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Cyclin A is an excellent proliferation marker for identifying luminal breast cancer subgroups using immunohistochemistry
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. 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 [en]
cyclin A, proliferation, luminal breast cancer, immunohistochemistry
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-223658OAI: oai:DiVA.org:uu-223658DiVA: diva2:713573
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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