| 1. |
- Aaltonen, Kirsimari, et al.
(författare)
-
Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides
- 2006
-
Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 94:11, s. 1697-1702
-
Tidskriftsartikel (refereegranskat)abstract
- Cyclin A has in some studies been associated with poor breast cancer survival, although all studies have not confirmed this. Its prognostic significance in breast cancer needs evaluation in larger studies. Tissue microarray (TMA) technique allows a simultaneous analysis of large amount of tumours on a single microscopic slide. This makes a rapid screening of molecular markers in large amount of tumours possible. Because only a small tissue sample of each tumour is punched on an array, the question has arisen about the representativeness of TMA when studying markers that are expressed in only a small proportion of cells. For this reason, we wanted to compare cyclin A expression on TMA and on traditional large sections. Two breast cancer TMAs were constructed of 200 breast tumours diagnosed between 1997-1998. TMA slides and traditional large section slides of these 200 tumours were stained with cyclin A antibody and analysed by two independent readers. The reproducibility of the two readers' results was good or even very good, with kappa values 0.71-0.87. The agreement of TMA and large section results was good with kappa value 0.62-0.75. Cyclin A overexpression was significantly (P<0.001) associated with oestrogen receptor and progesterone receptor negativity and high grade both on TMA and large sections. Cyclin A overexpression was significantly associated with poor metastasis-free survival both on TMA and large sections. The relative risks for metastasis were similar on TMA and large sections. This study suggests that TMA technique could be useful to study histological correlations and prognostic significance of cyclin A on breast cancer on a large scale.
|
|
| 2. |
- Ahlin, Cecilia, et al.
(författare)
-
Cyclin A is a proliferative marker with good prognostic value in node-negative breast cancer
- 2009
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 18:9, s. 2501-2506
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Proliferative markers are not recommended as prognostic factors for clinical use in breast cancer due to lack of standardization in methodology. However, proliferation is driving several gene expression signatures emphasizing the need for a reliable proliferative marker IF or clinical use. Studies suggest that cyclin A is a prognostic marker with satisfying reproducibility. We investigated cyclin A as a prognostic marker in node-negative breast cancer using previously defined cutoff values. Patients and Methods: In a case-control study, we defined 190 women who died from breast cancer as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size <= 50 mm, no lymph node metastases and no adjuvant chemotherapy. Tumor tissues were immunostained for cyclin A using commercially available antibodies. Results: We found a statistically significant association between expression of cyclin A and breast cancer death in a univariate model: odds ratio for cyclin A(ave) 2.7 [95% confidence interval (CI), 1.7-4.3] and cyclin A(max) 3.4 (CI, 2.1-5.5). Corresponding odds ratio for Ki67 were Ki67(ave) 1.9 (CI, 1.2-3.1) and Ki67(max) 1.7 (CI, 1.1-2.7) and for grade 3.1 (CI, 1.8-5.1). Cyclin A was strongly correlated to Ki67 and grade why a model including all was not appropriate. Conclusions: Cyclin A is a prognostic factor for breast cancer death in node-negative patients using standardized methodology regarding scoring and cutoff values. Adding cyclin A as a proliferative marker to established clinicopathologic factors will improve the separation of low and high risk breast cancer.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Ahlin, Cecilia, et al.
(författare)
-
Ki67 and cyclin A as prognostic factors in early breast cancer : What are the optimal cut-off values?
- 2007
-
Ingår i: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 51:4, s. 491-498
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: To find the optimal cut-off values for cyclin A and Ki67 in early breast cancer tumours and to evaluate their prognostic values. METHODS AND RESULTS: Tissue microarray (TMA) slides were constructed from 570 T1-4 N0-1 M0 breast cancer tumours. The TMA slides were stained for cyclin A and Ki67 using immunohistochemistry with commercial antibodies. To investigate the optimal cut-off values for cyclin A, Ki67 average and maximum values the material was split into two parts at cut-offs defined by dividing it into deciles. For each cut-off value the relative risk (RR) for metastasis-free survival (MFS) and overall survival (OS) was calculated comparing patients with high versus low cyclin A or Ki67 expression. When using a cut-off value around the seventh decile, cyclin A and Ki67 score correlated with the highest RR ratio for MFS in the chemotherapy-naïve subgroup. Among patients having received adjuvant chemotherapy, no statistically significant differences in MFS or OS were found. CONCLUSIONS: The optimal cut-off value for cyclin A average is 8% and for cyclin A maximum value 11%; for Ki67 the corresponding values are 15% and 22%. Additional studies are needed to verify these results.
|
|
| 6. |
- Humphries, Matthew P., et al.
(författare)
-
A case-matched gender comparison transcriptomic screen identifies eIF4E and eIF5 as potential prognostic markers in male breast cancer
- 2017
-
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 23:10, s. 2575-2583
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required.
|
|
| 7. |
- Klintman, Marie, et al.
(författare)
-
The Prognostic Value of Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), Cyclin B1, Cyclin A, and Ki67, Alone and in Combinations, in Node-Negative Premenopausal Breast Cancer
- 2013
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12
-
Tidskriftsartikel (refereegranskat)abstract
- Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off >= 10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95% CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95% CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95% CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95% CI: 1.1-6.7), and cyclin A (HR=2.7, 95% CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found.
|
|
| 8. |
- Lundgren, Claudia, et al.
(författare)
-
Cyclin E1 is a strong prognostic marker for death from lymph node negative breast cancer : A population-based case-control study
- 2015
-
Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 54:4, s. 538-544
-
Tidskriftsartikel (refereegranskat)abstract
- Background. A large proportion of women with lymph node negative breast cancer treated with systemic adjuvant treatment do not benefit from such therapy since the patient is already cured by local treatment. Several studies have suggested that proliferation markers are strong prognostic factors in early breast cancer. Cyclins are probably the most specific markers of cell proliferation. Previously high expression of cyclin E has been associated with breast cancer recurrence.Materials and methods. In this study we investigate the prognostic value of cyclin E1 in node negative breast cancer patients. In a population-based cohort 186 women who died from breast cancer were defined as cases and 186 women alive at the corresponding time as controls. Inclusion criteria were tumour size ≤ 50 mm, no lymph node metastases and no adjuvant chemotherapy. The study was designed to detect an odds ratio of 2.5 with a power of 90% and significance level of 0.05. Cyclin E1 was determined with immunohistochemistry (IHC) on tissue microarray (TMA).Results. High expression of cyclin E1 was significantly associated with breast cancer death, in both uni- and multivariate analyses with odds ratios (OR) 2.3 [univariate, 95% confidence interval (CI) 1.5-3.6] and 2.1 (multivariate, 95% CI 1.2-3.5).Discussion. Cyclin E1 is a strong prognostic factor for breast cancer death in a population-based and node negative patient cohort and can identify high-risk patients in this group.
|
|
| 9. |
- Löfdahl, Britta, et al.
(författare)
-
Inflammatory cells in node-negative breast cancer
- 2012
-
Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 51:5, s. 680-686
-
Tidskriftsartikel (refereegranskat)abstract
- Background.To study the impact of inflammatory cells in a clinically well-defined cohort of women with node-negative breast cancer in a nested case-control study design.Material and methods.The cohort was comprised of 190 women who died from breast cancer and 190 women still alive at the date of death for the corresponding breast cancer patients were used as controls. The inclusion criteria included; a tumour size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy. Immunohistochemical stainings for CD3, CD4, CD8, FoxP3, CD20, tryptase and CD68 were performed on TMA blocks, evaluated and correlated to each other and to age, tumour size, histological grade, ER, PgR, Ki67 and cyclin A.Results.There was no difference regarding the amount or content of inflammatory cells in the cases compared to controls. T- and B-cells were highly correlated to each other but these cell types correlated to a lesser extent to macrophages and not at all to mast cells. A weak tendency of correlations between all the subsets of inflammatory cells and histological grade, Ki67 and cyclin A was observed, although a negative correlation was seen for mast cells.Conclusion.The amount or content of inflammatory cells in invasive breast cancer did not appear to influence death in node-negative breast cancer.
|
|
| 10. |
- Nilsson, Cecilia, et al.
(författare)
-
Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact
- 2013
-
Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 52:1, s. 102-109
-
Tidskriftsartikel (refereegranskat)abstract
- Background. Male breast cancer (MBC) is an uncommon disease and there is limited information on the prognostic impact of routinely used clinicopathological parameters. Material and methods. In a retrospective setting, we reviewed 197 MBC patients with accessible paraffin-embedded tumor tissue and clinicopathological data. Immunohistochemical (IHC) stainings were performed on tissue microarrays and histological grading on conventional slides. Cox proportional regression models were applied for uni- and multivariate analyses using breast cancer death as the event. Results. Estrogen receptor (ER) and progesterone receptor positivity were demonstrated in 93% and 77% of patients, respectively. Nottingham histologic grade (NHG) III was seen in 41% and HER2 positivity in 11%. Classification into molecular subtypes using IHC markers according to three alternative definitions revealed luminal A and luminal B in 81% vs. 11%; 48% vs. 44% and 41% vs. 42% of cases. Two cases of basal-like were identified, but no cases of HER2-like. Factors associated with an increased risk of breast cancer death were node positivity (HR 4.5; 95% CI 1.8-11.1), tumor size andgt;20 mm (HR 3.3; 95% CI 1.4-7.9) and ER negativity (HR 10.9; 95% CI 3.2-37.9). No difference in breast cancer death between the luminal subgroups was demonstrated, regardless of definition. Conclusion. MBC tumors were more often of high grade, whereas HER2 overexpression was as frequent as in FBC. Lymph nodes, tumor size and ER status were independent predictors of breast cancer death. The prognostic impact of molecular subtyping in MBC seems to differ from that previously established in FBC.
|
|
