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Journal ArticleDOI

Measuring proliferation in breast cancer: practicalities and applications.

30 Nov 2006-Breast Cancer Research (BioMed Central)-Vol. 8, Iss: 6, pp 216-216
TL;DR: The potential clinical applications of proliferative indices are discussed, including their use as prognostic indicators and predictors of response to systemic therapy.
Abstract: Various methods are available for the measurement of proliferation rates in tumours, including mitotic counts, estimation of the fraction of cells in S-phase of the cell cycle and immunohistochemistry of proliferation-associated antigens. The evidence, advantages and disadvantages for each of these methods along with other novel approaches is reviewed in relation to breast cancer. The potential clinical applications of proliferative indices are discussed, including their use as prognostic indicators and predictors of response to systemic therapy.

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Citations
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Journal ArticleDOI
TL;DR: An update on the current knowledge on Ki67 and of the evidence in the published work about the prognostic and predictive role of this marker is provided, and information on the laboratory techniques used to determine Ki67 is provided.
Abstract: The leading parameters that define treatment recommendations in early breast cancer are oestrogen-receptor, progesterone-receptor, and human epidermal growth-factor status. Although some pathologists report Ki67 in addition to other biological markers, the existing guidelines of the American Society of Clinical Oncology do not include Ki67 in the list of required routine biological markers. The advent of new genetic tests has emphasised the role of proliferative genes, including Ki67, as prognostic and predictive markers. Additionally, randomised studies have retrospectively reviewed data and reported on the role of Ki67 in breast cancer. In light of new data, we have re-assessed evidence that could change guidelines to include Ki67 in the standard pathological assessment of early breast cancers. This review provides an update on the current knowledge on Ki67 and of the evidence in the published work about the prognostic and predictive role of this marker, and provides information on the laboratory techniques used to determine Ki67.

982 citations

Journal ArticleDOI
TL;DR: The elements impacting analytical validity of the Ki67 immunohistochemical assay, the evidence of its clinical utility and the current recommendations for its use in breast cancer management are reviewed.

154 citations

Journal ArticleDOI
01 Jan 2013-Oncology
TL;DR: The debate on the prognostic role of Ki67 in breast cancer is still open, although most of the studies have established a relation between Ki67 and overall and disease-free survival.
Abstract: Background: Ki67 is an immunohistochemical proliferation marker in many types of cancer and has been widely studied among breast cancer patients mostly through retrospective studies Methods: The MEDLINE/PubMed database was searched for publications with the medical subject heading ‘Ki 67’ and the key words ‘breast’, ‘cancer’, and ‘prognosis’ We restricted our search to articles published until 2012 Results: In this review, we included 78 articles and abstracts that were accessible and available in English An effort to further explain the role of Ki67 in the prognosis of breast cancer has been made Conclusions: The debate on the prognostic role of Ki67 in breast cancer is still open, although most of the studies have established a relation between Ki67 and overall and disease-free survival Further research should be made in order to establish Ki67 as a standard prognostic marker in breast cancer

127 citations

Journal ArticleDOI
TL;DR: Assessment of proliferation by using Ki-67LI and MS can distinguish subgroups of patients within luminal/hormone receptor-positive breast cancer significantly different in clinical outcomes, and could provide a cost-effective method for prognostic subclassification of luminal-horm one receptor- positive breast cancer in routine clinical practice.
Abstract: Although the prognostic significance of proliferation in early invasive breast cancer has been recognized for a long time, recent gene-expression profiling studies have reemphasized its biologic and prognostic value and the potential application of its assessment in routine practice, particularly to define prognostic subgroups of luminal/hormone receptor-positive (HR+) tumors. This study aimed to assess the prognostic value of a proliferation assay by using Ki-67 immunohistochemistry as compared with mitotic count scores. Proliferation was assessed by using Ki-67 labeling index (Ki-67LI) and mitotic scores in a large (n = 1,550) and well-characterized series of clinically annotated primary operable invasive breast cancer with long-term follow-up. Tumors were phenotyped based on their IHC profiles into luminal/HR+, HER2+, and triple-negative (TN) classes. We used a split-sample development and validation approach to determine the optimal Ki-67LI cut-offs. The optimal cut-points of Ki-67LI were 10% and 50% for the luminal class. Both Ki7LI and MS were able to split luminal tumors into subgroups with significantly variable outcomes, independent of other variables. Neither mitotic count scores nor Ki-67LI was associated with outcome in the HER2+ or the TN classes. Assessment of proliferation by using Ki-67LI and MS can distinguish subgroups of patients within luminal/hormone receptor-positive breast cancer significantly different in clinical outcomes. Overall, both Ki-67 LI and mitotic-count scores showed comparable results. The method described could provide a cost-effective method for prognostic subclassification of luminal/hormone receptor-positive breast cancer in routine clinical practice.

111 citations


Cites methods or result from "Measuring proliferation in breast c..."

  • ...Various techniques have been developed to quantify proliferation rates, including, mitotic-count estimates, measurement of DNA synthesis, and flow cytometry [1,7-9]....

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  • ...These findings confirm the prognostic relevance of routinely assessed MS in the luminal class, as previously reported in BC [1,7,8]....

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Journal ArticleDOI
TL;DR: Evidence is provided that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.
Abstract: Alterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study, we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2-stimulated ERE-luciferase activity in both MCF-7 and ER-transfected HEK293 cells. Furthermore, the inhibitor reduced E2-mediated transcription of the ER-regulated genes progesterone receptor and SDF-1. Competitive receptor-binding assays revealed that ABC294640 binds in the antagonist ligand-binding domain of the ER, acting as a partial antagonist similar to tamoxifen. Finally, treatment with ABC294640 inhibited ER-positive breast cancer tumor formation in vivo. After 15 d of treatment with ABC294640, tumor volume was reduced by 68.4% (P < 0.05; n = 5) compared with control tumors, with no marked weight loss or illness. Taken together, these results provide strong evidence that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.

109 citations

References
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Journal ArticleDOI
31 Jan 2002-Nature
TL;DR: DNA microarray analysis on primary breast tumours of 117 young patients is used and supervised classification is applied to identify a gene expression signature strongly predictive of a short interval to distant metastases (‘poor prognosis’ signature) in patients without tumour cells in local lymph nodes at diagnosis, providing a strategy to select patients who would benefit from adjuvant therapy.
Abstract: Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

9,664 citations


"Measuring proliferation in breast c..." refers background in this paper

  • ...High-throughput tissue microarrays can be used to screen for genes with differential expression between cancer cells and normal tissue [89,90] and gene expression signatures have been developed that can predict survival in breast cancer [91,92]....

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Journal ArticleDOI
TL;DR: The gene-expression profile studied is a more powerful predictor of the outcome of disease in young patients with breast cancer than standard systems based on clinical and histologic criteria.
Abstract: Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...

5,902 citations

Journal ArticleDOI
TL;DR: The results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained.
Abstract: Morphological assessment of the degree of differentiation has been shown in numerous studies to provide useful prognostic information in breast cancer, but until recently histological grading has not been accepted as a routine procedure, mainly because of perceived problems with reproducibility and consistency. In the Nottingham/Tenovus Primary Breast Cancer Study the most commonly used method, described by Bloom & Richardson, has been modified in order to make the criteria more objective. The revised technique involves semiquantitative evaluation of three morphological features--the percentage of tubule formation, the degree of nuclear pleomorphism and an accurate mitotic count using a defined field area. A numerical scoring system is used and the overall grade is derived from a summation of individual scores for the three variables: three grades of differentiation are used. Since 1973, over 2200 patients with primary operable breast cancer have been entered into a study of multiple prognostic factors. Histological grade, assessed in 1831 patients, shows a very strong correlation with prognosis; patients with grade I tumours have a significantly better survival than those with grade II and III tumours (P less than 0.0001). These results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained. Histological grade forms part of the multifactorial Nottingham prognostic index, together with tumour size and lymph node stage, which is used to stratify individual patients for appropriate therapy.

5,575 citations


Additional excerpts

  • ...Mitotic count estimates are widely used as a simple measure of cellular proliferation and are often incorporated into tumour grading systems [3]....

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Journal ArticleDOI
29 Oct 1982-Science
TL;DR: Monoclonal antibodies specific for 5-bromodeoxyuridine have been produced and applied in detecting low levels of DNA replication on a cell-by-cell basis in vitro and do not cross-react with thymidine.
Abstract: Monoclonal antibodies specific for 5-bromodeoxyuridine have been produced and applied in detecting low levels of DNA replication on a cell-by-cell basis in vitro. The immunoglobulin-producing hybridomas were derived from spleen cells of mice immunized with a conjugate of iodouridine and ovalbumin. The cells were fused with the plasmacytoma line SP2/0Ag14. The antibodies produced are highly specific for bromodeoxyuridine and iododeoxyuridine and do not cross-react with thymidine. DNA synthesis in cultured cells exposed to bromodeoxyuridine for as short a time as 6 minutes can be detected easily and rapidly by an immunofluorescent staining method and quantitated by flow cytometry.

2,722 citations


"Measuring proliferation in breast c..." refers background in this paper

  • ...In 1982 Gratzner [16] described the use of monoclonal...

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  • ...In 1982 Gratzner [16] described the use of monoclonal antibodies specific for 5-bromodeoxyuridine (BrdU) in the detection of DNA replication....

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