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- Abe, O, et al.
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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In: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Journal article (peer-reviewed)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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- Aaltonen, K. E., et al.
(author)
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Gene expression of breast cancer related genes in circulating tumour cells (CTCs) from patients with metastatic breast cancer
- 2015
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 26:Suppl. 3, s. 15-15
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Journal article (peer-reviewed)abstract
- Introduction: Detection of circulating tumour cells (CTCs) in peripheral blood has an established prognostic significance in patients with metastatic breast cancer. Change in the number of detected CTCs is also an indication of response to therapy. Characterisation of CTCs could provide easily accessible treatment predictive information of present cancer cells within the patient and could reveal important knowledge about the metastatic process. The aim of this pilot study was to characterize CTCs with regard to both treatment predictive and more experimental markers by analysing the expression of genes associated with breast cancer.Methods: Blood samples from twelve patients with metastatic breast cancer included in the ongoing CTC-MBC study at Lund University, Sweden (Clinical Trials Id. NCT01322893) were analysed in this pilot study. Systemic treatment included endocrine, targeted and chemotherapy regimen. Blood samples were collected before start of 1st line therapy and at four time points. If progression occurred, a new round of samples was taken. CTCs were isolated from whole blood using the commercial kits AdnaTest EMT1/stem cell and AdnaTest EMT2/stem cell (AdnaGen AG, Langenhagen, Germany). With this method, CTCs are captured using antibodies directed against EpCAM and MUC-1 (EMT1-kit) or EpCAM, HER2 and EGFR (EMT2-kit). Gene expression analyses from CTCs at each time point was performed by TATAA Biocenter (Gothenburg, Sweden) using qPCR. 38 breast cancer related genes were analysed including the oestrogen receptor (ESR), HER2, VEGFR2, ALDH1, PI3K, PTEN and TWIST1.Results: Using positive expression of pseudo-markers EpCAM, MUC1 and HER2 as definition of CTCs, 6 of 12 patients were positive for CTCs. However, gene expression of additional markers in potential CTCs suggests complex patterns such as an increase in TWIST1, ALDH1 and SATB1 at time of progression.Conclusions: We present gene expression data from CTCs isolated before and during therapy in metastatic breast cancer patients. This type of characterisation could provide information of importance for treatment response and clinical outcome.Clinical trial identification: NCT01322893, March 24 2011
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- Aaltonen, Kristina E., et al.
(author)
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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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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:28, s. 45544-45565
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Journal article (peer-reviewed)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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