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  • 1. Bergh, Jonas C. S.
    et al.
    Andersson, Anne
    Bjohle, Judith
    Bosch, Ana
    Carlsson, Lena
    Dreifaldt, Ann Charlotte
    Örebro University, School of Medical Sciences.
    Einbeigi, Zakaria
    Fredholm, Hanna
    Isaksson-Friman, Erika
    Foukakis, Theodoros
    Elinder, Ellinor
    Hellstrom, Mats
    Johansson, Hemming
    Lekberg, Tobias
    Lindman, Henrik
    Maes, Claudia
    Brandberg, Yvonne
    Hatschek, Thomas
    Docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer: Results from the Swedish PREDIX HER2 trial identifying a new potential de-escalation standard?2019In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 37, no 15Article in journal (Other academic)
    Abstract [en]

    Background: Neoadjuvant therapy produces high rates of pathological complete response (pCR) and is the standard of care in HER2 positive breast cancer; however, the optimal treatment regimen remains to be established.

    Methods: In this randomized phase II study patients ≥18 years with HER2 positive breast cancer > 20mm or verified lymph node metastases were randomized to 6 courses of docetaxel, trastuzumab and pertuzumab (DTP, group A) or trastuzumab emtansine (T-DM1, group B), q 21 days. The protocol allowed switch to the competing treatment upon lack of response or drug-related severe toxicity. Patients received postoperative epirubicin+cyclophosphamide, trastuzumab for a total of one year and endocrine therapy. Accrual was completed in October 2018 after randomization of 202 patients, data on pCR were available for 190 at the time for this abstract submission. Median age, 52 years (26-74), menopausal status, histological type and grade were well balanced between the treatment groups. 62.6% of the tumors were hormone receptor (HR) positive.

    Results: Primary endpoint was pathological objective response. 190 patients completed the protocol-specified preoperative treatment. pCR was achieved in 45.3% of patients, 46.4% in patients treated with DTP and 44.1% with T-DM1 (chi-sq., p = 0.75). In HR-positive tumors, pCR was obtained in 35.3% of patients, 35.9% in group A vs. 34.6% in group B (p = 0.87); in HR-negative tumors, the overall pCR rate was 62.0%, 66.7% in group A vs. 57.9% in group B (p = 0.45). Severe (grade 3/4) toxicity was reported at 68 occasions related to DTP, compared with 16 related to T-DM1, 26 vs. 3 caused by febrile neutropenia. Significantly better quality of life was reported by patients treated with T-DM1.

    Conclusions: Our data on TDM-1 demonstrates similar efficacy and less toxicity, in particular for patients with HER2 and HR positive cancers, being a potential new standard for neoadjuvant therapy.

  • 2. Brandberg, Yvonne
    et al.
    Andersson, Anne
    Bjohle, Judith
    Bosch, Ana
    Carlsson, Lena
    Dreifaldt, Ann Charlotte
    Örebro University, School of Medical Sciences.
    Einbeigi, Zakaria
    Fredholm, Hanna
    Isaksson-Friman, Erika
    Foukakis, Theodoros
    Elinder, Ellinor
    Hellström, Mats
    Johansson, Hemming
    Lekberg, Tobias
    Lindman, Henrik
    Bergh, Jonas C. S.
    Hatschek, Thomas
    Health-related quality of life in the Swedish PREDIX HER2 trial, evaluating docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer.2019In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 37, no 15Article in journal (Other academic)
    Abstract [en]

    Background: Neoadjuvant therapy combining docetaxel, trastuzumab and pertuzumab (DTP) was compared to trastuzumab emtansine (T-DM1) in the randomized phase 2 PREDIX HER2 trial. Patients, ≥18 years with HER2 positive breast cancer, ≥20mm or with verified lymph node metastases, were randomized to six courses of DTP (Standard arm) or T-DM1 (Experimental arm). Primary endpoint was pathological objective response to primary medical therapy at post-treatment surgery. Health related quality of life (HRQoL) was a secondary outcome, and is of specific interest as there was no difference between the randomization groups regarding the main endpoint (results presented in a separate abstract sent to ASCO 2019, Bergh et al.).

    Methods: Of 202 randomized patients, 190 are available for evaluation at this point. HRQoL was measured, using EORTC QLQ-C30 + EORTC QLQ-BR23, at baseline before randomization and after six courses.

    Results: No differences between the randomization arms were found at baseline. Results after six courses, based on 163 patients (86%) and adjusted to baseline values, revealed statistical significant differences (p≤0.01), favoring the experimental T-DM1 arm on 7 out of 15 of the EORTC QLQ-C30 variables (Physical functioning, Role functioning, Social functioning, Global quality of Life, Fatigue, Dyspnea, and Diarrhea). For the breast cancer specific questionnaire (EORTC-BR23), the experimental arm scored statistically significantly better on 5 out of 7 subscales (Body image, Sexual functioning, Sexual enjoyment, Systemic therapy side effects and Upset by hair loss). All of the statistical significant differences were of moderate or large clinical significance (≥10 scale scores). No differences between the randomization arms were found for the remaining HRQoL variables.

    Conclusions: The experimental arm reported better HRQoL than the control arm after six courses. Trastuzumab emtansine may be a useful treatment alternative due to better HRQoL and lower toxicity.

  • 3.
    Joensuu, Heikki
    et al.
    Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
    Kellokumpu-Lehtinen, Pirkko-Liisa
    Tampere University Hospital, Tampere, Finland.
    Huovinen, Riikka
    Turku University Central Hospital, Turku, Finland.
    Jukkola-Vuorinen, Arja
    Oulu University Hospital, Oulu, Finland.
    Tanner, Minna
    Tampere University Hospital, Tampere, Finland.
    Kokko, Riitta
    Kanta-Häme Central Hospital, Hämeenlinna, Finland.
    Ahlgren, Johan
    Gävle Hospital, Gävle, Sweden.
    Auvinen, Paivi
    Cancer Center, Kuopio University Hospital, Kuopio, Finland.
    Paija, Outi
    Turku University Central Hospital, Turku, Finland.
    Helle, Leena
    Kotka Central Hospital, Kotka, Finland.
    Villman, Kenneth
    Örebro University Hospital.
    Nyandoto, Paul
    Päijät-Häme Central Hospital, Lahti, Finland.
    Nilsson, Greger
    Uppsala University Hospital, Uppsala, Sweden.
    Pajunen, Marjo
    Jyväskylä Central Hospital, Jyväskylä, Finland.
    Asola, Raija
    Satakunta Central Hospital, Pori, Finland.
    Poikonen, Paula
    Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
    Leinonen, Mika
    4Pharma, Turku, Finland.
    Kataja, Vesa
    Cancer Center, Kuopio University Hospital, Kuopio, Finland; Vaasa Central Hospital, Vaasa, Finland.
    Bono, Petri
    Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
    Lindman, Henrik
    Uppsala University Hospital, Uppsala, Sweden.
    Adjuvant Capecitabine, Docetaxel, Cyclophosphamide, and Epirubicin for Early Breast Cancer: Final Analysis of the Randomized FinXX Trial2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 1, p. 11-18Article in journal (Refereed)
    Abstract [en]

    Purpose: Capecitabine is an active agent in the treatment of breast cancer. It is not known whether integration of capecitabine into an adjuvant regimen that contains a taxane, an anthracycline, and cyclophosphamide improves outcome in early breast cancer.

    Patients and Methods: Women with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive either three cycles of docetaxel and capecitabine (TX) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX; n = 753) or three cycles of docetaxel (T) followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF; n = 747). The primary end point was recurrence-free survival (RFS).

    Results: During a median follow-up time of 59 months, 214 RFS events occurred (local or distant recurrences or deaths; TX/CEX, n = 96; T/CEF, n = 118). RFS was not significantly different between the groups (hazard ratio [HR], 0.79; 95% CI, 0.60 to 1.04; P = .087; 5-year RFS, 86.6% for TX/CEX v 84.1% for T/CEF). Fifty-six patients assigned to TX/CEX died during the follow-up compared with 75 of patients assigned to T/CEF (HR, 0.73; 95% CI, 0.52 to 1.04; P = .080). In exploratory analyses, TX/CEX improved breast cancer-specific survival (HR, 0.64; 95% CI, 0.44 to 0.95; P = .027) and RFS in women with triple-negative disease and in women who had more than three metastatic axillary lymph nodes at the time of diagnosis. We detected little severe late toxicity.

    Conclusion: Integration of capecitabine into a regimen that contains docetaxel, epirubicin, and cyclophosphamide did not improve RFS significantly compared with a similar regimen without capecitabine. J Clin Oncol 30:11-18. (c) 2011 by American Society of Clinical Oncology

  • 4. Jädersten, Martin
    et al.
    Malcovati, Luca
    Dybedal, Ingunn
    Della Porta, Matteo Giovanni
    Invernizzi, Rosangela
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Pascutto, Cristiana
    Porwit, Anna
    Cazzola, Mario
    Hellström-Lindberg, Eva
    Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome2008In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 26, no 21, p. 3607-3613Article in journal (Refereed)
    Abstract [en]

    Purpose To assess the effect of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) treatment on survival and leukemic transformation in myelodysplastic syndrome (MDS).

    Patients and Methods We compared the long-term outcome of patients with MDS treated with EPO plus G-CSF (n = 121) with untreated patients (n = 237) with MDS using multivariate Cox regression with delayed entry, for the first time adjusting for all major prognostic variables (WHO classification, karyotype, cytopenias, level of transfusion-need, age, and sex).

    Results The erythroid response rate to EPO plus G-CSF was 39%, and the median response duration 23 months (range, 3 to 116+). In the multivariate analysis, treatment was associated with improved overall survival (hazard ratio, 0.61; 95% CI, 0.44 to 0.83; P = .002). Interestingly, this positive association was primarily observed in patients requiring fewer than 2 units of RBCs per month. Treatment was not linked to the rate of acute myeloid leukemia in any defined subgroup, including patients with an increase of marrow blasts or an unfavorable karyotype.

    Conclusion The inherent risk of leukemic evolution in MDS makes the current investigation highly relevant, in light of the recent reports of potential negative effects of EPO treatment on outcome in patients with cancer. We conclude that treatment of anemia in MDS with EPO plus G-CSF may have a positive impact on outcome in patients with no or low transfusion need, while not affecting the risk of leukemic transformation.

  • 5. Lehmann, S
    et al.
    Bykov, VJ
    Ali, D
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Cherif, H
    Tidefelt, Ulf
    Örebro University, School of Medicine, Örebro University, Sweden.
    Uggla, Bertil
    Örebro University, School of Medicine, Örebro University, Sweden.
    Yachnin, J
    Juliusson, G
    Moshfegh, A
    Paul, C
    Wiman, KG
    Andersson, PO
    Targeting p53 in vivo: a first-in-man study with the p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 29, p. 3633-3639Article in journal (Refereed)
    Abstract [en]

    PURPOSE: APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.

    PATIENTS AND METHODS: APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.

    RESULTS: MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.

    CONCLUSION: We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.

  • 6.
    Lü, Donghao
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Karolinska Institutet, Stockholm, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York NY, United States .
    Smedby, Karin Ekström
    Karolinska University Hospital, Stockholm, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Valdimarsdóttir, Unnur
    Karolinska Institutet, Stockholm, Sweden; University of Iceland, Reykjavík, Iceland.
    Cnattingius, Sven
    Karolinska University Hospital, Stockholm, Sweden .
    Fang, Fang
    Karolinska Institutet, Stockholm, Sweden.
    Maternal Cancer During Pregnancy and Risks of Stillbirth and Infant Mortality2017In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 35, no 14, p. 1522-1529, article id JCO2016699439Article in journal (Refereed)
    Abstract [en]

    Purpose: To examine whether maternal cancer during pregnancy is associated with increased risks of stillbirth and infant mortality.

    Methods: On the basis of nationwide health registers, we conducted a study of 3,947,215 singleton births in Sweden from 1973 through 2012. Exposure was defined as maternal cancer diagnosed during pregnancy (number of births = 984) or during the year after pregnancy (number of births = 2,723). We calculated incidence rate ratios (IRRs) for stillbirth and infant mortality, comparing exposed births to unexposed births. Small-for-gestational-age (SGA) and preterm births were examined as secondary outcomes.

    Results: Maternal cancer diagnosed during pregnancy was positively associated with stillbirth (IRR, 2.5; 95% CI, 1.2 to 5.0), mainly stillbirths assessed as SGA (IRR, 4.9; 95% CI, 2.2 to 11.0), and with preterm SGA births (relative risk 3.0; 95% CI, 2.1 to 4.4). Positive associations of maternal cancer diagnosed during pregnancy or the year after pregnancy were noted for both neonatal mortality (deaths within 0 to 27 days; IRR, 2.7; 95% CI, 1.3 to 5.6 and IRR, 2.0; 95% CI, 1.2 to 3.2, respectively) and preterm birth (IRR, 5.8; 95% CI, 5.3 to 6.5 and IRR, 1.6; 95% CI, 1.4 to 1.8, respectively). The positive association with preterm birth was due to iatrogenic instead of spontaneous preterm birth. Preterm birth explained 89% of the association of maternal cancer during pregnancy with neonatal mortality.

    Conclusion: Maternal cancer during pregnancy is associated with increased risks of rare but fatal outcomes, including stillbirth and neonatal mortality. This may be due to conditions associated with fetal growth restriction and iatrogenic preterm birth. Careful monitoring of fetal growth and cautious decision making on preterm delivery should therefore be reinforced.

  • 7. Matikas, Alexios
    et al.
    Zerdes, Ioannis
    Lovrot, John
    Richard, Francois
    Sotiriou, Christos
    Bergh, Jonas C. S.
    Valachis, Antonios
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Foukakis, Theodoros
    Prognostic implications of PD-L1 expression in breast cancer at the protein and mRNA levels2019In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 37, no 15, article id e14284Article in journal (Other academic)
    Abstract [en]

    Background: Conflicting data have been reported on the prognostic value of PD-L1 expression per immunohistochemistry (IHC) in breast cancer (BC). There is a paucity of data on the role of PD-L1 gene expression (GE).

    Methods: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched and data were extracted independently by two researchers. Outcomes included pooled PD-L1 positivity in tumor cells, immune cells or both, per subtype and per antibody used; and the prognostic value of PD-L1 positivity for DFS and OS. Heterogeneity was assessed using the Q and I2 statistics. A pooled GE analysis of 39 publicly available transcriptomic datasets was also performed.

    Results: Of the initial 4184 entries, 38 retrospective studies fulfilled the inclusion criteria. The overall pooled PD-L1 positivity rate in tumor cells was 24%, 33% in immune cells and 25% in both; highest positivity was reported with Dako 28-8 clone. PD-L1 IHC expression in tumor cells was prognostic for shorter DFS (HR = 1.36, 95% CI 1.02 – 1.83, p < 0.04) and OS (HR = 1.66; 95% CI 1.09 – 2.50, p = 0.02); there was significant heterogeneity. PD-L1 IHC expression in immune cells was associated with better DFS (HR = 0.61; 95% CI 0.51 – 0.73, p < 0.001) and OS (HR = 0.53, 95% CI 0.39 – 0.73, p < 0.001) in TNBC. In addition, higher PD-L1 GE predicted better survival in multivariate analysis in the entire population (HR = 0.70, 95% CI 0.60 – 0.82, p < 0.001 for DFS and HR = 0.84, 95% CI 0.75 – 0.93, p = 0.001 for OS) and in basal-like tumors (HR = 0.55, 95% CI 0.38 – 0.80, p = 0.001 for DFS and HR = 0.63, 95% CI 0.50 – 0.79, p < 0.001 for OS), pinteraction 0.124 for DFS and 0.005 for OS.

    Conclusions: The largest to our knowledge meta-analysis on IHC PD-L1 expression in BC informs on PD-L1 positivity rates and its prognostic value. Standardization is needed prior to routine implementation. PD-L1 GE is a promising prognostic factor, especially in basal-like BC.

  • 8. Mucci, Lorelei A.
    et al.
    Markt, Sarah
    Sigurdardottir, Lara
    Lockley, Steven W.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Stampfer, Meir J.
    Gudnason, Vilmundur
    Kraft, Peter
    Rider, Jennifer R.
    Czeisler, Charles A.
    Valdimarsdottir, Unnur Anna
    Circadian dysrhythm and advanced prostate cancer2014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 4Article in journal (Other academic)
    Abstract [en]

    Background: The circadian rhythm regulates diverse biologic pathways including tumor oncogenes, metabolism, and cell proliferation. Dysregulation of the circadian rhythm arises from faulty input signals such as exposure to light at night, variability in core circadian rhythm genes, and variation in outputs that regulate circadian behavior including melatonin. There is compelling biologic rationale, but little human data, on circadian dysrhythm and advanced prostate cancer.

    Methods: We undertook an integrative molecular epidemiology study of circadian dysrhythm and advanced prostate cancer among men in the Icelandic AGES-Reykjavik cohort and the U.S. Health Professionals Follow-up Study, which allowed integration of questionnaire data, biorepositories, and long-term follow-up. We characterized circadian dysrhythm using complimentary approaches: information on sleep problems from questionnaires, prediagnostic melatonin (6-sulfatoxymelatonin) measured on first morning void urine samples, and genetic variation across twelve circadian clock genes. We used multivariable regression models to estimate relative risks (RR) and 95% confidence intervals (CI) of associations with advanced prostate cancer, adjusted for potential confounders.

    Results: Twenty percent of men reported sleep problems. Men who had trouble falling asleep (RR = 2.1; 95% CI 0.7-6.2) and staying asleep (RR=3.2, 95% CI 1.1-9.7) had an increased risk of developing advanced prostate cancer. Men with sleep problems had significantly lower melatonin levels compared to those without. Low melatonin levels were associated with a statistically significant 4-fold higher risk of advanced prostate cancer compared to those with high levels (95% CI: 1.25-10.0). Variant alleles in two SNPs in cryptochrome (CRY1), involved in generating and maintaining circadian rhythms, were significantly associated with risk of advanced prostate cancer in both cohorts, with a gene-level p-value<0.01.

    Conclusions: Our results suggest there are multiple nodes in the circadian rhythm that are associated with an increased risk of advanced prostate cancer. As such, there is the potential for complimentary strategies to target circadian disruption and reduce the risk of advanced prostate cancer.

  • 9. Penney, K. L.
    et al.
    Sinnott, J. A.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Pawitan, Y.
    Hoshida, Y.
    Kraft, P.
    Stark, J. R.
    Fiorentino, M.
    Perner, S.
    Finn, S.
    Calza, S.
    Flavin, R.
    Freedman, M. L.
    Setlur, S.
    Sesso, H. D.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Martin, N.
    Kantoff, P. W.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Adami, H. O.
    Rubin, M.
    Loda, M.
    Golub, T. R.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Stampfer, M. J.
    Mucci, L. A.
    mRNA expression signature of Gleason grade predicts lethal prostate cancer2011In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, no 17, p. 2391-2396Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis.

    PATIENTS AND METHODS: Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases.

    RESULTS: We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006).

    CONCLUSION: Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.

  • 10.
    Wickberg, Åsa
    et al.
    Örebro University, School of Medical Sciences.
    Holmberg, Lars
    Medical School, King's College, London, United Kingdom; Uppsala University, Uppsala, Sweden.
    Adami, Hans-Olov
    Harvard School of Public Health, Boston MA, United States.
    Magnuson, Anders
    Örebro University Hospital, Örebro, Sweden.
    Villman, Kenneth
    Örebro University Hospital.
    Liljegren, Göran
    Örebro University Hospital, Örebro, Sweden.
    Reply to a. Levy et Al.2014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 29, p. 3340-3341Article in journal (Refereed)
  • 11.
    Wickberg, Åsa
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital, Örebro, Sweden; Uppsala University, Uppsala, Sweden.
    Holmberg, Lars
    Uppsala University, Uppsala, Sweden; Kings Coll, London, England.
    Adami, Hans-Olov
    Karolinska Institutet, Stockholm, Sweden; Harvard School of Public Health, Boston MA, USA.
    Magnuson, Anders
    Örebro University Hospital, Örebro, Sweden.
    Villman, Kenneth
    Örebro University Hospital.
    Liljegren, Göran
    Örebro University Hospital.
    Sector Resection With or Without Postoperative Radiotherapy for Stage I Breast Cancer: 20-Year Results of a Randomized Trial2014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 8, p. 791-797Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate how radiotherapy (XRT) adds to tumor control using a standardized surgical technique with meticulous control of surgical margins in a randomized trial with 20 years of follow-up.

    Patients and Methods: Three hundred eighty-one women with pT1N0 breast cancer were randomly assigned to sector resection with (XRT group) or without (non-XRT group) postoperative radiotherapy to the breast. With follow-up through 2010, we estimated cumulative proportion of recurrence, breast cancer death, and all-cause mortality.

    Results: The cumulative probability of a first breast cancer event of any type after 20 years was 30.9% in the XRT group and 45.1% in the non-XRT group (hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.82). The benefit of radiotherapy was achieved within the first 5 years. After 20 years, 50.4% of the women in the XRT group died compared with 54.0% in the non-XRT group (HR, 0.92; 95% CI, 0.71 to 1.19). The cumulative probability of contralateral cancer or death as a result of cancer other than breast cancer was 27.1% in the XRT group and 24.9% in the non-XRT group (HR, 1.17; 95% CI, 0.77 to 1.77). In an anticipated low-risk group, the cumulative incidence of first breast cancer of any type was 24.8% in the XRT group and 36.1% in the non-XRT group (HR, 0.61; 95% CI, 0.35 to 1.07).

    Conclusion: Radiotherapy protects against recurrences during the first 5 years of follow-up, indicating that XRT mainly eradicates undetected cancer foci present at primary treatment. The similar rate of recurrences beyond 5 years in the two groups indicates that late recurrences are new tumors. There are subgroups with clinically relevant differences in risk.

  • 12. Wiklund, Fredrik
    et al.
    Tretli, Steinar
    Choueiri, Toni K
    Signoretti, Sabina
    Fall, Katja
    Adami, Hans-Olov
    Department of Epidemology, Harvard School of Public Health, Boston, USA.
    Risk of bilateral renal cell cancer2009In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 27, no 23, p. 3737-41Article in journal (Refereed)
    Abstract [en]

    Purpose: The risk of developing bilateral kidney cancer has not been adequately defined in any large, population-based study with long-term follow-up to our knowledge.

    Patients and methods: We estimated the risk of metachronous bilateral renal cell cancer in patients diagnosed with unilateral kidney cancer, as recorded in the nationwide cancer registries of Norway and Sweden. Altogether 28,642 patients were followed for an average of 4.4 years. The standardized incidence ratio--the ratio of the observed number of bilateral cancers to the number expected on the basis of the incidence in the Norwegian and Swedish population at large--was used as a measure of relative risk. We used multivariate Poisson regression to separate the effects of the explanatory variables.

    Results: A synchronous bilateral renal cell cancer was reported in 86 patients. A total of 112 metachronous bilateral cancers were recorded during 126,493 person-years of follow-up compared with 35.8 expected, yielding an overall relative risk (RR) of 3.1 (95% CI, 2.6 to 3.8) and a cumulative incidence of 0.8% after 20 or more years of follow-up. In the multivariate analyses, risk increased monotonically with younger age at first diagnosis (P for trend < .001); compared with patients who were 60 years or older, those younger than 40 years were at a 17-fold higher risk (RR = 17.4; 95% CI, 10.1 to 29.8). We also found a modest but statistically significant decreasing trend with increasing duration of follow-up.

    Conclusion: The risk of metachronous bilateral renal cell cancer is drastically higher among patients first affected at a young age, suggesting a subset of early onset renal cell cancer with a strong genetic component.

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