| 1. |
- Moortgat-Pick, G., et al.
(författare)
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Physics at the e(+) e(-) linear collider
- 2015
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 75:8
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Forskningsöversikt (refereegranskat)abstract
- A comprehensive review of physics at an e(+) e(-) linear collider in the energy range of root s = 92 GeV-3 TeV is presented in view of recent and expected LHC results, experiments from low-energy as well as astroparticle physics. The report focusses in particular on Higgs-boson, top-quark and electroweak precision physics, but also discusses several models of beyond the standard model physics such as super-symmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analysed as well.
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| 2. |
- Akeroyd, A. G., et al.
(författare)
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Prospects for charged Higgs searches at the LHC
- 2017
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 77:5
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Forskningsöversikt (refereegranskat)abstract
- The goal of this report is to summarize the current situation and discuss possible search strategies for charged scalars, in non-supersymmetric extensions of the Standard Model at the LHC. Such scalars appear in Multi-HiggsDoublet models, in particular in the popular Two-HiggsDoublet model, allowing for charged and additional neutral Higgs bosons. These models have the attractive property that electroweak precision observables are automatically in agreement with the Standard Model at the tree level. For the most popular version of this framework, Model II, a discovery of a charged Higgs boson remains challenging, since the parameter space is becoming very constrained, and the QCD background is very high. We also briefly comment on models with dark matter which constrain the corresponding charged scalars that occur in these models. The stakes of a possible discovery of an extended scalar sector are very high, and these searches should be pursued in all conceivable channels, at the LHC and at future colliders.
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| 3. |
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| 4. |
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| 5. |
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| 7. |
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| 8. |
- Adam, Iris, et al.
(författare)
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Daily vocal exercise is necessary for peak performance singing in a songbird
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Vocal signals, including human speech and birdsong, are produced by complicated, precisely coordinated body movements, whose execution is fitness-determining in resource competition and mate choice. While the acquisition and maintenance of motor skills generally requires practice to develop and maintain both motor circuitry and muscle performance, it is unknown whether vocal muscles, like limb muscles, exhibit exercise-induced plasticity. Here, we show that juvenile and adult zebra finches (Taeniopygia castanotis) require daily vocal exercise to first gain and subsequently maintain peak vocal muscle performance. Experimentally preventing male birds from singing alters both vocal muscle physiology and vocal performance within days. Furthermore, we find females prefer song of vocally exercised males in choice experiments. Vocal output thus contains information on recent exercise status, and acts as an honest indicator of past exercise investment in songbirds, and possibly in all vocalising vertebrates.
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| 9. |
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| 10. |
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| 11. |
- Bechtle, P., et al.
(författare)
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MSSM interpretations of the LHC discovery : light or heavy Higgs?
- 2013
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 73:4, s. 2354-
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Tidskriftsartikel (refereegranskat)abstract
- A Higgs-like particle with a mass of about 126 GeV has been discovered at the LHC. Within the experimental uncertainties, the measured properties of this new state are compatible with those of the Higgs boson in the Standard Model (SM). While not statistically significant at present, the results show some interesting patterns of deviations from the SM predictions, in particular a higher rate in the gamma gamma decay mode observed by ATLAS and CMS, and a somewhat smaller rate in the tau(+)tau(-) mode. The LHC discovery is also compatible with the predictions of the Higgs sector of the Minimal Supersymmetric Standard Model (MSSM), interpreting the new state as either the light or the heavy CP-even MSSM Higgs boson. Within the framework of the MSSM with seven free parameters (pMSSM-7), we fit the various rates of cross section times branching ratio as measured by the LHC and Tevatron experiments under the hypotheses of either the light or the heavy CP-even Higgs boson being the new state around 126 GeV, with and without the inclusion of further low-energy observables. We find an overall good quality of the fits, with the best fit points exhibiting an enhancement of the gamma gamma rate, as well as a small suppression of the b (b) over bar and tau(+)tau(-) channels with respect to their SM expectations, depending on the details of the fit. For the fits including the whole dataset the light CP-even Higgs interpretation in the MSSM results in a higher relative fit probability than the SM fit. On the other hand, we find that the present data also permit the more exotic interpretation in terms of the heavy CP-even MSSM Higgs, which could give rise to experimental signatures of additional Higgs states in the near future.
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| 12. |
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| 13. |
- Ekholm, M., et al.
(författare)
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Effects of adjuvant tamoxifen over three decades on breast cancer–free and distant recurrence–free interval among premenopausal women with oestrogen receptor–positive breast cancer randomised in the Swedish SBII:2pre trial
- 2019
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 110, s. 53-61
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The primary aim was to compare 2 years of adjuvant tamoxifen versus no systemic treatment in premenopausal patients with oestrogen receptor (ER)–positive tumours, regarding breast cancer–free interval (BCFi) and distant recurrence–free 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 <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 >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 cancer–related 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.
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| 14. |
- Esserman, Laura J., et al.
(författare)
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Use of Molecular Tools to Identify Patients With Indolent Breast Cancers With Ultralow Risk Over 2 Decades
- 2017
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Ingår i: JAMA Oncology. - : AMER MEDICAL ASSOC. - 2374-2437 .- 2374-2445. ; 3:11, s. 1503-1510
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 15. |
- Holm, Karolina, et al.
(författare)
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Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes
- 2012
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Ingår i: Molecular Oncology. - : Elsevier. - 1574-7891 .- 1878-0261. ; 6:5, s. 494-506
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and Well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2-/Ki67low, ER+/HER2-/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer.
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| 16. |
- Holmqvist, P, et al.
(författare)
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Apoptosis and Bcl-2 expression in relation to age, tumor characteristics and prognosis in breast cancer
- 1999
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Ingår i: International Journal of Biological Markers. - 0393-6155 .- 1724-6008. ; 14:2, s. 84-91
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Tidskriftsartikel (refereegranskat)abstract
- The extent of apoptosis and the expression of Bcl-2 was investigated in tumor samples from 165 women who underwent surgery for primary breast carcinoma between 1989 and 1990 in South-East Sweden. Apoptosis was assessed by a DNA fragmentation assay for flow cytometry. Bcl-2 protein expression was analyzed with immunocytochemistry. Bcl-2 immunoreactivity correlated with estrogen receptor (ER) and progesterone receptor (PgR) positivity and was inversely correlated with p53 accumulation. Apoptosis increased with patient age and a high degree of apoptosis was negatively associated with Bcl-2 immunostaining. Apoptosis showed no significant correlation with any of the other variables studied, including prognosis. The group with Bcl-2-positive tumors tended to have a lower risk of distant recurrence than others, but the association of Bcl-2 with recurrence was different in groups divided by ER and PgR status. Whereas Bcl-2 positivity indicated a low recurrence rate among PgR-negative patients, in the PgR-positive group, those with Bcl-2-positive tumors showed a non significantly higher recurrence rate than Bcl-2-negative cases. In the PgR-positive group, Bcl-2-positive tumors also appeared more frequently to be lymph node positive and DNA aneuploid. The results suggest that hormone receptor status is of importance for the prognostic role of Bcl-2. Likewise, patient age merits consideration when apoptosis is studied in human cancer.
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| 17. |
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| 18. |
- Jirström, Karin, et al.
(författare)
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Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial
- 2005
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 58:11, s. 1135-1142
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Tidskriftsartikel (refereegranskat)abstract
- Background: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment.Aims: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer.Materials/methods: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression.Results: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly.Conclusions: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.
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| 19. |
- Johansson, Annelie, et al.
(författare)
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Clinical and molecular characteristics of estrogen receptor-positive ultralow risk breast cancer tumors identified by the 70-gene signature
- 2022
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 150:12, s. 2072-2082
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 20. |
- Johansson, Annelie, et al.
(författare)
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Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial
- 2022
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Ingår i: Journal of Clinical Oncology. - : Lippincott, Williams & Wilkins. - 0732-183X .- 1527-7755. ; 40:35, s. 4071-4082
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 21. |
- Lehn, Sophie, et al.
(författare)
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Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response
- 2014
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Ingår i: Bmc Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Yes-associated protein (YAP1) is frequently reported to function as an oncogene in many types of cancer, but in breast cancer results remain controversial. We set out to clarify the role of YAP1 in breast cancer by examining gene and protein expression in subgroups of patient material and by downregulating YAP1 in vitro and studying its role in response to the widely used anti-estrogen tamoxifen. Methods: YAP1 protein intensity was scored as absent, weak, intermediate or strong in two primary breast cancer cohorts (n = 144 and n = 564) and mRNA expression of YAP1 was evaluated in a gene expression dataset (n = 1107). Recurrence-free survival was analysed using the log-rank test and Cox multivariate analysis was used to test for independence. WST-1 assay was employed to measure cell viability and a luciferase ERE (estrogen responsive element) construct was used to study the effect of tamoxifen, following downregulation of YAP1 using siRNAs. Results: In the ER+ (Estrogen Receptor a positive) subgroup of the randomised cohort, YAP1 expression was inversely correlated to histological grade and proliferation (p = 0.001 and p = 0.016, respectively) whereas in the ER-(Estrogen Receptor a negative) subgroup YAP1 expression correlated positively to proliferation (p = 0.005). Notably, low YAP1 mRNA was independently associated with decreased recurrence-free survival in the gene expression dataset, specifically for the luminal A subgroup (p < 0.001) which includes low proliferating tumours of lower grade, usually associated with a good prognosis. This subgroup specificity led us to hypothesize that YAP1 may be important for response to endocrine therapies, such as tamoxifen, extensively used for luminal A breast cancers. In a tamoxifen randomised patient material, absent YAP1 protein expression was associated with impaired tamoxifen response which was significant upon interaction analysis (p = 0.042). YAP1 downregulation resulted in increased progesterone receptor (PgR) expression and a delayed and weaker tamoxifen in support of the clinical data. Conclusions: Decreased YAP1 expression is an independent prognostic factor for recurrence in the less aggressive luminal A breast cancer subgroup, likely due to the decreased tamoxifen sensitivity conferred by YAP1 downregulation.
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| 22. |
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| 23. |
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| 24. |
- Lundgren, Katja, et al.
(författare)
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Stromal Expression of beta-Arrestin-1 Predicts Clinical Outcome and Tamoxifen Response in Breast Cancer
- 2011
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Ingår i: Journal of Molecular Diagnostics. - : American Society for Investigative Pathology (ASIP). - 1525-1578 .- 1943-7811. ; 13:3, s. 340-351
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Tidskriftsartikel (refereegranskat)abstract
- The G-protein coupled receptor associated protein beta-arrestin-1 is crucial for the regulation of numerous biological processes involved in cancer progression, such as intracellular signaling and cell motility. The encoding gene ARRB1 is harbored in the same chromosomal region as the CCND1 gene (11q13). Amplification of CCND1, frequently encountered in breast cancer, often involves coamplification of additional oncogenes, as well as deletion of distal 11q genes. We investigated the clinical relevance of beta-arrestin-1 in breast cancer and elucidated a potential link between beta-arrestin-1 expression and CCND1 amplification. beta-Arrestin-1 protein expression was evaluated in two breast cancer patient cohorts, comprising 179 patients (cohort I) and 500 patients randomized to either tamoxifen or no adjuvant treatment (cohort H). Additionally, migration after beta-arrestin-1 overexpression or silencing was monitored in two breast cancer cell lines. Overexpression of beta-arrestin-1 reduced the migratory propensity of both cell lines, whereas silencing increased migration. In cohort I, high expression of stromal beta-arrestin-1 was linked to reduced patient survival, whereas in cohort II both high and absent stromal expression predicted a poor clinical outcome. Patients exhibiting low or moderate levels of stromal beta-arrestin-1 did not benefit from tamoxifen, in contrast to patients exhibiting absent or high expression. Furthermore, CCND1 amplification was inversely correlated with tumor cell expression of beta-arrestin-1, indicating ARRB1 gene deletion in CCND1-amplified breast cancers.
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| 25. |
- Paulsson, Janna, et al.
(författare)
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High expression of stromal PDGFRß is associated with reduced benefit of tamoxifen in breast cancer
- 2017
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Ingår i: The journal of pathology. Clinical research. - : Wiley-Blackwell. - 2056-4538. ; 3:1, s. 38-43
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 26. |
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| 27. |
- Stål, Olle, 1952-, et al.
(författare)
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ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer
- 2000
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Ingår i: Annals of Oncology. - 0923-7534 .- 1569-8041. ; 11:12, s. 1545-1550
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Tidskriftsartikel (refereegranskat)abstract
- Aim:We aimed to study the importance of erbB2 status in early stage postmenopausal breast cancer for patients who participated in a trial of five vs. two years of adjuvant tamoxifen.Patients and methods: We analysed the erbB2 status of the tumours from 577 patients participating in the trial, either by a DNA amplification assay (n=181) or by measurement of the protein level with flow cytometry (n=396).Results: ErbB2 was overexpressed or gene amplified in 102 of the patients (18%). Overall, erbB2-positive patients had a significantly lower recurrence-free probability than others, 62% at five years as compared to 83%, and showed a significantly decreased breast cancer survival rate (P=0.0007). ErbB2 status was significantly associated with recurrence and death in Cox multivariate analysis, adjusting for nodal status, tumour size and estrogen receptor status. The relative risk of recurrence (RR) for five vs. two years of tamoxifen was analysed in relation to erbB2 status for patients still disease-free two years after surgery. Whereas erbB2-negative patients showed significant benefit from prolonged treatment (RR=0.62, 95% confidence interval (95% CI): 0.42–0.93), no benefit was evident for erbB2-positive patients (RR=1.1, 95% CI: 0.41–3.2). When the same analysis was restricted to ER-positive patients a similar difference in relative hazard was obtained but the difference was not strictly significant (P=0.065).Conclusions: For early stage breast cancer patients treated with adjuvant tamoxifen, overexpression of erbB2 is an independent marker of poor prognosis. The results suggest that overexpression decreases the benefit from prolonged tamoxifen treatment.
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| 28. |
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| 29. |
- Stål, P, et al.
(författare)
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Clinical trial : the safety and short-term efficacy of recombinant cholera toxin B subunit in the treatment of active Crohn's disease.
- 2010
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley. - 0269-2813 .- 1365-2036. ; 31:3, s. 387-395
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The cholera toxin B subunit ameliorates experimentally induced colitis in mice. In humans, cholera toxin B subunit has never been tested in the treatment of Crohn's disease (CD). AIM: To evaluate the safety and efficacy of treatment with recombinant cholera toxin B subunit of patients with CD. METHODS: An open-label, multicentre, nonrandomized trial including 15 patients with mild/moderate CD. Patients received an oral solution of 5 mg recombinant cholera toxin B subunit three times weekly for 2 weeks. Reduction in CD Activity Index (CDAI) with >100 between baseline and days 15, 29, 42 and 70 defined clinical response. Patients with CDAI score < or = 150 were defined as being in remission. RESULTS: A significant decrease in CDAI score was observed. Response rates were 40% in the full analysis set and 42% in the per protocol analysis. Two patients receiving adjuvant treatment after day 29 were excluded, after which 40% were in remission at 4 weeks and 30% at 8 weeks post-treatment. Mild side effects (arthralgia, headache and pruritus) were seen in 33% of patients. CONCLUSIONS: Treatment with recombinant cholera toxin B subunit was safe. Approximately 40% of patients with active CD responded to treatment. Randomized studies are needed to establish the clinical efficacy of recombinant cholera toxin B subunit.
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| 30. |
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| 31. |
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| 32. |
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| 33. |
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| 34. |
- Yu, Nancy Y., et al.
(författare)
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Assessment of Long-term Distant Recurrence-Free Survival Associated With Tamoxifen Therapy in Postmenopausal Patients With Luminal A or Luminal B Breast Cancer
- 2019
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Ingår i: JAMA Oncology. - : AMER MEDICAL ASSOC. - 2374-2437 .- 2374-2445. ; 5:9, s. 1304-1309
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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