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Characterization of Male Breast Cancer: From Molecule to Clinical Outcome
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.
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. , p. 65
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 771
Keyword [en]
male breast cancer, immunohistochemistry, prognostic, cyclins, gene expression, genomic profiling
National Category
Cancer and Oncology
Research subject
Oncology; Oncology
Identifiers
URN: urn:nbn:se:uu:diva-172670ISBN: 978-91-554-8356-2 (print)OAI: oai:DiVA.org:uu-172670DiVA, id: diva2:515760
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
List of papers
1. Similarities and differences in the characteristics and primary treatment of breast cancer in men and women: a population based study (Sweden)
Open this publication in new window or tab >>Similarities and differences in the characteristics and primary treatment of breast cancer in men and women: a population based study (Sweden)
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2011 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, no 7, p. 1083-1088Article in journal (Refereed) Published
Abstract [en]

Purpose. Male breast cancer (MBC) is an uncommon disease. In the absence of randomized studies, current guidelines are mainly based on data on the management of female breast cancer (FBC). In light of concerns regarding the quality and extent of management in men, the aim of the present study was to investigate whether there are differences in tumor characteristics, treatment and outcome in male compared with FBC patients.

Methods. Cohorts of male and female breast cancer were retrospectively analyzed. All male patients diagnosed with invasive breast cancer between 1993 and 2007 were identified from the Regional Breast Cancer Register of the Uppsala-rebro Region in Sweden. To increase the power of the study and obtain comparable cohorts we sampled four FBC patients (n = 396) for each MBC patient (n = 99) with similar age at diagnosis and time of diagnosis.

Results. No differences were seen in stage at diagnosis between MBC and FBC. Men underwent mastectomy more often than women (92% vs. 44%, p < 0.001). Radiotherapy was delivered less often to MBC than FBC (44% vs. 56%, p = 0.034), but radiotherapy given after mastectomy (44% vs. 39%, p = 0.47) did not differ between the groups. No differences were found regarding adjuvant chemotherapy (16% vs. 21%; p = 0.31) or adjuvant endocrine therapy (59% vs. 52%, p = 0.24). Both overall survival (41% vs. 55%, p = 0.001) and relative survival (74% vs. 88%, p = 0.015) were inferior in MBC compared to FBC.

Conclusion. Concerns regarding less extensive treatment in MBC patients were not supported by this study. Although no differences in the stage of the disease or treatment intensity could be demonstrated, outcome was inferior in the male group.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-159455 (URN)10.3109/0284186X.2011.602114 (DOI)000294868000011 ()
Available from: 2011-10-04 Created: 2011-10-03 Last updated: 2017-12-08Bibliographically approved
2. Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact
Open this publication in new window or tab >>Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact
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2013 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 1, p. 102-109Article in journal (Refereed) Published
Abstract [en]

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 > 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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-172675 (URN)10.3109/0284186X.2012.711952 (DOI)000312505900013 ()22928693 (PubMedID)
Available from: 2012-04-13 Created: 2012-04-12 Last updated: 2017-12-07Bibliographically approved
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, p. 87-94Article 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. Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker
Open this publication in new window or tab >>Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker
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2012 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1, p. R31-Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION:

Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC).

METHODS:

A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs.

RESULTS:

Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC.

CONCLUSIONS:

We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-172739 (URN)10.1186/bcr3116 (DOI)000307444100040 ()22333393 (PubMedID)
Available from: 2012-04-13 Created: 2012-04-13 Last updated: 2017-12-07Bibliographically approved
5. High-resolution genomic profiling of male breast cancer reveals differences hidden behind the similarities with female breast cancer
Open this publication in new window or tab >>High-resolution genomic profiling of male breast cancer reveals differences hidden behind the similarities with female breast cancer
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2011 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 129, no 3, p. 747-760Article in journal (Refereed) Published
Abstract [en]

Male breast cancer (MBC) is extremely rare and poorly characterized on the molecular level. Using high-resolution genomic data, we aimed to characterize MBC by genomic imbalances and to compare it with female breast cancer (FBC), and further to investigate whether the genomic profiles hold any prognostic information. Fifty-six fresh frozen MBC tumors were analyzed using high-resolution tiling BAC arrays. Significant regions in common between cases were assessed using Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. A publicly available genomic data set of 359 FBC tumors was used for reference purposes. The data revealed a broad pattern of aberrations, confirming that MBC is a heterogeneous tumor type. Genomic gains were more common in MBC than in FBC and often involved whole chromosome arms, while losses of genomic material were less frequent. The most common aberrations were similar between the genders, but high-level amplifications were more common in FBC. We identified two genomic subgroups among MBCs; male-complex and male-simple. The male-complex subgroup displayed striking similarities with the previously reported luminal-complex FBC subgroup, while the male-simple subgroup seems to represent a new subgroup of breast cancer occurring only in men. There are many similarities between FBC and MBC with respect to genomic imbalances, but there are also distinct differences as revealed by high-resolution genomic profiling. MBC can be divided into two comprehensive genomic subgroups, which may be of prognostic value. The male-simple subgroup appears notably different from any genomic subgroup so far defined in FBC.

Keyword
Male breast cancer, Array-CGH, BRCA2, Molecular subtypes, BPH
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-159225 (URN)10.1007/s10549-010-1262-8 (DOI)000294680600008 ()
Available from: 2011-09-27 Created: 2011-09-26 Last updated: 2017-12-08Bibliographically approved

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