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PPH3 is an independent prognostic factor in node negative breast cancer, however outperformed by cyclin A in the ER positive patients.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
(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 [en]
PPH3, phosphorylated histone 3, proliferation, breast cancer, prognostic factor, ER positive
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-223661OAI: oai:DiVA.org:uu-223661DiVA: diva2:713572
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2014-06-30
In thesis
1. The Prognostic Impact of Proliferation Markers in Breast Cancer with Emphasis on Cyclin B1 and PPH3
Open this publication in new window or tab >>The Prognostic Impact of Proliferation Markers in Breast Cancer with Emphasis on Cyclin B1 and PPH3
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
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:nbn:se:uu:diva-223648 (URN)978-91-554-8962-5 (ISBN)
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

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