| 1. |
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| 2. |
- Aaltonen, Kristina E., et al.
(författare)
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Molecular characterization of circulating tumor cells from patients with metastatic breast cancer reflects evolutionary changes in gene expression under the pressure of systemic therapy
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:28, s. 45544-45565
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Tidskriftsartikel (refereegranskat)abstract
- Resistance to systemic therapy is a major problem in metastatic breast cancer (MBC) that can be explained by initial tumor heterogeneity as well as by evolutionary changes during therapy and tumor progression. Circulating tumor cells (CTCs) detected in a liquid biopsy can be sampled and characterized repeatedly during therapy in order to monitor treatment response and disease progression. Our aim was to investigate how CTC derived gene expression of treatment predictive markers (ESR1/HER2) and other cancer associated markers changed in patient blood samples during six months of first-line systemic treatment for MBC. CTCs from 36 patients were enriched using CellSearch (Janssen Diagnostics) and AdnaTest (QIAGEN) before gene expression analysis was performed with a customized gene panel (TATAA Biocenter). Our results show that antibodies against HER2 and EGFR were valuable to isolate CTCs unidentified by CellSearch and possibly lacking EpCAM expression. Evaluation of patients with clinically different breast cancer subgroups demonstrated that gene expression of treatment predictive markers changed over time. This change was especially prominent for HER2 expression. In conclusion, we found that changed gene expression during first-line systemic therapy for MBC could be a possible explanation for treatment resistance. Characterization of CTCs at several time-points during therapy could be informative for treatment selection.
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| 3. |
- Aamand Grabau, Dorthe, et al.
(författare)
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The prevalence of immunohistochemically determined oestrogen receptor positivity in primary breast cancer is dependent on the choice of antibody and method of heat-induced epitope retrieval - prognostic implications?
- 2013
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Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 52:8, s. 1657-1666
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Tidskriftsartikel (refereegranskat)abstract
- Background. Oestrogen receptor (ER) status is important for the choice of systemic treatment of breast cancer patients. However, most data from randomised trials on the effect of adjuvant endocrine therapy according to ER status are based on the cytosol methods. Comparisons with immunohistochemical methods have given similar results. The aim of the present study was to examine whether different ER antibodies and heat-induced epitope retrieval (HIER) methods influence the prevalence of ER-positivity in primary breast cancer. Material and methods. This study is based on patients included in a clinical trial designed to compare the effect of two years of adjuvant tamoxifen versus no adjuvant systemic treatment in premenopausal women. From 1986 to 1991, 564 patients from two study centres in Sweden were enrolled and randomised. Patients were randomised independently of ER status. In the present study, ER status was assessed on tissue microarrays with the three different ER antibody/HIER combinations: 1D5 in citrate pH 6 (n = 390), SP1 in Tris pH 9 (n = 390) and PharmDx in citrate pH 6 (n = 361). Results. At cut-offs of 1% and 10%, respectively, the prevalence of ER-positivity was higher with SP1 (75% and 72%) compared with 1D5 (68% and 66%) and PharmDx (66% and 62%). At these cut-offs, patients in the discordant groups (SP1-positive and 1D5-negative) seem to have a prognosis intermediate between those of the double-positive and double-negative groups. Comparison with the ER status determined by the cytosol-based methods in the discordant group also showed an intermediate pattern. The repeatability was good for all antibodies and cut-offs, with overall agreement andgt;= 93%. Conclusion. The present study shows that the choice of antibody and HIER method influences the prevalence of ER-positivity. We suggest that this be taken into consideration when choosing a cut-off for clinical decision making.
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| 4. |
- Abrahamsson, Johan, et al.
(författare)
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Circulating tumor cells in patients with advanced urothelial carcinoma of the bladder : Association with tumor stage, lymph node metastases, FDG-PET findings, and survival
- 2017
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Ingår i: Urologic Oncology. - : Elsevier BV. - 1078-1439. ; 35:10, s. 9-606
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Tidskriftsartikel (refereegranskat)abstract
- Background: There are currently no methods in clinical use that can detect early systemic dissemination of urothelial tumor cells. Objective: To evaluate measurement of circulating tumor cells (CTCs) as a biomarker for disseminated disease in patients with advanced bladder cancer. Design, setting, and participants: Between March 2013 and October 2015, 88 patients were prospectively included in the study: 78 were scheduled for radical cystectomy (RC) ± perioperative chemotherapy and 10 treated with palliative chemotherapy. The CellSearch CTC test was further assessed in this context by investigating expression of epithelial cell adhesion molecule (EpCAM) in primary tumors obtained at cystectomy from an independent cohort of 409 patients. Outcome measurements and statistical analysis: Presence of CTCs was tested for association with tumor stage, lymph node metastases, metastatic disease on [18 F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), and cancer-specific and progression-free survival. Results: CTCs were detected in 17/88 patients (19%). In 61 patients who underwent FDG-PET-computed tomography (CT), a statistically significant association with presence of CTCs was found for radiological metastatic disease but not for normal PET-CT results (12/35 [34%] vs. 2/26 [8%], P = 0.014). After a median follow-up time of 16.5 months (95% CI: 9.6-21.4), presence of CTCs was associated with an increased risk of progression among patients treated with RC with or without perioperative chemotherapy (n = 75, P = 0.049). A multivariate analysis adjusted for clinical tumor stage, clinical lymph node status, and age showed that CTCs were an independent marker of progression (n = 75; hazard ratio = 2.78; 95% CI: 1.005-7.69; P = 0.049) but not of cancer-specific death (P = 0.596). In 409 cystectomised patients, more than 392 (96%) of the bladder tumors expressed EpCAM. Conclusions: CTCs were present in 19% of patients with advanced urothelial tumors and were associated with metastatic disease on FDG-PET-CT and with increased risk of disease progression after RC. A significant portion of urothelial cancer cells do express EpCAM and can thus be identified using EpCAM-antigen-based CTC detection methods.
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| 5. |
- Alkner, Sara, et al.
(författare)
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AIB1 is a predictive factor for tamoxifen response in premenopausal women
- 2010
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Ingår i: ANNALS OF ONCOLOGY. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 21:2, s. 238-244
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clinical trials implicate the estrogen receptor ( ER) coactivator amplified in breast cancer 1 (AIB1) to be a prognostic and a treatment-predictive factor, although results are not unanimous. We have further investigated this using a controlled randomised trial of tamoxifen versus control. Materials and methods: A total of 564 premenopausal women were entered into a randomised study independent of ER status. Using a tissue microarray, AIB1 and ER were analysed by immunohistochemistry. Results: AIB1 scores were obtained from 349 women. High AIB1 correlated to factors of worse prognosis (human epidermal growth factor receptor 2, Nottingham histological grade 3, and lymph node metastases) and to ER negativity. In the control arm, high AIB1 was a negative prognostic factor for recurrence- free survival (RFS) (P = 0.02). However, ER-positive patients with high AIB1 responded significantly to tamoxifen treatment (P = 0.002), increasing RFS to the same level as for systemically untreated patients with low AIB1. Although ER-positive patients with low AIB1 had a better RFS from the beginning, this was not further improved by tamoxifen (P = 0.8). Conclusions: In the control group, high AIB1 was a negative prognostic factor. However, ER-positive patients with high AIB1 responded significantly to tamoxifen. This implicates high AIB1 to be an independent predictive factor of improved response to tamoxifen and not, as has previously been discussed, a factor predicting tamoxifen resistance.
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| 6. |
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| 7. |
- Alkner, Sara, et al.
(författare)
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Prediction of outcome after diagnosis of metachronous contralateral breast cancer.
- 2011
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although 2-20% of breast cancer patients develop a contralateral breast cancer (CBC), prognosis after CBC is still debated. Using a unique patient cohort, we have investigated whether time interval to second breast cancer (BC2) and mode of detection are associated to prognosis. METHODS: Information on patient-, tumour-, treatment-characteristics, and outcome was abstracted from patients' individual charts for all patients diagnosed with metachronous CBC in the Southern Healthcare Region of Sweden from 1977-2007. Distant disease-free survival (DDFS) and risk of distant metastases were primary endpoints. RESULTS: The cohort included 723 patients with metachronous contralateral breast cancer as primary breast cancer event. Patients with less than three years to BC2 had a significantly impaired DDFS (p = 0.01), and in sub-group analysis, this effect was seen primarily in patients aged <50. By logistic regression analysis, patients diagnosed with BC2 within routine follow-up examinations had a significantly lower risk of developing metastases compared to those who were symptomatic at diagnosis (p < 0.0001). Chemotherapy given after breast BC1 was a negative prognostic factor for DDFS, whereas endocrine treatment and radiotherapy given after BC2 improved DDFS. CONCLUSIONS: In a large cohort of patients with CBC, we found the time interval to BC2 to be a strong prognostic factor for DDFS in young women and mode of detection to be related to risk of distant metastases. Future studies of tumour biology of BC2 in relation to prognostic factors found in the present study can hopefully provide biological explanations to these findings.
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| 8. |
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| 9. |
- Alkner, Sara, et al.
(författare)
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Prior Adjuvant Tamoxifen Treatment in Breast Cancer Is Linked to Increased AIB1 and HER2 Expression in Metachronous Contralateral Breast Cancer.
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- The estrogen receptor coactivator Amplified in Breast Cancer 1 (AIB1) has been associated with an improved response to adjuvant tamoxifen in breast cancer, but also with endocrine treatment resistance. We hereby use metachronous contralateral breast cancer (CBC) developed despite prior adjuvant tamoxifen for the first tumor as an "in vivo"-model for tamoxifen resistance. AIB1-expression in the presumable resistant (CBC after prior tamoxifen) and naïve setting (CBC without prior tamoxifen) is compared and correlated to prognosis after CBC.
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| 10. |
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| 11. |
- Alkner, Sara, et al.
(författare)
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Protocol for the T-REX-trial: tailored regional external beam radiotherapy in clinically node-negative breast cancer patients with 1-2 sentinel node macrometastases - an open, multicentre, randomised non-inferiority phase 3 trial.
- 2023
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Ingår i: BMJ open. - 2044-6055. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- Modern systemic treatment has reduced incidence of regional recurrences and improved survival in breast cancer (BC). It is thus questionable whether regional radiotherapy (RT) is still beneficial in patients with sentinel lymph node (SLN) macrometastasis. Postoperative regional RT is associated with an increased risk of arm morbidity, pneumonitis, cardiac disease and secondary cancer. Therefore, there is a need to individualise regional RT in relation to the risk of recurrence.In this multicentre, prospective randomised trial, clinically node-negative patients with oestrogen receptor-positive, HER2-negative BC and 1-2 SLN macrometastases are eligible. Participants are randomly assigned to receive regional RT (standard arm) or not (intervention arm). Regional RT includes the axilla level I-III, the supraclavicular fossa and in selected patients the internal mammary nodes. Both groups receive RT to the remaining breast. Chest-wall RT after mastectomy is given in the standard arm, but in the intervention arm only in cases of widespread multifocality according to national guidelines. RT quality assurance is an integral part of the trial.The trial aims to include 1350 patients between March 2023 and December 2028 in Sweden and Norway. Primary outcome is recurrence-free survival (RFS) at 5years. Non-inferiority will be declared if outcome in the de-escalation arm is not >4.5percentage units below that with regional RT, corresponding to an HR of 1.41 assuming 88% 5-year RFS with standard treatment. Secondary outcomes include locoregional recurrence, overall survival, patient-reported arm morbidity and health-related quality of life. Gene expression analysis and tumour tissue-based studies to identify prognostic and predictive markers for benefit of regional RT are included.The trial protocol is approved by the Swedish Ethics Authority (Dnr-2022-02178-01, 2022-05093-02, 2023-00826-02, 2023-03035-02). Results will be presented at scientific conferences and in peer-reviewed journals.NCT05634889.
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| 12. |
- Alkner, Sara, et al.
(författare)
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Quality assessment of radiotherapy in the prospective randomized SENOMAC trial
- 2024
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Ingår i: Radiotherapy and Oncology. - 0167-8140 .- 1879-0887. ; 197
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Recommendations for regional radiotherapy (RT) of sentinel lymph node (SLN)-positive breast cancer are debated. We here report a RT quality assessment of the SENOMAC trial.Materials and Methods: The SENOMAC trial randomized clinically node-negative breast cancer patients with 1–2 SLN macrometastases to completion axillary lymph node dissection (cALND) or SLN biopsy only between 2015–2021. Adjuvant RT followed national guidelines. RT plans for patients included in Sweden and Denmark until June 2019 were collected (N = 1176) and compared to case report forms (CRF). Dose to level I (N = 270) and the humeral head (N = 321) was analyzed in detail.Results: CRF-data and RT plans agreed in 99.3 % (breast/chest wall) and in 96.6 % of patients (regional RT). Congruence for whether level I was an intended RT target was lower (78 %). In accordance with Danish national guidelines, level I was more often an intended target in the SLN biopsy only arm (N = 334/611, 55 %,) than in the cALND arm (N = 174/565, 31 %,). When an intended target, level I received prescribed dose to 100 % (IQR 98–100 %) of the volume. However, even when not an intended target, full dose was delivered to > 80 % of level I (IQR 75–90 %). The intentional inclusion of level I in the target volume more than doubled the dose received by ≥ 50 % of the humeral head.Conclusion: Congruence between CRF data and RT plans was excellent. Level I received a high dose coverage even when not intentionally included in the target. Including level I in target significantly increased dose to the humeral head.
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| 13. |
- Alkner, Sara, et al.
(författare)
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Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women : Results from a controlled randomised trial
- 2009
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 45:14, s. 2496-2502
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial. Patients and methods: Premenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years. Results: In the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients less than40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40-49 years of age or ≥50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time. Conclusion: In this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women less than40 years of age. The effect of tamoxifen was not significantly dependent on time.
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| 14. |
- Alkner, Sara, et al.
(författare)
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The role of AIB1 and PAX2 in primary breast cancer: validation of AIB1 as a negative prognostic factor.
- 2013
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 24:5, s. 1244-1252
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe steroid-receptor coactivator amplified in breast cancer one (AIB1) is implicated to be a prognostic factor, although the results are not unanimous. Recently its effect was suggested to be modified by paired box 2 gene product (PAX2).Patients and methodsUsing immunohistochemistry (IHC) AIB1 and PAX2 were investigated in two cohorts of early breast cancer, including systemically untreated premenopausal lymph-node-negative women and pre- and postmenopausal women receiving tamoxifen.ResultsAIB1 scores were available for 490 patients and PAX2 scores were available for 463 patients. High AIB1 was a negative prognostic factor for distant disease-free survival (DDFS, P = 0.02) and overall survival (OS, P < 0.001) in systemically untreated women, while no prognostic effect was seen in the tamoxifen-treated cohort, indicating AIB1 to be a predictor of tamoxifen response. In systemically untreated patients, PAX2 was not a prognostic factor, nor did it modify the effect of AIB1. However, in ER-positive patients receiving tamoxifen, PAX2 appeared to be a positive prognostic factor in premenopausal patients, while a negative factor in postmenopausal. The interaction between the menopausal status and PAX2 was significant (P = 0.01).ConclusionsIn an independent cohort of low-risk premenopausal patients, we validate AIB1 as a negative prognostic factor, indicating AIB1 to be an interesting target for new anti-cancer therapies. The effect of PAX2 warrants further studies.
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| 15. |
- Appelgren, M., et al.
(författare)
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Patient-reported outcomes one year after positive sentinel lymph node biopsy with or without axillary lymph node dissection in the randomized SENOMAC trial
- 2022
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Ingår i: Breast. - : Elsevier BV. - 0960-9776 .- 1532-3080. ; 63, s. 16-23
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: This report evaluates whether health related quality of life (HRQoL) and patient-reported arm morbidity one year after axillary surgery are affected by the omission of axillary lymph node dissection (ALND). Methods: The ongoing international non-inferiority SENOMAC trial randomizes clinically node-negative breast cancer patients (T1-T3) with 1-2 sentinel lymph node (SLN) macrometastases to completion ALND or no further axillary surgery. For this analysis, the first 1181 patients enrolled in Sweden and Denmark between March 2015, and June 2019, were eligible. Data extraction from the trial database was on November 2020. This report covers the secondary outcomes of the SENOMAC trial: HRQoL and patient-reported arm morbidity. The EORTC QLQC30, EORTC QLQ-BR23 and Lymph-ICF questionnaires were completed in the early postoperative phase and at one-year follow-up. Adjusted one-year mean scores and mean differences between the groups are presented corrected for multiple testing.
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| 16. |
- Axelsson, Ulrika, et al.
(författare)
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A multicenter study investigating the molecular fingerprint of psychological resilience in breast cancer patients : Study protocol of the SCAN-B resilience study
- 2018
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Individual patients differ in their psychological response when receiving a cancer diagnosis, in this case breast cancer. Given the same disease burden, some patients master the situation well, while others experience a great deal of stress, depression and lowered quality of life. Patients with high psychological resilience are likely to experience fewer stress reactions and better adapt to and manage the life threat and the demanding treatment that follows the diagnosis. If this phenomenon of mastering difficult situations is reflected also in biomolecular processes is not much studied, nor has its capacity for impacting the cancer prognosis been addressed. This project specifically aims, for the first time, to investigate how a breast cancer patient's psychological resilience is coupled to biomolecular parameters using advanced "omics" and, as a secondary aim, whether it relates to prognosis and quality of life one year after diagnosis. Method: The study population consists of newly diagnosed breast cancer patients enrolled in the Sweden Cancerome Analysis Network - Breast (SCAN-B) at four hospitals in Sweden. At the time of cancer diagnosis, the patient fills out the standardized method to measure psychological resilience, the "Connor-Davidson Resilience scale" (CD-RISC), the quality of life measure SF-36, as well as providing social and socioeconomic variables. In addition, one blood sample is collected. At the one-year follow-up, the patient will be subjected to the same assessments, and we also collect information regarding smoking, exercise habits, and BMI, as well as patients' trust in the treatment and their satisfaction with the care and treatment. Discussion: This explorative hypothesis-generating project will pave the way for larger validation studies, potentially leading to a standardized method of measuring psychological resilience as an important parameter in cancer care. Revealing the body-mind interaction, in terms of psychological resilience and quality of life, will herald the development of truly personalized psychosocial care and cancer intervention treatment strategies. Trial registration: This is a retrospectively registered trial at ClinicalTrials.gov, ID: NCT03430492on February 6, 2018.
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| 17. |
- Bengtsson, Ylva, et al.
(författare)
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Serum copper, zinc and copper/zinc ratio in relation to survival after breast cancer diagnosis: A prospective multicenter cohort study
- 2023
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Ingår i: Redox Biology. - 2213-2317. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe essential trace elements copper and zinc, and their ratio (copper/zinc), are important for maintaining redox homeostasis. Previous studies suggest that these elements may impact breast cancer survival. However, no epidemiological study has so far been conducted on the potential association between copper and copper/zinc levels and survival after breast cancer diagnosis. In this study, we aimed to examine the relationship between serum copper, zinc and copper/zinc levels and survival following breast cancer diagnosis.Patients and methodsThe Sweden Cancerome Analysis Network – Breast Initiative (SCAN-B) is a population-based cohort study including multiple participating hospitals in Sweden. A total of 1998 patients diagnosed with primary invasive breast cancer were followed for approximately nine years. Serum levels of copper and zinc and their ratio at the time of diagnosis was analyzed in relation to breast cancer survival using multivariate Cox regression, yielding hazard ratios (HR) with 95% confidence intervals.ResultsA higher copper/zinc ratio was associated with lower overall survival after breast cancer diagnosis. Comparing patients with a copper/zinc ratio in quartile 4 vs 1, the crude HR was 2.29 (1.65–3.19) (Ptrend ConclusionThere is evidence that the serum copper/zinc ratio provides an independent predictive value for overall survival following breast cancer diagnosis.
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| 18. |
- Bergenfelz, Caroline, et al.
(författare)
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Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells, which increase in cancer patients. The molecular mechanism behind their generation and function is unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer, the presence and relevance of monocytic-MDSCs (Mo-MDSCs) is unknown. Here we report for the first time an enrichment of functional blood Mo-MDSCs in breast cancer patients before they acquire a typical Mo-MDSC surface phenotype. A clear population of Mo-MDSCs with the typical cell surface phenotype (CD14+HLA-DRlow/-CD86low/-CD80low/-CD163low/-) increased significantly first during disease progression and correlated to metastasis to lymph nodes and visceral organs. Furthermore, monocytes, comprising the Mo-MDSC population, from patients with metastatic breast cancer resemble the reprogrammed immunosuppressive monocytes in patients with severe infections, both by their surface and functional phenotype but also at their molecular gene expression profile. Our data suggest that monitoring the Mo-MDSC levels in breast cancer patients may represent a novel and simple biomarker for assessing disease progression.
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| 19. |
- Berger, Karoline, 1991, et al.
(författare)
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Tumor co-expression of progranulin and sortilin as a prognostic biomarker in breast cancer
- 2021
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 20. |
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| 21. |
- Bjarnadottir, Olöf, et al.
(författare)
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Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial
- 2013
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 138:2, s. 499-508
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Tidskriftsartikel (refereegranskat)abstract
- Lipophilic statins purportedly exert anti-tumoral effects on breast cancer by decreasing proliferation and increasing apoptosis. HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, is the target of statins. However, data on statin-induced effects on HMGCR activity in cancer are limited. Thus, this pre-operative study investigated statin-induced effects on tumor proliferation and HMGCR expression while analyzing HMGCR as a predictive marker for statin response in breast cancer treatment. The study was designed as a window-of-opportunity trial and included 50 patients with primary invasive breast cancer. High-dose atorvastatin (i.e., 80 mg/day) was prescribed to patients for 2 weeks before surgery. Pre- and post-statin paired tumor samples were analyzed for Ki67 and HMGCR immunohistochemical expression. Changes in the Ki67 expression and HMGCR activity following statin treatment were the primary and secondary endpoints, respectively. Up-regulation of HMGCR following atorvastatin treatment was observed in 68 % of the paired samples with evaluable HMGCR expression (P = 0.0005). The average relative decrease in Ki67 expression following atorvastatin treatment was 7.6 % (P = 0.39) in all paired samples, whereas the corresponding decrease in Ki67 expression in tumors expressing HMGCR in the pre-treatment sample was 24 % (P = 0.02). Furthermore, post-treatment Ki67 expression was inversely correlated to post-treatment HMGCR expression (rs = -0.42; P = 0.03). Findings from this study suggest that HMGCR is targeted by statins in breast cancer cells in vivo, and that statins may have an anti-proliferative effect in HMGCR-positive tumors. Future studies are needed to evaluate HMGCR as a predictive marker for the selection of breast cancer patients who may benefit from statin treatment.
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| 22. |
- Björk Gunnarsdottir, Frida, et al.
(författare)
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Co-localization of CD169+ macrophages and cancer cells in lymph node metastases of breast cancer patients is linked to improved prognosis and PDL1 expression
- 2020
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Ingår i: OncoImmunology. - 2162-4011. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is the most common form of cancer in women worldwide. Although the survival among breast cancer patients has improved, there is still a large group of patients with dismal prognosis. One of the most important prognostic factors for poor prognosis is lymph node metastasis. Increasing knowledge concerning the lymph nodes of breast cancer patients indicates that they are affected by the primary tumor. In this study we show that presence of CD169+ subcapsular sinus macrophages in contact with lymph node metastases in breast cancer patients, is related to better prognosis after adjuvant tamoxifen treatment, but only in patients with PDL1+ primary tumors. This is in contrast to the prognostic effect of CD169+ primary tumor-associated macrophages (TAMs). We further show that CD169+ macrophages were spatially associated with expression of PDL1 on nearby cells, both in primary tumors and metastatic lymph node, although PDL1 expression in metastatic lymph node as such did not have further prognostic impact. Our data suggest that CD169+ resident lymph node macrophages have a unique function in targeting immune responses against breast cancer and should be further investigated in detail.
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| 23. |
- Borgquist, Signe, et al.
(författare)
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Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:5, s. R79-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We have previously reported that tumour-specific expression of the rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR), in the mevalonate pathway is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up. METHODS: The expression of HMG-CoAR was assessed by immunohistochemistry on tissue microarrays with tumour specimens from 498 consecutive cases of breast cancer with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the rate of recurrence-free survival (RFS) and breast cancer specific survival (BCSS). RESULTS: In line with our previous findings, tumour-specific HMG-CoAR expression was associated with low grade (p < 0.001), small size (p = 0.007), oestrogen receptor (ER) positive (p = 0.01), low Ki-67 (p = 0.02) tumours. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS, even when adjusted for established prognostic factors (relative risk [RR] = 0.60, 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In ER-negative tumours, however, there was a trend, that was not significantly significant, towards a shorter RFS in HMG-CoAR expressing tumours. CONCLUSIONS: HMG-CoAR expression is an independent predictor of a prolonged RFS in primary breast cancer. This may, however, not be true for ER-negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status.
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| 24. |
- Brennan, Donal J., et al.
(författare)
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CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6421-6431
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Hypoxia in breast cancer is associated with poor prognosis and down-regulation of the estrogen receptor. Carbonic anhydrase IX (CA IX) is a hypoxia-inducible gene that has been associated with poor outcome in many epithelial cancers. Previous studies of CA IX in breast cancer have been carried out on mixed cohorts of premenopausal and postmenopausal patients with locally advanced disease and varying treatment regimens. We examined the potential prognostic and predictive role of CA IX in premenopausal breast cancer patients. Experimental Design: Using tissue microarrays, we analyzed CA IX expression in 400 stage 11 breast cancers from premenopausal women. The patients had previously participated in a randomized control trial comparing 2 years of tamoxifen to no systemic adjuvant treatment. Median follow-up was 13.9 years. Results: CA IX expression correlated positively with tumor size, grade, hypoxia-inducible factor 1 alpha Ki-67, cyclin E, and cyclin A2 expression. CA IX expression correlated negatively with cyclin D1, estrogen receptor, and progesterone receptor. CA IX expression was associated with a reduced relapse-free survival (P = 0.032), overall survival (P = 0.022), and breast cancer specific survival (P = 0.005). Multivariate analysis revealed that CA IX was an independent prognostic marker in untreated patients with one to three positive lymph nodes (hazard ratio, 3.2; 95% confidence interval, 1.15-9.13; P = 0.027). Conclusion: CA IX is marker of poor prognosis in premenopausal breast cancer patients and it is an independent predictor of survival in patients with one to three positive lymph nodes. As all these patients received locoregional radiation therapy, CA IX may be associated with resistance to radiotherapy.
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| 25. |
- Brennan, D. J., et al.
(författare)
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The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ER alpha, and is an independent prognostic factor in node-negative breast cancer
- 2012
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 31:30, s. 3483-3494
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Tidskriftsartikel (refereegranskat)abstract
- Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n = 690; P = 0.002, 0.013). We also show that CART increases the transcriptional activity of ER alpha in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy. Oncogene (2012) 31, 3483-3494; doi:10.1038/onc.2011.519; published online 5 December 2011
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