEX analysis were compared in 313 patients with available data from all methods. Kaplan Meier estimates and Cox regression were used to evaluate the treatment-predictive value for recurrence-free interval (RFi) and overall survival (OS). Median follow-up for event-free patients was 26 (RFi) and 33 (OS) years. Results: The mRNA data of ESR1 and PGR distributed bimodally, patterns confirmed in an independent cohort. Kappa-values between all methods were 0.76 and 0.79 for ER and PR, respectively. Tamoxifen improved RFi in patients with ER-positive (ER+) or PR-positive (PR+) tumours (Hazard Ratio [HR] and 95% confidence interval [CI]), cytosol-ER+ 0.53 [0.36-0.79]; IHC-ER+ 0.55 [0.38-0.79]; GEX-ER+ 0.54 [0.37-0.77]; cytosol-PR+ 0.49 [0.34-0.72]; IHC-PR+ 0.58 [0.40-0.85]; GEX-PR+ 0.55 [0.38-0.80]). Results were similar for OS. Interpretation: These methods can all identify patients that benefit from 2 years of tamoxifen with equal performance, indicating that GEX data might be used to guide adjuvant tamoxifen therapy.

  • 2.
    Nordenskjold, Anna
    et al.
    Southern Alvsborg Hosp, Sweden; Sahlgrens Univ Hosp, Sweden.
    Fohlin, Helena
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Regional Cancer Center.
    Rosell, Johan
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Regional Cancer Center. Linköping University, Department of Biomedical and Clinical Sciences.
    Bengtsson, Nils-Olof
    Umea Univ Hosp, Sweden.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Hatschek, Thomas
    Karolinska Inst, Sweden.
    Lindman, Henrik
    Uppsala Univ Hosp, Sweden.
    Malmstrom, Per
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden.
    Wallgren, Arne
    Sahlgrens Univ Hosp, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Breast cancer survival and incidence of second primary cancers after 30 years in a randomized study of two versus five years of adjuvant tamoxifen therapy2023In: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 71, p. 63-68Article in journal (Refereed)
    Abstract [en]

    Background: Tamoxifen is an established treatment for breast cancer, but its long-term effects on survival and on secondary cancers are not fully evaluated. Material and methods: We studied 30 years outcome of 4124 postmenopausal patients who were randomized to receive (totally) two or five years of adjuvant tamoxifen.Results: After 5 years of follow-up, when tamoxifen treatment was finished in both groups, until 15 years of follow-up, overall mortality (HR 0.80, 95% CI 0.72-0.90, p < 0.001), breast cancer mortality for all patients (HR 0.80, 95% CI 0.68-0.94, p = 0.006) and breast cancer mortality for patients with estrogen receptor positive disease (HR 0.67, 95% CI 0.55-0.83, p < 0.001) were significantly reduced in the five-year group as compared to the two-year group. After 15 years, the difference remained but did not further increase. In the five-year group, the incidence of contralateral breast cancer was gradually reduced during the entire period of observation. The incidence of lung cancer was also reduced in the five-year group. In contrast there was an increased endometrial cancer incidence in the five-year group and for those receiving 40 mg of tamoxifen this incidence was further increased.Conclusion: Three more years of tamoxifen therapy reduced the risk of breast cancer mortality. The difference was established during the first 15 years after randomization. Moreover, the incidence of contralateral breast cancer gradually decreased for 30 years. The incidence of lung cancer was reduced in the five-year group. In contrast the incidence of endometrial cancer was increased.

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  • 3.
    Lundgren, Christine
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden; Lund Univ, Sweden.
    Tutzauer, Julia
    Lund Univ, Sweden.
    Church, Sarah E.
    NanoString Technol Inc, WA USA.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ekholm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Forsare, Carina
    Lund Univ, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ferno, Marten
    Lund Univ, Sweden.
    Bendahl, Par-Ola
    Lund Univ, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer: data from the randomized SBII:2 trial2023In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 25, no 1, article id 110Article in journal (Refereed)
    Abstract [en]

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

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  • 4.
    Johansson, Annelie
    et al.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Yu, Nancy Y.
    Karolinska Inst, Sweden.
    Iftimi, Adina
    Karolinska Inst, Sweden.
    Tobin, Nicholas P.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Van 'T Veer, Laura
    Univ Calif San Francisco, CA USA; Univ Calif San Francisco, CA 94140 USA.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Benz, Christopher C.
    Univ Calif San Francisco, CA 94143 USA; Buck Inst Res Aging, CA USA.
    Fornander, Tommy
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Pérez-Tenorio, Gizeh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Yau, Christina
    Buck Inst Res Aging, CA USA; Univ Calif San Francisco, CA USA.
    Lindström, Linda S.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Clinical and molecular characteristics of estrogen receptor-positive ultralow risk breast cancer tumors identified by the 70-gene signature2022In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 150, no 12, p. 2072-2082Article in journal (Refereed)
    Abstract [en]

    The metastatic potential of estrogen receptor (ER)-positive breast cancers is heterogeneous and distant recurrences occur months to decades after primary diagnosis. We have previously shown that patients with tumors classified as ultralow risk by the 70-gene signature have a minimal long-term risk of fatal breast cancer. Here, we evaluate the previously unexplored underlying clinical and molecular characteristics of ultralow risk tumors in 538 ER-positive patients from the Stockholm tamoxifen randomized trial (STO-3). Out of the 98 ultralow risk tumors, 89% were luminal A molecular subtype, whereas 26% of luminal A tumors were of ultralow risk. Compared to other ER-positive tumors, ultralow risk tumors were significantly (Fishers test, P < .05) more likely to be of smaller tumor size, lower grade, progesterone receptor (PR)-positive, human epidermal growth factor 2 (HER2)-negative and have low Ki-67 levels (proliferation-marker). Moreover, ultralow risk tumors showed significantly lower expression scores of multi-gene modules associated with the AKT/mTOR-pathway, proliferation (AURKA), HER2/ERBB2-signaling, IGF1-pathway, PTEN-loss and immune response (IMMUNE1 and IMMUNE2) and higher expression scores of the PIK3CA-mutation-associated module. Furthermore, 706 genes were significantly (FDR < 0.001) differentially expressed in ultralow risk tumors, including lower expression of genes involved in immune response, PI3K/Akt/mTOR-pathway, histones, cell cycle, DNA repair, apoptosis and higher expression of genes coding for epithelial-to-mesenchymal transition and homeobox proteins, among others. In conclusion, ultralow risk tumors, associated with minimal long-term risk of fatal disease, differ from other ER-positive tumors, including luminal A molecular subtype tumors. Identification of these characteristics is important to improve our prediction of nonfatal vs fatal breast cancer.

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  • 5.
    Ellegård, Sander
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Engvall, Kristina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Dept Oncol, Sweden.
    Asowed, Mustafa
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Elander, Nils
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Long-term follow-up of early stage HER2-positive breast cancer patients treated with trastuzumab: A population-based real world multicenter cohort study2022In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 12, article id 861324Article in journal (Refereed)
    Abstract [en]

    IntroductionSince its introduction in standard of care, trastuzumab has revolutionized the treatment of patients with early and late stages of HER2-positive breast cancer. While the initial clinical trials were convincing and lead to major changes in practice, more knowledge on the long-term outcome and tolerability is needed. The present study was designed to assess the survival, prognostic factors and relapse patterns after the implementation of trastuzumab in a real-world cohort. MethodsAll cases of HER2-positive breast cancer diagnosed between 2006 and 2014 in the Southeast Healthcare Region of Sweden were retrospectively identified. Medical records were thoroughly reviewed with regard to clinicopathological parameters, treatments, relapse pattern and adverse events. Results643 patients were identified and 599 were eligible for analysis. Breast cancer specific survival, distant recurrence free survival and local recurrence free survival were 93.4%, 89.7% and 98.0% for trastuzumab treated patients and 87.4%, 81.6% and 87.4% in patients not treated with trastuzumab, respectively. ER status, nodal status and trastuzumab treatment were all independent prognostic factors in multivariable analysis. No new safety concerns were discovered. ConclusionThe real-world outcome of trastuzumab-treated patients with early HER2-positive breast cancer is similar to what has been previously reported in long-term follow up of prospective clinical trials. ER status, nodal status and trastuzumab treatment are independent prognostic factors for breast cancer specific mortality rate, distant recurrence rate and locoregional recurrence rate in HER2-positive patients in the trastuzumab era.

  • 6.
    Lundgren, Christine
    et al.
    Reg Jonkoping Cty, Sweden; Lund Univ, Sweden.
    Bendahl, Pär-Ola
    Lund Univ, Sweden.
    Church, Sarah E.
    NanoString Technol Inc, WA USA.
    Ekholm, Maria
    Reg Jonkoping Cty, Sweden; Univ Gothenburg, Sweden.
    Fernö, Mårten
    Lund Univ, Sweden.
    Forsare, Carina
    Lund Univ, Sweden.
    Krüger, Ute
    Lund Univ, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Rydén, Lisa
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    PAM50 subtyping and ROR score add long-term prognostic information in premenopausal breast cancer patients2022In: npj Breast Cancer, E-ISSN 2374-4677, Vol. 8, no 1, article id 61Article in journal (Refereed)
    Abstract [en]

    PAM50 intrinsic subtyping and risk of recurrence (ROR) score are approved for risk profiling in postmenopausal women. We aimed to examine their long-term prognostic value in terms of breast cancer-free interval (BCFi) and overall survival (OS) (n = 437) in premenopausal women randomised to 2 years of tamoxifen versus no systemic treatment irrespective of hormone-receptor status. Intrinsic subtyping added independent prognostic information in patients with oestrogen receptor-positive/human epidermal growth factor 2-negative tumours for BCFi and OS after maximum follow-up (overall P-value 0.02 and 0.006, respectively) and those with high versus low ROR had worse prognosis (maximum follow-up: hazard ratio (HR)(BCFi): 1.70, P 0.04). The prognostic information by ROR was similar regarding OS and in multivariable analysis. These results support that PAM50 subtyping and ROR score provide long-term prognostic information in premenopausal women. Moreover, tamoxifen reduced the incidence of breast cancer events only in patients with Luminal A(PAM50) tumours (0-10 years: HRBCFi(Luminal A): 0.41, HRBCFi(Luminal B): 1.19, P-interaction = 0.02).

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  • 7.
    Johansson, Annelie
    et al.
    Karolinska Inst, Sweden.
    Dar, Huma
    Karolinska Inst, Sweden.
    Veer, Laura J. van t
    Univ Calif San Francisco, CA USA.
    Tobin, Nicholas P.
    Karolinska Inst, Sweden.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Nordenskjöld, Anna
    Gothenburg Univ, Sweden.
    Johansson, Ulla
    Karolinska Univ Hosp, Sweden.
    Hartman, Johan
    Karolinska Inst, Sweden.
    Skoog, Lambert
    Karolinska Inst, Sweden.
    Yau, Christina
    Buck Inst Res Aging, CA USA; Univ Calif San Francisco, CA USA.
    Benz, Christopher C.
    Buck Inst Res Aging, CA USA; Univ Calif San Francisco, CA USA.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Lindstrom, Linda S.
    Karolinska Inst, Sweden.
    Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial2022In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 40, no 35, p. 4071-4082Article in journal (Refereed)
    Abstract [en]

    PURPOSETo assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer.METHODSSecondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node-positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years.RESULTSIn estrogen receptor-positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio [HR], 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed (P = .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit.CONCLUSIONThis study shows 20-year benefit from 2 years of adjuvant endocrine therapy in estrogen receptor-positive premenopausal patients and suggests differential treatment benefit on the basis of tumor genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical.

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  • 8.
    Dar, Huma
    et al.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Johansson, Annelie
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Nordenskjöld, Anna
    Sahlgrens Acad, Sweden; Southern Alvsborg Hosp, Sweden.
    Iftimi, Adina
    Karolinska Inst, Sweden.
    Yau, Christina
    Univ Calif San Francisco, CA USA.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Benz, Christopher
    Univ Calif San Francisco, CA 94143 USA.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Fornander, Tommy
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Lindström, Linda S.
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Assessment of 25-Year Survival of Women With Estrogen Receptor-Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy A Secondary Analysis of Data From the Stockholm Tamoxifen Randomized Clinical Trial2021In: JAMA Network Open, E-ISSN 2574-3805, Vol. 4, no 6, article id e2114904Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Clinically used breast cancer markers, such as tumor size, tumor grade, progesterone receptor (PR) status, and Ki-67 status, are known to be associated with short-term survival, but the association of these markers with long-term (25-year) survival is unclear. OBJECTIVE To assess the association of clinically used breast cancer markers with long-term survival and treatment benefit among postmenopausal women with lymph node-negative, estrogen receptor [ER]-positive and ERBB2-negative breast cancer who received tamoxifen therapy. DESIGN, SETTING, AND PARTICIPANTS This study was a secondary analysis of data from a subset of 565 women with ER-positive/ERBB2-negative breast cancer who participated in the Stockholm tamoxifen (STO-3) randomized clinical trial. The STO-3 clinical trial was conducted from 1976 to 1990 and comprised 1780 postmenopausal women with lymph node-negative breast cancer who were randomized to receive adjuvant tamoxifen therapy or no endocrine therapy. Complete 25-year follow-up data through December 31, 2016, were obtained from Swedish national registers. Immunohistochemical markers were reannotated in 2014. Data were analyzed from April to December 2020. INTERVENTIONS Patients in the original STO-3 clinical trial were randomized to receive 2 years of tamoxifen therapy vs no endocrine therapy. In 1983, patients who received tamoxifen therapy without cancer recurrence during the 2-year treatment and who consented to continued participation in the STO-3 study were further randomized to receive 3 additional years of tamoxifen therapy or no endocrine therapy. MAIN OUTCOMES AND MEASURES Distant recurrence-free interval (DRFI) by clinically used breast cancer markers was assessed using Kaplan-Meier and multivariable Cox proportional hazards analyses adjusted for age, period of primary diagnosis, tumor size (T1a and T1b [T1a/b], T1c, and T2), tumor grade (1-3), PR status (positive vs negative), Ki-67 status (low vs medium to high), and STO-3 clinical trial arm (tamoxifen treatment vs no adjuvant treatment). A recursive partitioning analysis was performed to evaluate which markers were able to best estimate long-term DRFI. RESULTS The study population comprised 565 postmenopausal women (mean [SD] age, 62.0 [5.3] years) with lymph node-negative, ER-positive/ERBB2-negative breast cancer. A statistically significant difference in long-term DRFI was observed by tumor size (88% for T1a/b vs 76% for T1c vs 63% for T2 tumors; log-rank P <.001) and tumor grade (81% for grade 1 vs 77% for grade 2 vs 65% for grade 3 tumors; log-rank P =.02) but not by PR status or Ki-67 status. Patients with smaller tumors (hazard ratio [HR], 0.31 [95% CI, 0.17-0.55] for T1a/b tumors and 0.58 [95% CI, 0.38-0.88] for T1c tumors) and grade 1 tumors (HR, 0.48; 95% CI, 0.24-0.95) experienced a significant reduction in the long-term risk of distant recurrence compared with patients with larger (T2) tumors and grade 3 tumors, respectively. A significant tamoxifen treatment benefitwas observed among patients with larger tumors (HR, 0.53 [95% CI, 0.32-0.89] for T1c tumors and 0.34 [95% CI, 0.16-0.73] for T2 tumors), lower tumor grades (HR, 0.24 [95% CI, 0.07-0.82] for grade 1 tumors and 0.50 [95% CI, 0.31-0.80] for grade 2 tumors), and PR-positive status (HR, 0.38; 95% CI, 0.24-0.62). The recursive partitioning analysis revealed that tumor sizewas the most important characteristic associated with long-term survival, followed by clinical trial arm among patients with larger tumors. CONCLUSIONS AND RELEVANCE This secondary analysis of data from the STO-3 clinical trial indicated that, among the selected subgroup of patients, tumor size followed by tumor grade were the markers most significantly associated with long-term survival. Furthermore, a significant long-term tamoxifen treatment benefit was observed among patients with larger tumors, lower tumor grades, and PR-positive tumors.

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  • 9.
    Sandström, Josefine
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Balian, Alien
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lockowandt, Rebecca
    Linköping University, Department of Biomedical and 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 Inst, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lindstrom, Linda
    Karolinska Inst, Sweden.
    Perez Tenorio, Gizeh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    IP6K2 predicts favorable clinical outcome of primary breast cancer2021In: Molecular and clinical oncology, ISSN 2049-9450, E-ISSN 2049-9469, Vol. 14, no 5, article id 94Article in journal (Refereed)
    Abstract [en]

    The inositol hexakisphosphate kinase (IP6K) 1 and 2 genes are localized at 3p21.31, a highly altered gene-dense chromosomal region in cancer. The IP6Ks convert IP6 to IP7, which inhibits activation of the tumor-promoting PI3K/Akt/mTOR signaling pathway. IP6K2 has been suggested to be involved in p53-induced apoptosis, while IP6K1 may stimulate tumor growth and migration. The present study aimed to elucidate the role of the two IP6Ks in predicting outcome in patients with breast cancer. To the best of our knowledge, the role of IP6K was analyzed for the first time in tumors from three cohorts of patients with breast cancer; one Swedish low-risk cohort, one Dutch cohort and the TCGA dataset. Analyses of gene -and protein expression and subcellular localization were included. IP6K2 gene expression was associated with ER positivity and nuclear p-Akt. Improved prognosis was detected with high IP6K2 gene expression compared with low IP6K2 gene expression in systemically untreated patients in the Swedish low-risk and Dutch cohorts. In the TCGA dataset, IP6K2 prognostic value was significant when selecting for tumors with wild-type TP53. A multivariable analysis testing IP6K2 against other cancer-related genes at 3p.21.31, including IP6K1 and clinical biomarkers, revealed that IP6K2 was associated with decreased risk of distant recurrence. IP6K1 was associated with increased risk of distant recurrence in the multivariable test and protein analysis revealed trends of worse prognosis with high IP6K1 in the cytoplasm. The expression levels of IP6K1 and IP6K2 were associated to a high extent; however, a diverging prognostic value of the two genes was observed in breast cancer. The present data suggest that IP6K2 can be a favorable prognostic factor, while IP6K1 may not be.

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  • 10.
    Lokkegaard, Sanne
    et al.
    Univ Southern Denmark, Denmark.
    Elias, Daniel
    Univ Southern Denmark, Denmark.
    Alves, Carla L.
    Univ Southern Denmark, Denmark.
    Bennetzen, Martin V.
    Univ Southern Denmark, Denmark.
    Laenkholm, Anne-Vibeke
    Zealand Univ Hosp, Denmark.
    Bak, Martin
    Odense Univ Hosp, Denmark.
    Gjerstorff, Morten F.
    Univ Southern Denmark, Denmark.
    Johansen, Lene E.
    Univ Southern Denmark, Denmark.
    Vever, Henriette
    Univ Southern Denmark, Denmark.
    Bjerre, Christina
    Copenhagen Univ Hosp, Denmark.
    Kirkegaard, Tove
    Danish Canc Soc Res Ctr, Denmark.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Univ Hosp, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lindström, Linda S.
    Karolinska Inst, Sweden.
    Esserman, Laura J.
    Univ Calif San Francisco, CA 94115 USA.
    Lykkesfeldt, Anne E.
    Danish Canc Soc Res Ctr, Denmark.
    Andersen, Jens S.
    Univ Southern Denmark, Denmark.
    Leth-Larsen, Rikke
    Univ Southern Denmark, Denmark.
    Ditzel, Henrik J.
    Univ Southern Deanmark, Denmark; Odense Univ Hosp, Denmark.
    MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit2021In: npj Breast Cancer, E-ISSN 2374-4677, Vol. 7, no 1, article id 2Article in journal (Refereed)
    Abstract [en]

    Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser(315,33)), CHK1(Ser(317)), and cdc25b(Ser(323)), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

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  • 11.
    Berger, Karoline
    et al.
    Univ Gothenburg, Sweden.
    Rhost, Sara
    Univ Gothenburg, Sweden.
    Rafnsdottir, Svanheidur
    Univ Gothenburg, Sweden; Natl Univ Hosp Iceland, Iceland.
    Hughes, Eamon
    Univ Gothenburg, Sweden.
    Magnusson, Ylva
    Univ Gothenburg, Sweden.
    Ekholm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden; Department of Oncology, Region Jönköping County, Jönköping, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. 3 Department of Oncology, Region Jönköping County, Jönköping, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden.
    Landberg, Goran
    Univ Gothenburg, Sweden.
    Tumor co-expression of progranulin and sortilin as a prognostic biomarker in breast cancer2021In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 21, no 1, article id 185Article in journal (Refereed)
    Abstract [en]

    Background The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients. Methods We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers. Results Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ER alpha positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance. Conclusion Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.

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  • 12.
    Sjostrom, Martin
    et al.
    Lund Univ, Sweden.
    Veenstra, Cynthia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Holmberg, Erik
    Univ Gothenburg, Sweden.
    Karlsson, Per
    Univ Gothenburg, Sweden.
    Killander, Fredrika
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Malmstrom, Per
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Nimeus, Emma
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Ferno, Marten
    Lund Univ, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast-conserving surgery: a long-term follow-up of the SweBCG91-RT randomised trial2020In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 14, no 11, p. 2713-2726Article in journal (Refereed)
    Abstract [en]

    Experimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) after adjuvant radiotherapy (RT) in primary breast cancer. HGF, phosphorylated Met (pMet) and phosphorylated Akt (pAkt) were evaluated immunohistochemically on tissue microarrays from 1004 patients in the SweBCG91-RT trial, which randomly assigned patients to breast-conserving therapy, with or without adjuvant RT. HGF was evaluated in the stroma (HGF(str)); pMet in the membrane (pMet(mem)); HGF, pMet and pAkt in the cytoplasm (HGF(cyt), pMet(cyt), pAkt(cyt)); and pAkt in the nucleus (pAkt(nuc)). The prognostic and treatment predictive effects were evaluated to primary endpoint IBTR as first event during the first 5 years. Patients with tumours expressing low levels of HGF(cyt) and pMet(cyt) and high levels of pAkt(nuc) derived a larger benefit from RT [hazard ratio (HR): 0.11 (0.037-0.30), 0.066 (0.016-0.28) and 0.094 (0.028-0.31), respectively] compared to patients with high expression of HGF(cyt)and pMet(cyt), and low pAkt(nuc) [HR: 0.36 (0.19-0.67), 0.35 (0.20-0.64) and 0.47 (0.32-0.71), respectively; interaction analyses:P = 0.052, 0.035 and 0.013, respectively]. These differences remained in multivariable analysis when adjusting for patient age, tumour size, histological grade, St Gallen subtype and systemic treatment (interaction analysis,P-values: 0.085, 0.027, and 0.023, respectively). This study suggests that patients with immunohistochemically low HGF(cyt), low pMet(cyt)and high pAkt(nuc)may derive an increased benefit from RT after breast-conserving surgery concerning the risk of developing IBTR.

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  • 13.
    Fohlin, Helena
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Region Östergötland, Regionledningskontoret, Regional Cancer Center.
    Bekkhus, Tove
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sandström, Josefine
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Low RAB6C expression is a predictor of tamoxifen benefit in estrogen receptor-positive/progesterone receptor-negative breast cancer2020In: Molecular and clinical oncology, ISSN 2049-9450, E-ISSN 2049-9469, Vol. 12, no 5, p. 415-420Article in journal (Refereed)
    Abstract [en]

    Over the last few decades, improved and more individualized treatment has contributed to the increased survival rate of patients with breast cancer. However, certain patients may receive excessive treatment resulting in undesired side effects. In a previous study, it was demonstrated that systemically untreated patients with estrogen receptor (ER)-positive/progesterone receptor (PR)-negative tumors with high Ras-related protein Rab-6C (RAB6C) expression levels (RAB6C(+)) had prolonged distant recurrence-free survival compared with that of patients exhibiting low RAB6C (RAB6C(-))-expressing tumors. The aim of the present study was to investigate whether RAB6C predicts the effectiveness of tamoxifen treatment. The present study used a dataset comprising 486 female patients with ER+ tumors from a randomized study conducted by the Stockholm Breast Cancer Study Group between November 1976 and August 1990. The patients were considered as low-risk if their tumor size was <= 30 mm and their lymph node status was negative. Patients were followed up until distant recurrence, mortality or when 25 years after randomization was achieved, whichever occurred first. For patients with ER+/PR-/RAB6C(+) tumors, prolonged distant recurrence-free survival could not be observed if the patients were treated with tamoxifen [hazard ratio (HR), 1.82; 95% confidence interval (CI), 0.69-4.79; P=0.23], whereas patients with ER+/PR-/RAB6C(-) tumors had 75% reduced distant recurrence risk (HR, 0.25; 95% CI, 0.09-0.70; P=0.008). In the ER+/PR+ subgroup, patients with RAB6C(-) and RAB6C(+) tumors benefited from tamoxifen treatment, though it was most evident in the RAB6C(+) group (HR, 0.27; 95% CI, 0.13-0.58; P=0.001). The results of the present study indicated that, for patients with ER+/PR- tumors, those with low RAB6C expression benefited from tamoxifen treatment, whereas no benefit was observed in patients with high RAB6C levels.

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  • 14.
    Fohlin, Helena
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Regional Cancer Center. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bekkhus, Tove
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sandström, Josefine
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Division of Health Care Analysis. Linköping University, Faculty of Medicine and Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    RAB6C is an independent prognostic factor of estrogen receptor-positive/progesterone receptor-negative breast cancer2020In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 19, no 1, p. 52-60Article in journal (Refereed)
    Abstract [en]

    The majority of breast cancer tumors are estrogen receptor-positive (ER+) and can be treated with endocrine therapy. However, certain patients may exhibit a good prognosis without systemic treatment. The aim of the present study was to identify novel prognostic factors for patients with ER breast cancer tumors using gene copy data, and to investigate if these factors have prognostic value in subgroups categorized by progesterone receptor status (PR). Public data, including the whole genome gene copy data of 199 systemically untreated patients with ER+ tumors, were utilized in the present study. To assess prognostic value, patients were divided into two groups using the median gene copy number as a cut-off for the SNPs that were the most variable. One SNP was identified, which indicated that the Ras-related protein Rab-6C (RAB6C) gene may exhibit prognostic significance. Therefore, RAB6C protein expression was subsequently investigated in a second independent cohort, consisting of 469 systematically untreated patients (of which 310 were ER+) who received long term follow-up. In the public data set, a distant recurrence risk reduction of 55% was determined for copy numbers above the median value of RAB6C compared with numbers below [multivariable adjusted hazard ratio (HR), 0.45; 95% CI 0.28-0.72; P=0.001)]. It was also more pronounced in the ER+/PR- subgroup (HR, 0.15; 95% CI, 0.05-0.46; P=0.001). In the second cohort, patients of the ER+/PR- subgroup who exhibited high RAB6C expression had a reduced distant recurrence risk (HR, 0.17; 95% CI, 0.05-0.60; P=0.006). However, this was not identified among ER+/PR- tumors (HR, 1.31; 95% CI, 0.69-2.48; P=0.41). The results of the present study indicated that RAB6C serves as an independent prognostic factor of distant recurrence risk in systemically untreated patients with an ER+/PR- tumor.

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  • 15.
    Lundgren, Christine
    et al.
    Reg Jonkoping Cty, Sweden; Lund Univ, Sweden.
    Bendahl, Par-Ola
    Lund Univ, Sweden.
    Ekholm, Maria
    Reg Jonkoping Cty, Sweden; Lund Univ, Sweden.
    Ferno, Marten
    Lund Univ, Sweden.
    Forsare, Carina
    Lund Univ, Sweden.
    Kruger, Ute
    Lund Univ, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ryden, Lisa
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Tumour-infiltrating lymphocytes as a prognostic and tamoxifen predictive marker in premenopausal breast cancer: data from a randomised trial with long-term follow-up2020In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 22, no 1, article id 140Article in journal (Refereed)
    Abstract [en]

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

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  • 16.
    Yu, Nancy Y.
    et al.
    Karolinska Inst, Sweden.
    Iftimi, Adina
    Karolinska Inst, Sweden.
    Yau, Christina
    Univ Calif San Francisco, CA USA; Buck Inst Res Aging, CA USA.
    Tobin, Nicholas P.
    Karolinska Inst, Sweden.
    van t Veer, Laura
    Univ Calif San Francisco, CA USA.
    Hoadley, Katherine A.
    Univ N Carolina, NC 27515 USA.
    Benz, Christopher C.
    Buck Inst Res Aging, CA USA.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Czene, Kamila
    Karolinska Inst, Sweden.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Lindstrom, Linda S.
    Karolinska Inst, Sweden.
    Assessment of Long-term Distant Recurrence-Free Survival Associated With Tamoxifen Therapy in Postmenopausal Patients With Luminal A or Luminal B Breast Cancer2019In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 5, no 9, p. 1304-1309Article in journal (Refereed)
    Abstract [en]

    Key PointsQuestionWhat is the long-term survival associated with tamoxifen therapy for postmenopausal patients with luminal A or luminal B subtype tumors? FindingsThis secondary analysis of the Stockholm Tamoxifen (STO-3) trial of 462 postmenopausal patients with lymph node-negative breast cancer found that patients with luminal A or luminal B tumor subtypes had a long-term risk of distant metastatic breast cancer and benefited from tamoxifen therapy for 15 years and 5 years after diagnosis, respectively. MeaningPatients with luminal A tumor subtype appeared to have a long-term benefit from tamoxifen therapy, and patients with luminal B subtype appeared to have an early benefit from therapy, when the risk of distant metastatic disease was high. This secondary analysis of the Stockholm Tamoxifen (STO-3) clinical trial, which was conducted from 1976 to 1990, assessed the long-term survival associated with tamoxifen therapy in postmenopausal patients with luminal A or B breast cancer tumor subtypes. ImportancePatients with estrogen receptor (ER)-positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood. ObjectiveTo compare the long-term survival from tamoxifen therapy for patients with luminal A or luminal B tumor subtype. Design, Setting, and ParticipantsSecondary analysis of patients from the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, which randomized postmenopausal patients with lymph node-negative breast cancer to receive adjuvant tamoxifen or no endocrine therapy. Tumor tissue sections were assessed in 2014 using immunohistochemistry and Agilent microarrays. Only patients with luminal A or B subtype tumors were evaluated. Complete long-term follow-up data up to the end of the STO-3 trial on December 31, 2012, were obtained from the Swedish National registers. Data analysis for the secondary analysis was conducted in 2017 and 2018. InterventionsPatients were randomized to receive at least 2 years of tamoxifen therapy or no endocrine therapy; patients without recurrence who reconsented were further randomized to 3 additional years of tamoxifen therapy or no endocrine therapy. Main Outcomes and MeasuresDistant recurrence-free interval (DRFI) by luminal A and luminal B subtype and trial arm was assessed by Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs) that were adjusted for patient and tumor characteristics. ResultsIn the STO-3 treated trial arm, 183 patients had luminal A tumors and 64 patients had luminal B tumors. In the untreated arm, 153 patients had luminal A tumors and 62 had luminal B tumors. Age at diagnosis ranged from 45 to 73 years. A statistically significant difference in DRFI by trial arm was observed (log rank, Pamp;lt;.001 [luminal A subtype, n=336], P=.04 [luminal B subtype, n=126]): the 25-year DRFI for luminal A vs luminal B subtypes was 87% (95% CI, 82%-93%) vs 67% (95% CI, 56%-82%) for treated patients, and 70% (95% CI, 62%-79%) vs 54% (95% CI, 42%-70%) for untreated patients, respectively. Patients with luminal A tumors significantly benefited from tamoxifen therapy for 15 years after diagnosis (HR, 0.57; 95% CI, 0.35-0.94), and those with luminal B tumors benefited from tamoxifen therapy for 5 years (HR, 0.38; 95% CI, 0.24-0.59). Conclusions and RelevancePatients with luminal A subtype tumors had a long-term risk of distant metastatic disease, which was reduced by tamoxifen treatment, whereas patients with luminal B tumors had an early risk of distant metastatic disease, and tamoxifen benefit attenuated over time.

  • 17.
    Ekholm, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Dept Oncol, Jönköping, Sweden; Lund Univ, Sweden.
    Bendahl, P. O.
    Lund Univ, Sweden.
    Ferno, M.
    Lund Univ, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ryden, L.
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Effects of adjuvant tamoxifen over three decades on breast cancerefree and distant recurrence-free interval among premenopausal women with oestrogen receptor-positive breast cancer randomised in the Swedish SBII:2pre trial2019In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 110, p. 53-61Article in journal (Refereed)
    Abstract [en]

    Aims: The primary aim was to compare 2 years of adjuvant tamoxifen versus no systemic treatment in premenopausal patients with oestrogen receptor (ER) epositive tumours, regarding breast cancerefree interval (BCFi) and distant recurrenceefree interval (D-RFi), with 30 years of follow-up and for specified intervals. Moreover, we aimed to investigate the effects of adjuvant tamoxifen on the incidence of secondary malignancies and survival after distant recurrence. Methods: Premenopausal patients with primary breast cancer were randomised to 2 years of tamoxifen (n=277) or no systemic treatment (n=287), irrespective of ER status. Information regarding events was collected by a review of medical records and from national registers. Results: The median follow-up for all patients without events was 28 years, and only four of the patients alive had a follow-up of amp;lt;20 years. With 30 years of follow-up, tamoxifen prolonged BCFi in the intention-to-treat population (hazard ratio [HR] = 0.76, 95% confidence interval (CI) 0.61-0.94, p = 0.011) compared with no treatment. In patients with ER-positive tumours (n = 362), tamoxifen prolonged BCFi (HR = 0.62, 95% CI 0.47-0.82, p = 0.001) and D-RFi (HR = 0.73, 95% CI 0.54-0.99, p = 0.043). The positive effect on BCFi was significant also for the interval amp;gt; 15-30 years (HR = 0.53, 95% CI 0.28-0.98, p = 0.042). For patients with ER-positive tumours who were diagnosed with distant recurrence (n=165), survival after distant recurrence was shorter among tamoxifen-treated patients (median, 29 months versus 43 months). The incidence of contralateral breast cancer was 42% lower in the tamoxifen group (HR=0.58, 95% CI 0.35-0.96, p=0.035), whereas no differences were observed regarding other secondary malignancies. Conclusions: With three decades of follow-up, 2 years of adjuvant tamoxifen reduced the incidence of breast cancererelated events and distant recurrence, and the carryover effect seems to extend beyond 15 years. Moreover, adjuvant tamoxifen seems to be associated with shorter survival after diagnosis of distant recurrence. (C) 2019 The Authors. Published by Elsevier Ltd.

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  • 18.
    Ellegård, Sander
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Veenstra, Cynthia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Pérez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fagerström, Victor
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Department of Surgery, Kalmar Hospital, Kalmar.
    Gårsjö, Jon
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Gert, Krista
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sundquist, Marie
    Department of Surgery, Kalmar Hospital, Kalmar.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Wingren, Sten
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab2019In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 17, no 3, p. 3371-3381Article in journal (Refereed)
    Abstract [en]

    Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linkoping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of amp;gt;= 6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (amp;gt;= 3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.

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  • 19.
    Karlsson, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Veenstra, Cynthia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Gårsjö, Jon
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    PTPN2 deficiency along with activation of nuclear Akt predict endocrine resistance in breast cancer2019In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 145, no 3, p. 599-607Article in journal (Refereed)
    Abstract [en]

    Purpose The protein tyrosine phosphatase, non-receptor type 2 (PTNP2) regulates receptor tyrosine kinase signalling, preventing downstream activation of intracellular pathways like the PI3K/Akt pathway. The gene encoding the protein is located on chromosome 18p11; the 18p region is commonly deleted in breast cancer. In this study, we aimed to evaluate PTPN2 protein expression in a large breast cancer cohort, its possible associations to PTPN2 gene copy loss, Akt activation, and the potential use as a clinical marker in breast cancer. Methods PTPN2 protein expression was analysed by immunohistochemistry in 664 node-negative breast tumours from patients enrolled in a randomised tamoxifen trial. DNA was available for 146 patients, PTPN2 gene copy number was determined by real-time PCR. Results PTPN2 gene loss was detected in 17.8% of the tumours. Low PTPN2 protein expression was associated with higher levels of nuclear-activated Akt (pAkt-n). Low PTPN2 as well as the combination variable low PTPN2/high pAkt-n could be used as predictive markers of poor tamoxifen response. Conclusion PTPN2 negatively regulates Akt signalling and loss of PTPN2 protein along with increased pAkt-n is a new potential clinical marker of endocrine treatment efficacy, which may allow for further tailored patient therapies.

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  • 20.
    Veenstra, Cynthia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Mirwani, Sanam Mirwani
    Linköping University, Department of Clinical and Experimental Medicine. 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 Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Perez Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    The effects of PTPN2 loss on cell signalling and clinical outcome in relation to breast cancer subtype2019In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 145, no 7, p. 1845-1856Article in journal (Refereed)
    Abstract [en]

    PurposeThe protein tyrosine phosphatase PTPN2 dephosphorylates several tyrosine kinases in cancer-related signalling pathways and is thought to be a tumour suppressor. As PTPN2 is not frequently studied in breast cancer, we aimed to explore the role of PTPN2 and the effects of its loss in breast cancer.MethodsProtein expression and gene copy number of PTPN2 were analysed in a cohort of pre-menopausal breast cancer patients with immunohistochemistry and droplet digital PCR, respectively. PTPN2 was knocked down in three cell lines, representing different breast cancer subtypes, with siRNA transfection. Several proteins related to PTPN2 were analysed with Western blot.ResultsLow PTPN2 protein expression was found in 50.2% of the tumours (110/219), gene copy loss in 15.4% (33/214). Low protein expression was associated with a higher relapse rate in patients with Luminal A and HER2-positive tumours, but not triple-negative tumours. In vitro studies further suggested a subtype-specific role of PTPN2. Knockdown of PTPN2 had no effect on the triple-negative cell line, whilst knockdown in MCF7 inhibited phosphorylation of Met and promoted that of Akt. Knockdown in SKBR3 led to increased Met phosphorylation and decreased Erk phosphorylation as well as EGF-mediated STAT3 activation.ConclusionWe confirm previous studies showing that the PTPN2 protein is lost in half of the breast cancer cases and gene deletion occurs in 15-18% of the cases. Furthermore, the results suggest that the role of PTPN2 is subtype-related and should be further investigated to assess how this could affect breast cancer prognosis and treatment response.

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  • 21.
    Lindstrom, Linda S.
    et al.
    Karolinska Inst, Sweden.
    Yau, Christina
    Univ Calif San Francisco, CA USA; Buck Inst Res Aging, CA USA.
    Czene, Kamila
    Karolinska Inst, Sweden.
    Thompson, Carlie K.
    Univ Calif San Francisco, CA USA.
    Hoadley, Katherine A.
    Univ North Carolina Chapel Hill, NC USA.
    vant Veer, Laura J.
    Univ Calif San Francisco, CA 94140 USA; Univ Calif San Francisco, CA 94143 USA.
    Balassanian, Ron
    Univ Calif San Francisco, CA 94140 USA.
    Bishop, John W.
    Univ Calif Davis, CA 95616 USA.
    Carpenter, Philip M.
    Univ Southern Calif, CA USA; Univ Calif Irvine, CA USA.
    Chen, Yunn-Yi
    Univ Calif San Francisco, CA 94140 USA.
    Datnow, Brian
    Univ Calif San Diego, CA 92093 USA.
    Hasteh, Farnaz
    Univ Calif San Diego, CA 92093 USA.
    Krings, Gregor
    Univ Calif San Francisco, CA 94140 USA.
    Lin, Fritz
    Univ Calif Irvine, CA USA.
    Zhang, Yanhong
    Univ Calif Davis, CA 95616 USA.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Benz, Christopher C.
    Univ Calif San Francisco, CA USA; Buck Inst Res Aging, CA USA.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Borowsky, Alexander D.
    Univ Calif Davis, CA 95616 USA.
    Esserman, Laura J.
    Univ Calif San Francisco, CA USA.
    Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer2018In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 110, no 7, p. 726-733, article id djx270Article in journal (Refereed)
    Abstract [en]

    Background: Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods: The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Raos quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results: A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P amp;lt; .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio (HR] = 1.98, 95% confidence interval (CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI -1.18 to 4.99). Conclusions: Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors.

  • 22.
    Forsare, Carina
    et al.
    Lund Univ, Sweden.
    Bak, Martin
    Odense Univ Hosp, Denmark.
    Falck, Anna-Karin
    Helsingborg Hosp, Sweden.
    Grabau, Dorthe
    Lund Univ, Sweden.
    Killander, Fredrika
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Malmstrom, Per
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sundqvist, Marie
    Cty Hosp, Sweden.
    Bendahl, Par-Ola
    Lund Univ, Sweden.
    Ferno, Marten
    Lund Univ, Sweden.
    Non-linear transformations of age at diagnosis, tumor size, and number of positive lymph nodes in prediction of clinical outcome in breast cancer2018In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, article id 1226Article in journal (Refereed)
    Abstract [en]

    BackgroundPrognostic factors in breast cancer are often measured on a continuous scale, but categorized for clinical decision-making. The primary aim of this study was to evaluate if accounting for continuous non-linear effects of the three factors age at diagnosis, tumor size, and number of positive lymph nodes improves prognostication. These factors will most likely be included in the management of breast cancer patients also in the future, after an expected implementation of gene expression profiling for adjuvant treatment decision-making.MethodsFour thousand four hundred forty seven and 1132 women with primary breast cancer constituted the derivation and validation set, respectively. Potential non-linear effects on the log hazard of distant recurrences of the three factors were evaluated during 10years of follow-up. Cox-models of successively increasing complexity: dichotomized predictors, predictors categorized into three or four groups, and predictors transformed using fractional polynomials (FPs) or restricted cubic splines (RCS), were used. Predictive performance was evaluated by Harrells C-index.ResultsUsing FP-transformations, non-linear effects were detected for tumor size and number of positive lymph nodes in univariable analyses. For age, non-linear transformations did, however, not improve the model fit significantly compared to the linear identity transformation. As expected, the C-index increased with increasing model complexity for multivariable models including the three factors. By allowing more than one cut-point per factor, the C-index increased from 0.628 to 0.674. The additional gain, as measured by the C-index, when using FP- or RCS-transformations was modest (0.695 and 0.696, respectively). The corresponding C-indices for these four models in the validation set, based on the same transformations and parameter estimates from the derivation set, were 0.675, 0.700, 0.706, and 0.701.ConclusionsCategorization of each factor into three to four groups was found to improve prognostication compared to dichotomization. The additional gain by allowing continuous non-linear effects modeled by FPs or RCS was modest. However, the continuous nature of these transformations has the advantage of making it possible to form risk groups of any size.

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  • 23.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Alayev, Anya
    Yeshiva Univ, NY 10033 USA.
    Berman, Adi Y.
    Yeshiva Univ, NY 10033 USA.
    Fornander, Tommy
    Karolinska Inst, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Holz, Marina K.
    Yeshiva Univ, NY 10033 USA; Albert Einstein Coll Med, NY 10467 USA; Albert Einstein Coll Med, NY 10467 USA.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer2018In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, no 1, p. 17-27Article in journal (Refereed)
    Abstract [en]

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

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  • 24.
    Zardavas, Dimitrios
    et al.
    Breast Int Grp, Belgium.
    te Marvelde, Luc
    Canc Council, Australia.
    Milne, Roger L.
    Canc Council, Australia; Univ Melbourne, Australia.
    Fumagalli, Debora
    Breast Int Grp, Belgium.
    Fountzilas, George
    Aristotle Univ Thessaloniki, Greece.
    Kotoula, Vassiliki
    Aristotle Univ Thessaloniki, Greece.
    Razis, Evangelia
    Hygeia Hosp, Greece.
    Papaxoinis, George
    Hippokrateion Hosp, Greece.
    Joensuu, Heikki
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Moynahan, Mary Ellen
    Mem Sloan Kettering Canc Ctr, NY 10021 USA.
    Hennessy, Bryan T.
    Beaumont Hosp, Ireland; Royal Coll Surg, Ireland.
    Bieche, Ivan
    Curie Inst, France.
    Saal, Lao H.
    Lund Univ, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Iacopetta, Barry
    Univ Western Australia, Australia.
    Jensen, Jeanette Dupont
    Univ Southern Denmark, Denmark.
    OToole, Sandra
    Garvan Inst Med Res, Australia.
    Lopez-Knowles, Elena
    Garvan Inst Med Res, Australia; Royal Marsden NHS Trust, England; Inst Canc Res, England.
    Barbaraeschi, Mattia
    Santa Chiara Hosp, Italy.
    Noguchi, Shinzaburo
    Osaka Univ, Japan.
    Azim, Hatem A. Jr.
    Amer Univ Beirut, Lebanon.
    Lerma, Enrique
    Univ Autonoma Barcelona, Spain.
    Bachelot, Thomas
    Ctr Rech Cancerol Lyon, France.
    Wang, Qing
    Linköping University.
    Perez Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    de Velde, Cornelis J. H. Can
    Leiden Univ, Netherlands.
    Rea, Daniel W.
    Univ Birmingham, England.
    Sabine, Vicky
    Univ Guelph, Canada.
    Bartlett, John M. S.
    Ontario Inst Canc Res, Canada.
    Sotiriou, Christos
    Univ Libre Bruxelles, Belgium.
    Michiels, Stefan
    Gustave Roussy, France; Univ Paris Saclay, France.
    Loi, Sherene
    Univ Melbourne, Australia.
    Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data2018In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, no 10, p. 981-+Article in journal (Refereed)
    Abstract [en]

    PurposePhosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data.Patients and MethodsAssociations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes.ResultsData from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P amp;lt; .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P amp;lt; .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P amp;lt; .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); amp;gt; 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS (P = .043), but not for the DDFS and OS end points.ConclusionIn this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors. (C) 2018 by American Society of Clinical Oncology

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  • 25.
    Blockhuys, S.
    et al.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Celauro, E.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Feizi, A.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fierro-González, J.C.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Wittung-Stafshede, P.
    Department Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden .
    Defining the human copper proteome and analysis of its expression variation in cancers.2017In: Metallomics : integrated biometal science, ISSN 1756-591X, Vol. 9, no 2, p. 112-123Article in journal (Refereed)
    Abstract [en]

    Copper (Cu) is essential for living organisms, and acts as a cofactor in many metabolic enzymes. To avoid the toxicity of free Cu, organisms have specific transport systems that 'chaperone' the metal to targets. Cancer progression is associated with increased cellular Cu concentrations, whereby proliferative immortality, angiogenesis and metastasis are cancer hallmarks with defined requirements for Cu. The aim of this study is to gather all known Cu-binding proteins and reveal their putative involvement in cancers using the available database resources of RNA transcript levels. Using the database along with manual curation, we identified a total of 54 Cu-binding proteins (named the human Cu proteome). Next, we retrieved RNA expression levels in cancer versus normal tissues from the TCGA database for the human Cu proteome in 18 cancer types, and noted an intricate pattern of up- and downregulation of the genes in different cancers. Hierarchical clustering in combination with bioinformatics and functional genomics analyses allowed for the prediction of cancer-related Cu-binding proteins; these were specifically inspected for the breast cancer data. Finally, for the Cu chaperone ATOX1, which is the only Cu-binding protein proposed to have transcription factor activities, we validated its predicted over-expression in patient breast cancer tissue at the protein level. This collection of Cu-binding proteins, with RNA expression patterns in different cancers, will serve as an excellent resource for mechanistic-molecular studies of Cu-dependent processes in cancer.

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  • 26.
    Hilborn, Erik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Estrogen and androgen-converting enzymes 17 beta-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17 beta-hydroxysteroid dehydrogenase type 1, 2, and breast cancer2017In: Oncotarget, E-ISSN 1949-2553, Vol. 8, no 18, p. 30552-30562Article, review/survey (Refereed)
    Abstract [en]

    Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex steroids is determined by the availability from the circulation, and on local conversion. This conversion is primarily mediated by aromatase, steroid sulfatase, and 17 beta-hydroxysteroid dehydrogenases. In postmenopausal women, this is the primary source of estrogens in the breast. Up to 70-80% of all breast cancers express the estrogen receptor-a, responsible for promoting the growth of the tissue. Further, 60-80% express the androgen receptor, which has been shown to have tissue protective effects in estrogen receptor positive breast cancer, and a more ambiguous response in estrogen receptor negative breast cancers. In this review, we summarize the function and clinical relevance in cancer for 17 beta-hydroxysteroid dehydrogenases 1, which facilitates the reduction of estrone to estradiol, dehydroepiandrosterone to androstendiol and dihydrotestosterone to 3 alpha- and 3 beta-diol as well as 17 beta-hydroxysteroid dehydrogenases 2 which mediates the oxidation of estradiol to estrone, testosterone to androstenedione and androstendiol to dehydroepiandrosterone. The expression of 17 beta-hydroxysteroid dehydrogenases 1 and 2 alone and in combination has been shown to predict patient outcome, and inhibition of 17 beta-hydroxysteroid dehydrogenases 1 has been proposed to be a prime candidate for inhibition in patients who develop aromatase inhibitor resistance or in combination with aromatase inhibitors as a first line treatment. Here we review the status of inhibitors against 17 beta-hydroxysteroid dehydrogenases 1. In addition, we review the involvement of 17 beta-hydroxysteroid dehydrogenases 4, 5, 7, and 14 in breast cancer.

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  • 27.
    Paulsson, Janna
    et al.
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Rydén, Lisa
    Division of Surgery, Department of Clinical Sciences Lund UniversityLundSweden; Department of Surgery Skåne University Hospital Lund, Sweden.
    Strell, Carina
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Frings, Oliver
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Tobin, Nicholas P
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Fornander, Tommy
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    Bergh, Jonas
    Department of Oncology-PathologyCancer Center Karolinska, Karolinska InstitutetStockholmSweden; Radiumhemmet, Karolinska University Hospital Stockholm, Sweden.
    Landberg, Göran
    Department of Pathology Sahlgrenska Cancer Centre, University of Gothenburg Gothenburg, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Östman, Arne
    Department of Oncology-Pathology Cancer Center Karolinska, Karolinska Institutet Stockholm, Sweden.
    High expression of stromal PDGFRß is associated with reduced benefit of tamoxifen in breast cancer2017In: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 3, no 1, p. 38-43Article in journal (Refereed)
    Abstract [en]

    Cancer-associated fibroblasts (CAFs) regulate tumour growth, metastasis and response to treatment. Recent studies indicate the existence of functionally distinct CAF subsets. Suggested mechanisms whereby CAFs can impact on treatment response include paracrine signalling affecting cancer cell drug sensitivity and effects on tumour drug uptake. PDGFRß is an important regulator of fibroblasts. Experimental studies have linked PDGFRß-positive fibroblasts to metastasis and also to reduced tumour drug uptake. This study has investigated the potential role of PDGFRß-positive fibroblasts in response to adjuvant tamoxifen treatment of breast cancer. Analyses of two breast cancer collections from randomised studies analysing adjuvant tamoxifen treatment in early breast cancer demonstrated significant benefit of tamoxifen in the group with low stromal PDGFRß, which was not observed in the group with high stromal PDGFRß. In general terms these findings provide novel evidence, derived from analyses of randomised clinical studies, of response-predictive capacity of a marker-defined subset of CAFs and, more specifically, identify stromal PDGFRß as a marker related to tamoxifen benefit in early breast cancer.

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  • 28.
    Ehinger, Anna
    et al.
    Lund University, Sweden; Blekinge County Hospital, Sweden.
    Malmstrom, Per
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Bendahl, Pär-Ola
    Lund University, Sweden.
    Elston, Christopher W.
    Nottingham University Hospital NHS Trust, England.
    Falck, Anna-Karin
    Helsingborg Hospital, Sweden.
    Forsare, Carina
    Lund University, Sweden.
    Grabau, Dorthe
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Ryden, Lisa
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ferno, Marten
    Lund University, Sweden.
    Histological grade provides significant prognostic information in addition to breast cancer subtypes defined according to St Gallen 20132017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 1, p. 68-74Article in journal (Refereed)
    Abstract [en]

    Background: The St Gallen surrogate definition of the intrinsic subtypes of breast cancer consist of five subgroups based on estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki-67. PgR and Ki-67 are used for discriminating between the Luminal A-like and Luminal B-like (HER2-negative) subtypes. Histological grade (G) has prognostic value in breast cancer; however, its relationship to the St Gallen subtypes is not clear. Based on a previous pilot study, we hypothesized that G could be a primary discriminator for ER-positive/HER2-negative breast cancers that were G1 or G3, whereas Ki-67 and PgR could provide additional prognostic information specifically for patients with G2 tumors. To test this hypothesis, a larger patient cohort was examined. Patients and methods: Six hundred seventy-one patients (amp;gt;= 35 years of age, pT1-2, pN0-1) with ER-positive/HER2-negative breast cancer and complete data for PgR, Ki-67, G, lymph node status, tumor size, age, and distant disease-free survival (DDFS; median follow-up 9.2 years) were included. Results: Luminal A-like tumors were mostly G1 or G2 (90%) whereas Luminal B-like tumors were mostly G2 or G3 (87%) and corresponded with good and poor DDFS, respectively. In Luminal B-like tumors that were G1 (n = 23), no metastasis occurred, whereas 14 of 40 Luminal A-like tumors that were G3 metastasized. In the G2 subgroup, low PgR and high Ki-67 were associated with an increased risk of distant metastases, hazard ratio (HR) and 95% confidence interval (CI) 1.8 (0.95-3.4) and 1.5 (0.80-2.8), respectively. Conclusions: Patients with ER-positive/HER2-negative/G1 breast cancer have a good prognosis, similar to that of Luminal A-like, while those with ER-positive/HER2-negative/G3 breast cancer have a worse prognosis, similar to that of Luminal B-like, when assessed independently of PgR and Ki-67. Therapy decisions based on Ki-67 and PgR might thus be restricted to the subgroup G2.

  • 29.
    Rosell, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Business support and Development, Regional Cancer Center.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bengtsson, Nils-Olof
    Umeå University Hospital, Sweden.
    Fornander, Tommy
    Karolinska University Hospital, Sweden.
    Hatschek, Thomas
    Karolinska University Hospital, Sweden.
    Lindman, Henrik
    Uppsala University 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 Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, 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 Medicine and Health Sciences.
    Long-term effects on the incidence of second primary cancers in a randomized trial of two and five years of adjuvant tamoxifen2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 4, p. 614-617Article in journal (Refereed)
    Abstract [en]

    Background: Tamoxifen is a well established treatment for breast cancer, but its long-term effects on the incidence of secondary cancers are not fully evaluated.Material and methods: We have studied 4128 postmenopausal patients with early stage breast cancer who were alive and free of breast cancer recurrence after two years of tamoxifen, and who were randomized to receive totally two or five years of therapy.Results: Compared to patients randomized to two years of tamoxifen the incidence of contralateral breast cancer [hazard ratio (HR) 0.73; 95% CI 0.56-0.96] and of lung cancer (HR 0.45; 95% CI 0.27-0.77), especially squamous cell and small cell lung cancer, were reduced in the five-year group, and similar results were seen when restricting the analysis to the 10-year period after treatment stopped. An increased incidence of endometrial cancer was observed in the five-year group, but the excess risk decreased over time.Conclusion: Further studies of the effects of tamoxifen on the risk of different histological types of lung cancer are needed.

  • 30.
    Schroeder, Brock
    et al.
    Biotheranostics, Inc., San Diego, CA USA.
    Zhang, Yi
    Biotheranostics, Inc., San Diego, CA USA.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Institute, Stockholm, Sweden.
    Brufsky, Adam
    University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
    Sgroi, Dennis C
    Massachusetts General Hospital, Boston, MA USA.
    Schnabel, Catherine A.
    Biotheranostics, Inc., San Diego, CA USA.
    Risk stratification with Breast Cancer Index for late distant recurrence in patients with clinically low-risk (T1N0) estrogen receptor-positive breast cancer2017In: npj Breast Cancer, E-ISSN 2374-4677, Vol. 3Article in journal (Refereed)
    Abstract [en]

    Patients with early-stage, hormone receptor-positive breast cancer with favorable clinicopathologic features are often not recommended for extended endocrine therapy. However, even patients with T1N0 disease remain at significant risk of distant recurrence up to 15 years following 5 years of endocrine therapy, highlighting the need for further stratification based on individualized risk to select patients for extended endocrine therapy. In this study, the incremental utility of genomic classification to stratify clinically low-risk patients for late distant recurrence was evaluated using the Breast Cancer Index. In 547 T1N0 patients from two cohorts that were disease-free at 5 years post-diagnosis, Breast Cancer Index categorized 32 and 36% from each cohort, respectively, with high risk of late distant recurrence that was associated with significantly reduced distant recurrence-free survival (86.7 and 89.6%) between years 5-15 and 5-10 compared to Breast Cancer Index low risk (95.4%; P?=?0.0263 and 98.4%; P?=?0.008). Findings support consideration of genomic classification in clinically low-risk hormone receptor-positive patients to identify candidates for extended endocrine therapy.

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  • 31.
    van t Veer, Laura J.
    et al.
    University of Calif San Francisco, CA 94115 USA.
    Yau, Christina
    University of Calif San Francisco, CA 94115 USA; Buck Institute Research Aging, CA 94945 USA.
    Yu, Nancy Y.
    Karolinska Institute, Sweden.
    Benz, Christopher C.
    Buck Institute Research Aging, USA; University of Calif San Francisco,USA.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Institute, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Esserman, Laura J.
    University of Calif San Francisco, CA 94115 USA.
    Sofie Lindstrom, Linda
    Karolinska Institute, Sweden.
    Tamoxifen therapy benefit for patients with 70-gene signature high and low risk2017In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 166, no 2, p. 593-601Article in journal (Refereed)
    Abstract [en]

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

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  • 32.
    Hilborn, Erik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Alexeyenko, Andrey
    Karolinska Institute, Sweden; National Bioinformat Infrastruct Sweden, Sweden.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    The regulation of hydroxysteroid 17 beta-dehydrogenase type 1 and 2 gene expression in breast cancer cell lines by estradiol, dihydrotestosterone, microRNAs, and genes related to breast cancer2017In: Oncotarget, E-ISSN 1949-2553, Vol. 8, no 37, p. 62183-62194Article in journal (Refereed)
    Abstract [en]

    Aim. To investigate the influence of estrogen, androgen, microRNAs, and genes implicated in breast cancer on the expression of HSD17B1 and HSD17B2. Materials. Breast cancer cell lines ZR-75-1, MCF7, T47D, SK-BR-3, and the immortalized epithelial cell line MCF10A were used. Cells were treated either with estradiol or dihydrotestosterone for 6, 24, 48 hours, or 7 days or treated with miRNAs or siRNAs predicted to influence HSD17B expression Results and discussion. Estradiol treatment decreased HSD17B1 expression and had a time-dependent effect on HSD17B2 expression. This effect was lost in estrogen receptor-alpha down-regulated or negative cell lines. Dihydrotestosterone treatment increased HSD17B2 expression, with limited effect on HSD17B1 expression. No effect was seen in cells without AR or in combination with the AR inhibitor hydroxyflutamide. The miRNA-17 up-regulated HSD17B1, while miRNA-210 and miRNA-7-5p had up- and down-regulatory effect and miRNA-1304-3p reduced HSD17B1 expression. The miRNA-204-5p, 498, 205-3p and 579-3p reduced HSD17B2 expression. Downregulation of CX3CL1, EPHB6, and TP63 increased HSD17B1 and HSD17B2 expression, while GREB1 downregulation suppressed HSD17B1 and promoted HSD17B2 expression. Conclusion. We show that HSD17B1 and HSD17B2 are controlled by estradiol, dihydrotestosterone, and miRNAs, as well as modulated by several breast cancer-related genes, which could have future clinical applications.

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  • 33.
    Esserman, Laura J.
    et al.
    University of Calif San Francisco, CA 94115 USA.
    Yau, Christina
    University of Calif San Francisco, CA 94115 USA; Buck Institute Research Aging, CA USA.
    Thompson, Carlie K.
    University of Calif San Francisco, CA 94115 USA.
    vant Veer, Laura J.
    University of Calif San Francisco, CA 94115 USA.
    Borowsky, Alexander D.
    University of Calif Davis, CA 95616 USA.
    Hoadley, Katherine A.
    University of N Carolina, NC USA.
    Tobin, Nicholas P.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Benz, Christopher C.
    University of Calif San Francisco, CA 94115 USA; Buck Institute Research Aging, CA USA.
    Lindstrom, Linda S.
    University Hospital, Sweden; Karolinska Institute, Sweden.
    Use of Molecular Tools to Identify Patients With Indolent Breast Cancers With Ultralow Risk Over 2 Decades2017In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 3, no 11, p. 1503-1510Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE The frequency of cancers with indolent behavior has increased with screening. Better tools to identify indolent tumors are needed to avoid overtreatment. OBJECTIVE To determine if a multigene classifier is associated with indolent behavior of invasive breast cancers in women followed for 2 decades. DESIGN, SETTING, AND PARTICIPANTS This is a secondary analysis of a randomized clinical trial of tamoxifen vs no systemic therapy, with more than 20-year follow-up. An indolent threshold (ultralow risk) of the US Food and Drug Administration-cleared MammaPrint 70-gene expression score was established above which no breast cancer deaths occurred after 15 years in the absence of systemic therapy. Immunohistochemical markers (n = 727 women) and Agilent microarrays, for MammaPrint risk scoring (n = 652 women), were performed from formalin-fixed paraffin-embedded primary tumor blocks. Participants were postmenopausal women with clinically detected node-negative breast cancers treated with mastectomy or lumpectomy and radiation enrolled in the Stockholm tamoxifen (STO-3) trial, 1976 to 1990. EXPOSURES After 2 years of tamoxifen vs no systemic therapy, regardless of hormone receptor status, patients without relapse who reconsented were further randomized to 3 additional years or none. MAIN OUTCOMES AND MEASURES Breast cancer-specific survival assessed by Kaplan-Meier analyses and multivariate Cox proportional hazard modeling, adjusted for treatment, patient age, year of diagnosis, tumor size, grade, hormone receptors, and ERBB2/HER2 and Ki67 status. RESULTS In this secondary analysis of node-negative postmenopausal women, conducted in the era before mammography screening, among the 652 women with MammaPrint scoring available (median age, 62.8 years of age), 377 (58%) and 275 (42%) were MammaPrint low and high risk, respectively, while 98 (15%) were ultralow risk. At 20 years, women with 70-gene high and low tumors but not ultralow tumors had a significantly higher risk of disease-specific death compared with ultralow-risk patients by Cox analysis (hazard ratios, 4.73 [95% CI, 1.38-16.22] and 4.54 [95% CI, 1.40-14.80], respectively). There were no deaths in the ultralow-risk tamoxifen-treated arm at 15 years, and these patients had a 20-year disease-specific survival rate of 97%, whereas for untreated patients the survival rate was 94%. Recursive partitioning identified ultralow risk as the most significant predictor of good outcome. In tumors "not ultralow risk," tumor size greater than 2 cm was the most predictive of outcome. CONCLUSIONS AND RELEVANCE The ultralow-risk threshold of the 70-gene MammaPrint assay can identify patients whose long-term systemic risk of death from breast cancer after surgery alone is exceedingly low.

  • 34.
    Hilborn, Erik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Gacic, Jelena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Fornander, Tommy
    Karolinska Institute, Sweden.
    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.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-alpha-negative breast cancer2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 114, no 3, p. 248-255Article in journal (Refereed)
    Abstract [en]

    Background: Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining tamoxifen treatment efficiency requires evaluation. Purpose: To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer. Methods Patients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow-up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point. Results: In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR) = 0.34; 95% confidence interval (CI) = 0.14-0.81; P = 0.015), whereas the opposite was seen in the AR- group (HR = 2.92; 95% CI = 1.16-7.31; P = 0.022). Interaction test was significant P < 0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR = 0.12; 95% CI = 0.014-0.95 P = 0.044), whereas patients with AR- tumours had worse outcome when treated with tamoxifen (HR = 3.98; 95% CI = 1.32-12.03; P = 0.014). Interaction test was significant P = 0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression. Conclusions: AR can predict tamoxifen treatment benefit in patients with ER- tumours and triple-negative breast cancer.

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  • 35.
    Manna, Subrata
    et al.
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Bostner, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Sun, Yang
    Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
    Miller, Lance D
    Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina. The Comprehensive Cancer Center of Wake Forest University, Winston Salem, North Carolina, USA.
    Alayev, Anya
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Schwartz, Naomi S
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York, USA.
    Lager, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm South General Hospital, Karolinska Institute, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Yu, Jane J
    Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Holz, Marina K
    Department of Biology; Stern College for Women of Yeshiva University; New York, New York. Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York, USA.
    ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer.2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 6, p. 1421-1431Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Estrogen-related receptor alpha (ERRα) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERRα in randomized cohorts of tamoxifen-treated and adjuvant-untreated patients.

    EXPERIMENTAL DESIGN: Cox proportional hazards regression was used to evaluate the significance of associations between ERRα gene expression levels and patient DMFS in a previously published microarray dataset representing 2,000 breast tumor cases derived from multiple medical centers worldwide. The 912 tumors used for immunostaining were from a tamoxifen-randomized primary breast cancer trial conducted in Stockholm, Sweden, during 1976-1990. Mouse model was used to study the effect of tamoxifen treatment on lung colonization of MDA-MB-231 control cells and MDA-MB-231 cells with stable knockdown of ERRα. The phenotypic effects associated with ERRα modulation were studied using immunoblotting analyses and wound-healing assay.

    RESULTS: We found that in ER-negative and triple-negative breast cancer (TNBC) adjuvant-untreated patients, ERRα expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERRα gene and protein expression. Reduced ERRα expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies.

    CONCLUSION: Taken together, these data show that ERRα expression predicts response to tamoxifen treatment, and ERRα could be a biomarker of tamoxifen sensitivity and a prognostic factor in TNBC. Clin Cancer Res; 1-11. ©2015 AACR.

  • 36.
    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, 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.

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  • 37.
    Gabrielson, Marike
    et al.
    University of Örebro, Sweden; Karolinska Institute, Sweden.
    Reizer, Edwin
    University of Örebro, 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.
    Tina, Elisabet
    University of Örebro, Sweden.
    Mitochondrial regulation of cell cycle progression through SLC25A432016In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 469, no 4, p. 1090-1096Article in journal (Refereed)
    Abstract [en]

    An increasing body of evidence is pointing towards mitochondrial regulation of the cell cycle. In a previous study of HER2-positive tumours we could demonstrate a common loss in the gene encoding for the mitochondrial transporter SLC25A43 and also a significant relation between SLC25A43 protein expression and S-phase fraction. Here, we investigated the consequence of suppressed SLC25A43 expression on cell cycle progression and proliferation in breast epithelial cells. In the present study, we suppressed SLC25A43 using siRNA in immortalised non-cancerous breast epithelial MCF10A cells and HER2-positive breast cancer cells BT-474. Viability, apoptosis, cell proliferation rate, cell cycle phase distribution, and nuclear Ki-67 and p21, were assessed by flow cytometry. Cell cycle related gene expressions were analysed using real-time PCR. We found that SLC25A43 knockdown in MCF10A cells significantly inhibited cell cycle progression during G(1)-to-S transition, thus significantly reducing the proliferation rate and fraction of Ki-67 positive MCF10A cells. In contrast, suppressed SLC25A43 expression in BT-474 cells resulted in a significantly increased proliferation rate together with an enhanced G(1)-to-S transition. This was reflected by an increased fraction of Ki-67 positive cells and reduced level of nuclear p21. In line with our previous results, we show a role for SLC25A43 as a regulator of cell cycle progression and proliferation through a putative mitochondrial checkpoint. These novel data further strengthen the connection between mitochondrial function and the cell cycle, both in non-malignant and in cancer cells. (C) 2015 Elsevier Inc. All rights reserved.

  • 38.
    Nordenskjold, Anna
    et al.
    Sahlgrens Acad, Sweden; Southern Alvsborg Hospital, Sweden.
    Fohlin, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden; Regional Cancer Centre Stockholm Gotland, Sweden.
    Lofdahl, Britta
    St Göran Hospital, Sweden.
    Skoog, Lambert
    Karolinska University Hospital, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Progesterone receptor positivity is a predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer2016In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 160, no 2, p. 313-322Article in journal (Refereed)
    Abstract [en]

    The independent predictive information from progesterone receptor (PgR) positivity for breast cancer treated with tamoxifen has been questioned after an overview by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). However, the studies in the overview were to a large content performed before modern PgR immunohistochemistry (IHC) was developed. We therefore investigated the predictive value of PgR determined with IHC in estrogen receptor (ER)-positive tumors from patients participating in the Stockholm trial of adjuvant tamoxifen therapy. The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. The patients were stratified according to tumor size and lymph node status in high-risk and low-risk groups. In this study, we evaluated 618 patients with ER-positive "low-risk" breast cancer (size aecurrency sign 30 mm, lymph node-negative) for whom PgR was determined by IHC at one pathology laboratory. The median time of follow-up was 21 years. Patients with ER-positive tumors that were also PgR-positive by IHC did benefit from tamoxifen, while we could not show any long-term benefit for those with tumors positive for ER only (recurrence rate ratio 0.43, 95 % CI 0.29-0.62 and 0.87, 95 % CI 0.52-1.46, respectively). We further investigated the influence of different levels of PgR positivity on recurrence risk. The results show that at all receptor levels with aeyen10 % stained PgR-positive cells, the patients did benefit from tamoxifen. There was no clear linear trend in benefit with increasing proportion of stained cells. PgR positivity determined by IHC is a marker indicating long-term benefit from adjuvant tamoxifen in patients with ER-positive tumors.

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  • 39.
    Ekholm, Maria
    et al.
    Lund University, Sweden; Ryhov County Hospital, Sweden.
    Bendahl, Par-Ola
    Lund University, Sweden.
    Ferno, Marten
    Lund University, Sweden.
    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.
    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.
    Ryden, Lisa
    Lund University, Sweden.
    Two Years of Adjuvant Tamoxifen Provides a Survival Benefit Compared With No Systemic Treatment in Premenopausal Patients With Primary Breast Cancer: Long-Term Follow-Up (> 25 years) of the Phase III SBII:2pre Trial2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 19, p. 2232-+Article in journal (Refereed)
    Abstract [en]

    Purpose The aim of this study was to evaluate the long-term effect of 2 years of adjuvant tamoxifen compared with no systemic treatment (control) in premenopausal patients with breast cancer over different time periods through long-term (amp;gt; 25 years) follow-up. Patients and Methods Premenopausal patients with primary breast cancer (N = 564) were randomly assigned to 2 years of tamoxifen (n = 276) or no systemic treatment (n = 288). Data regarding date and cause of death were obtained from the Swedish Cause of Death Register. End points were cumulative mortality (CM) and cumulative breast cancer-related mortality (CBCM). The median follow-up for the 250 patients still alive in April 2014 was 26.3 years (range, 22.7 to 29.7 years). Results In patients with estrogen receptor-positive tumors (n = 362), tamoxifen was associated with a marginal reduction in CM (hazard ratio [HR], 0.77; 95% CI, 0.58 to 1.03; P = .075) and a significant reduction in CBCM (HR, 0.73; 95% CI, 0.53 to 0.99; P = .046). The effect seemed to vary over time (CM years 0 to 5: HR, 1.05; 95% CI, 0.64 to 1.73; years amp;gt;5 to 15: HR, 0.58; 95% CI, 0.37 to 0.91; and after 15 years: HR, 0.82; 95% CI, 0.48 to 1.42; CBCM years 0 to 5: HR, 1.09; 95% CI, 0.65 to 1.82; years amp;gt;5 to 15: HR, 0.53; 95% CI, 0.33 to 0.86; and after 15 years: HR, 0.72; 95% CI, 0.36 to 1.44). Conclusion Two years of adjuvant tamoxifen resulted in a long-term survival benefit in premenopausal patients with estrogen receptor-positive primary breast cancer. (C) 2016 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/

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  • 40.
    Gothlin Eremo, Anna
    et al.
    University of Örebro, Sweden.
    Tina, Elisabet
    Örebro University Hospital, Sweden.
    Wegman, Pia
    Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    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.
    Fransen, Karin
    University of Örebro, Sweden.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Regional Cancer Centre Stockholm Gotland, Sweden.
    Wingren, Sten
    University of Örebro, Sweden.
    HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen2015In: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed)
    Abstract [en]

    The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (Pless than0.0005), PgR-negativity (Pless than0.0005), tumor size greater than20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

  • 41.
    Karlsson, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Veenstra, Cynthia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Emin, Shad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dutta, Chhanda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fornander, Tommy
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer2015In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 153, no 1, p. 31-40Article in journal (Refereed)
    Abstract [en]

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

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  • 42.
    Busch, Susann
    et al.
    Gothenburg University, Sweden.
    Sims, Andrew H.
    University of Edinburgh, Scotland.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ferno, Marten
    Lund University, Sweden.
    Landberg, Goran
    Gothenburg University, Sweden; University of Manchester, England.
    Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 7, p. 1457-1469Article in journal (Refereed)
    Abstract [en]

    One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease.

  • 43.
    Bojmar, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Zhang, Haiying
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Costa da Silva, Bruno
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Karlsson, Elin
    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.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Vincent, Theresa
    Departments of Physiology and Biophysics and Cell and Developmental Biology, Weill Cornell Medical College, New York, USA / Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    Lyden, David
    Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
    Sandström, Per
    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 Surgery in Linköping.
    miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome2015Manuscript (preprint) (Other academic)
    Abstract [en]

    The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast  tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.

  • 44.
    Johansson, Henrik J
    et al.
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Sanchez, Betzabe C
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Forshed, Jenny
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Health Sciences.
    Fohlin, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden. Linköping University, Faculty of Health Sciences.
    Lewensohn, Rolf
    Department of Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
    Hall, Per
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, 17177 Sweden.
    Bergh, Jonas
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Lehtiö, Janne
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden.
    Linderholm, Barbro K
    Department Oncology-Pathology, Cancer Proteomics Mass spectrometry, Science for Life Laboratory, Karolinska Institutet, SE-171 65 Stockholm, Sweden // Department of Oncology, Sahlgrenska Academy and University Hospital, SE-413 45 Gothenburg, Sweden.
    Proteomics profiling identify CAPS as a potential predictive marker of tamoxifen resistance in estrogen receptor positive breast cancer2015In: Clinical Proteomics, ISSN 1542-6416, E-ISSN 1559-0275, Vol. 12, no 1, p. 8-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite the success of tamoxifen since its introduction, about one-third of patients with estrogen (ER) and/or progesterone receptor (PgR) - positive breast cancer (BC) do not benefit from therapy. Here, we aim to identify molecular mechanisms and protein biomarkers involved in tamoxifen resistance.

    RESULTS: Using iTRAQ and Immobilized pH gradient-isoelectric focusing (IPG-IEF) mass spectrometry based proteomics we compared tumors from 12 patients with early relapses (<2 years) and 12 responsive to therapy (relapse-free > 7 years). A panel of 13 proteins (TCEAL4, AZGP1, S100A10, ALDH6A1, AHNAK, FBP1, S100A4, HSP90AB1, PDXK, GFPT1, RAB21, MX1, CAPS) from the 3101 identified proteins, potentially separate relapse from non-relapse BC patients. The proteins in the panel are involved in processes such as calcium (Ca(2+)) signaling, metabolism, epithelial mesenchymal transition (EMT), metastasis and invasion. Validation of the highest expressed proteins in the relapse group identify high tumor levels of CAPS as predictive of tamoxifen response in a patient cohort receiving tamoxifen as only adjuvant therapy.

    CONCLUSIONS: This data implicate CAPS in tamoxifen resistance and as a potential predictive marker.

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  • 45.
    Karlsson, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Magic, Ivana
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bostner, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dyrager, Christine
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lysholm, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Hallbeck, Anna-Lotta
    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.
    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.
    Lundström, Patrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 12, p. e0145013-Article in journal (Refereed)
    Abstract [en]

    Background

    The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.

    Materials and methods

    Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.

    Results

    Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.

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  • 46.
    Bostner, Josefine
    et al.
    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. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bivik Eding, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. 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.
    Franzén, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Konstantinell, Aelita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Fornander, Tommy
    Karolinska University Hospital, Sweden.
    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.
    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.
    S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts2015In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, no 3, p. 331-343Article in journal (Refereed)
    Abstract [en]

    Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, P=0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, Pless than0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, P=0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, P=0.00041 (cytoplasm), P=0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.

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  • 47.
    Hilborn, Erik
    et al.