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The Prognostic Impact of Proliferation Markers in Breast Cancer with Emphasis on Cyclin B1 and PPH3
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to investigate the prognostic role of the proliferation markers cyclin B1 and Phosphorylated Histone 3 (PPH3) in breast cancer (BC).

In paper I we used an experimental study design, we compared women dying early from their BC with women free from relapse more than eight years after initial diagnosis. All women had stage I, node-negative and hormone receptor positive disease. None had received adjuvant chemotherapy. We found that low-risk node negative patients with high expression of cyclin B1 had a significantly worse outcome than patients with low expression of cyclin B1.

In paper II a population-based case control study was performed to further investigate the prognostic value of cyclin B1. One hundred and ninety women who died from BC were defined as cases and 190 women alive at the time for the corresponding case’s death were defined as controls. Inclusion criteria were tumor size 50 mm, no lymph node metastases, and no adjuvant chemotherapy. Two investigators evaluated the stainings independently. Cyclin B1 was found to be a prognostic factor for BC death that could identify high-risk patients with a good to very good reproducibility.

Paper III aimed to investigate the role of proliferation in male breast cancer (MBC). One hundred and ninety-seven MBC tumors were stained for cyclin A, B1, D1 and Ki67. Overexpression of cyclin A and B1 and elevated mitotic count were predictive of breast cancer death. Ki67 was re-evaluated and different cut-offs were used, but no prognostic value could be demonstrated. On the other hand high levels of cyclin D1 were associated with better outcome in MBC.

In paper IV we applied the immunohistochemichal panel suggested from international guidelines to the same patient material as in paper II, to discriminate luminal A from luminal B BC. We wanted to evaluate if different cut-off values of Ki67, cyclin A or B1 could more clearly separate luminal A from B. Cyclin A, B1 and Ki67 (cut-off 20%) could detect difference in outcome between these subtypes with cyclin A showing greater prognostic value.

The aim of paper V was to examine the prognostic role of PPH3 compared to the proliferation markers Ki67, cyclin A and cyclin B1 with focus on ER positive disease. PPH3 was found to be a prognostic factor for breast cancer death but in the multivariate analysis including all proliferation markers, only cyclin A remained a prognostic factor.

Finally, we conclude that both cyclin B1 and PPH3 are prognostic factors for breast cancer death, but are outperformed by cyclin A in ER positive patients. In male breast cancer prognostic factors need to be further studied. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2014. , 89 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1004
Keyword [en]
proliferation, cyclin B1, Phosphorylated Histone 3, cyclin A, breast cancer, node negative, prognostic factor, luminal
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-223648ISBN: 978-91-554-8962-5 (print)OAI: oai:DiVA.org:uu-223648DiVA: diva2:713725
Public defence
2014-06-14, Gunnesalen Psykiatrins hus, Alademiska Sjukhuset, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-05-22 Created: 2014-04-23 Last updated: 2014-08-15
List of papers
1. Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer
Open this publication in new window or tab >>Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer
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2010 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, no 6, 816-820 p.Article in journal (Refereed) Published
Abstract [en]

Patients with low-risk node negative breast cancer have an excellent prognosis with 5% breast cancer mortality at 10 years. However, prognostic factors are needed to identify poor prognostic patients who might benefit from adjuvant systemic therapy. Proliferation has been identified as the most important component of gene expression profiles. Cyclin B is a proliferative marker easily assessed by immunohistochemistry. We wanted to examine cyclin B as a prognostic factor in low-risk breast cancer patients. Patients and methods. Using an experimental study design, we compared women dying early from their breast cancer (n=17) with women free from relapse more than eight years after initial diagnosis (n=24). All women had stage I, node negative and hormone receptor positive disease. None had received adjuvant chemotherapy. Tumor samples were immunostained for cyclin B using commercial antibodies. Results. The mean percentage of cyclin B (12%) was significantly higher (p=0.001) in women dying from their breast cancer compared with women free from relapse ( 5%). High cyclin B (>= 9%) identified 11/17 patients dying from breast cancer and low cyclin B identified 22/24 patients free from relapse. The sensitivity and specificity of cyclin B was 65% and 92%, respectively. Discussion. We found that low-risk node negative patients with high expression of cylin B had a significantly worse outcome than patients with low expression of cyclin B. Cyclin B could separate patients with poor survival from those with good survival with 80% accuracy. We suggest that cyclin B might be a potent prognostic factor in this low-risk patient group.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-135616 (URN)10.3109/02841861003691937 (DOI)000280591800009 ()20307242 (PubMedID)
Available from: 2010-12-07 Created: 2010-12-07 Last updated: 2014-08-15Bibliographically approved
2.
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3. High proliferation is associated with inferior outcome in male breast cancer patients
Open this publication in new window or tab >>High proliferation is associated with inferior outcome in male breast cancer patients
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2013 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 26, no 1, 87-94 p.Article in journal (Refereed) Published
Abstract [en]

Assessment of proliferation is important in female breast cancer and individual treatment decisions are based upon its results, especially in the lumina! subgroups. Gene expression analyses fail to group male breast cancer into the intrinsic subgroups previously established in female breast cancer. Even though proliferation has been shown to divide malebreast cancer into molecular subgroups with different prognoses, the clinical importance ofproliferation markers has not yet been elucidated. Previous studies in male breast cancer have demonstrated contradictory results regarding the prognostic impact of histological grade and Ki-67, parameters strongly associated with proliferation. The aim of the present project was to studyproliferation in male breast cancer by assessing other proliferation-related markers viz. cyclins A, B, D1 and mitotic count. A total of 197 male breast cancer cases with accessible paraffin-embedded material and outcome data were investigated. Immunohistochemical stainings were performed on tissue microarrays. Kaplan-Meier estimates and the Cox proportional regression models were used for survival analyses with breast cancer death as the event. The subset ofpatients with high expression of cyclin A (hazard ratio (HR) 3.7; P=0.001) and B (HR 2.7; P=0.02) demonstrated a poorer survival. Furthermore, high mitotic count was associated with an increased risk of breast cancer death (HR 2.5; P=0.01). In contrast, cyclin D1 overexpression was predictive of better breast cancer survival (HR 0.3; P=0.001). In conclusion, high levels of cyclin A and B expression and an elevated mitotic count result in a two to threefold higher risk forbreast cancer death, whereas cyclin D1 overexpression halves the risk. The clinical utility of these proliferation markers needs further elucidation. 

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-172676 (URN)10.1038/modpathol.2012.145 (DOI)000313306900010 ()
Available from: 2012-04-13 Created: 2012-04-12 Last updated: 2017-12-07Bibliographically approved
4. Cyclin A is an excellent proliferation marker for identifying luminal breast cancer subgroups using immunohistochemistry
Open this publication in new window or tab >>Cyclin A is an excellent proliferation marker for identifying luminal breast cancer subgroups using immunohistochemistry
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background. Gene arrays have demonstrated different outcomes for breast cancer subtypes highlighting the heterogeneity of breast cancer. The limited availability of gene expression analysis and financial issues have  contributed to the development of surrogate markers to identify corresponding subgroups using IHC. 2011 ESMO and St Gallen guidelines suggest the use of an IHC panel consisting of ER, PgR, HER2 and Ki67 cut-off value ≥14 % (Ki6714%) for discriminating luminal A from B.The cut-off value suggested from 2013 St Gallens guidelines was ≥20% (Ki6720%). We wanted to evaluate if the different cut-off values for Ki67 or cyclins A/B1  could reliably separate luminal A from B.

 

Patients. 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. Immunohistochemical evaluation of ER, PgR, HER2, Ki 67, cyclin A and cyclin B1 were utilized for subgrouping.

 

Results. Conditional logistic regression analysis was used to estimate odds ratios (OR) for breast cancer death. Ki6714% did not detect differences in outcome between luminal A and B breast cancer (OR 1.4, 95% CI 0.8-2.26 p-value 0.24). Corresponding values for  cyclin A was OR 3.6 (95% CI 1.8-7.0 p-value 0.00), cyclin B1  2.2 (95% CI 1.1-4.5  p-value 0.04) and Ki6720% 2.0 (95% CI 1.1-3.9 p-value 0.04) using  luminal A as reference.

Conclusion.   In our study, Ki6714% failed to detect any difference in outcome between luminal A and B. In contrast, using cyclin A as a proliferation marker luminal B was found to have an almost 3.5 -fold higher risk of dying from breast cancer. Cyclin B1 and Ki6720%, could also separate luminal A from B but cyclin A  separated more effectively these subtypes . We conclude that cyclin A distinctly  separates luminal A from B in node negative breast cancer.

Keyword
cyclin A, proliferation, luminal breast cancer, immunohistochemistry
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-223658 (URN)
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2014-06-30
5. PPH3 is an independent prognostic factor in node negative breast cancer, however outperformed by cyclin A in the ER positive patients.
Open this publication in new window or tab >>PPH3 is an independent prognostic factor in node negative breast cancer, however outperformed by cyclin A in the ER positive patients.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background. Proliferation conveys prognostic information and directs treatment choices in early and especially in estrogen receptor (ER) positive breast cancer. Ki67 is the proliferation marker, which is recommended by the 2013 St Gallen International Breast Cancer Conference to distinguish Luminal A-like from Luminal B-like breast cancer. However, the lack of standardization and absence of a clearly established cut-off value are limitations for the clinical use of Ki67. Recent studies in node negative breast cancer suggest that phosphorylated histone 3 (PPH3) may predict breast cancer death. Our aim was to examine the prognostic role of PPH3 compared to the proliferation markers Ki67, cyclin A and cyclin B1 in node negative breast cancer with a special focus on ER positive disease.

Patients and methods. In a case-control study, we defined 190 women who died from node negative breast cancer as cases and 190 women who were 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. Of these 380 subjects, 249 had ER positive disease. Tumor tissues were immunostained for PPH3 using commercially available antibodies. The actual number of immunostained cells in 10 fields of view (PPH3 index) and the percentage of immunostained cells counting 200 and 500 tumor cells were calculated.

Results. In node negative patients, PPH3 indexrevealed an odds ratio (OR) for breast cancer death of 2.6 (95% confidence interval (CI) 1.6-4.5 p-value <0.001). PPH3 was strongly correlated to Ki67, histological grade, mitotic count and cyclin A and B1. In ER positive patients the OR for PPH3 index was 2.9 (95% CI 1.6-5.2 p-value <0.001) while the OR for Cyclin A was 3.8 (95% CI 2.2-6.6 p-value <0.001), for cyclin B1 2.9 (95%CI 1.7-4.9 p-value <0.001) and for Ki67 1.6 (95% CI 0.9-4.9 p-value 0,09). However, multivariate analyses showed that cyclin A was the only independent prognostic marker for breast cancer death in ER positive patients, OR 3.6 (95% CI 1.6-8.1 p-value 0.002).

Conclusion. In this study of node negative breast cancer patients, PPH3 showed to be a prognostic factor for breast cancer death. In ER positive patients PPH3 and cyclin A/B1 but not Ki67 could predict breast cancer death. However in the multivariate analysis of proliferation markers, only cyclin A remains as a prognostic factor. 

Keyword
PPH3, phosphorylated histone 3, proliferation, breast cancer, prognostic factor, ER positive
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-223661 (URN)
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2014-06-30

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