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High proliferation is associated with inferior outcome in male breast cancer patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund.
Department of Oncology, Örebro University Hospital, Örebro, Sweden.
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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. 

Place, publisher, year, edition, pages
2013. Vol. 26, no 1, 87-94 p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-172676DOI: 10.1038/modpathol.2012.145ISI: 000313306900010OAI: oai:DiVA.org:uu-172676DiVA: diva2:515480
Available from: 2012-04-13 Created: 2012-04-12 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Characterization of Male Breast Cancer: From Molecule to Clinical Outcome
Open this publication in new window or tab >>Characterization of Male Breast Cancer: From Molecule to Clinical Outcome
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to investigate different aspects of male breast cancer (MBC), and to compare these with findings in female breast cancer (FBC). In paper I, a population–based study was performed to investigate possible differences in treatment and outcome between MBC and FBC patients. MBC and FBC presented with a similar distribution of stage. Although no differences in primary treatment strategy were demonstrated, MBC patients had significantly poorer overall and relative survival, indicating a more aggressive disease. Paper II aimed to assess the value of clinicopathological factors and molecular subtypes in MBC. One hundred and ninety-seven MBC tumors were characterized using immunohistochemistry (IHC) and the findings were correlated to outcome. Lymph node positivity, larger tumor size and ER-negativity were independent risk factors for breast cancer death. Tumor grade, HER2, Ki 67 or IHC classification into molecular subtypes did not demonstrate any prognostic information. In paper III, the same patient material as in paper II was used for evaluation of proliferation markers. High levels of cyclin A and cyclin B expression and an elevated mitotic count were predictive of breast cancer death. Ki-67 was re-evaluated using different cut-offs, but no prognostic value could be demonstrated. Contrarily, overexpression of cyclin D1 was associated with a lower risk of breast cancer death. In papers IV-V, the molecular background of MBC tumors was investigated.  Global GEX analyses were performed and two novel subgroups of MBC tumors were identified; luminal M1 and luminal M2. When comparing the degree of similarity with the “intrinsic” subtypes in FBC tumors, more than half of the MBC tumors remained unclassified.  Comparative genomic hybridization was used to investigate DNA aberrations. Two MBC subgroups were identified, of which one did not resemble any of the female subgroups. In both studies on the molecular level, a majority of patients were classified into the subgroup with a more aggressive tumor behavior. In conclusion, MBC seems to be a unique tumor entity. The established molecular subtypes in FBC are not applicable in MBC. Other prognostic profiles, specific for MBC, need to be identified.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 771
Keyword
male breast cancer, immunohistochemistry, prognostic, cyclins, gene expression, genomic profiling
National Category
Cancer and Oncology
Research subject
Oncology; Oncology
Identifiers
urn:nbn:se:uu:diva-172670 (URN)978-91-554-8356-2 (ISBN)
Public defence
2012-06-02, Aulan, Ingång 21, Västmanlands sjukhus Västerås, Västerås, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2012-05-11 Created: 2012-04-12 Last updated: 2012-08-01Bibliographically approved
2. 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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Nilsson, CeciliaKoliadi, AnthoulaBergkvist, LeifFjällskog, Marie-Louise

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