| 11. |
- Deb, Siddhartha, et al.
(författare)
-
Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer
- 2014
-
Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 27:9, s. 1223-1230
-
Tidskriftsartikel (refereegranskat)abstract
- Male breast cancer is poorly understood with a large proportion arising in the familial context particularly with the BRCA2 germline mutation. As phenotypic and genotypic differences between sporadic and familial male breast cancers have been noted, we investigated the importance of a hypoxic drive in these cancers as this pathway has been shown to be of importance in familial female breast cancer. Expression of two major hypoxia-induced proteins, the hypoxia-inducible factor-1 alpha (HIF1A) and the carbonic anhydrase IX (CA9), examined within a large cohort including 61 familial (3 BRCA1, 28 BRCA2, 30 BRCAX) and 225 sporadic male breast cancers showed that 31% of all male breast cancers expressed either HIF1A (25%) and/or CA9 (8%) in the combined cohort. Expression of HIF1A correlated with an increased incidence of a second-major malignancy (P=0.04), histological tumor type (P=0.005) and basal phenotype (P=0.02). Expression of CA9 correlated with age (P=0.004) in sporadic cases and an increased tumor size (P=0.003). Expression of HIF1A was prognostic for disease-specific survival in sporadic male breast cancers (HR: 3.8, 95% CI: 1.5-9.8, P=0.006) but not within familial male breast cancer, whereas CA9 was only prognostic in familial male breast cancers (HR: 358.0, 95% CI: 9.3-13781.7, P=0.002) and not in sporadic male breast cancer. This study found that hypoxic drive is less prevalent in male breast cancer compared with female breast cancer, possibly due to a different breast microenvironment. The prognostic impact of HIF1A is greatest in sporadic male breast cancers with an alternate dominant mechanism for the oncogenic drivers suggested in high risk familial male breast cancers.
|
|
| 12. |
- Grönberg, Malin, et al.
(författare)
-
Expression of ghrelin is correlated to a favorable outcome in invasive breast cancer
- 2012
-
Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 51:3, s. 386-393
-
Tidskriftsartikel (refereegranskat)abstract
- Background. Expression of the peptide hormones ghrelin and obestatin has previously been demonstrated in human mammary glands. However, the clinical implications of the expression of these peptides in breast cancer are unclear. The aim of this study was to investigate the potential clinical value of ghrelin and obestatin as breast cancer biomarkers. Methods. A tissue microarray containing breast cancer specimens from 144 patients was immunostained with antibodies directed towards ghrelin and obestatin. Using varying cut-offs, the expression of the two peptides was evaluated and correlated to previously known prognostic factors in breast cancer and to the outcome. Cox regression analysis was used to assess whether these markers may predict survival of breast cancer patients. Results. Moderate to strong immunoreactivity for ghrelin and obestatin was observed in 71.5% and 77.1% of the cases, respectively. Ghrelin and obestatin expression was significantly but weakly correlated to low histological grade, estrogen receptor positivity, small tumor size and low proliferation. Only ghrelin expression was significantly correlated to better recurrence-free and breast cancer-specific survival (HR = 0.3-0.4, p = 0.02-0.05) in both uni- and multivariate analyses. The optimal cut-off was any ghrelin expression versus none. Reproducibility between the two readers was very good for both stainings with kappa values of 0.94-1.00. Conclusions. Patients with tumors expressing ghrelin had 2.5-3 times lower risk for recurrence or breast cancer death than those lacking ghrelin expression. Ghrelin expression is easily assessable with high reproducibility using immunohistochemistry. Further investigations are needed to establish the clinical significance of ghrelin as a biomarker in breast cancer.
|
|
| 13. |
|
|
| 14. |
- Johansson, Ida, et al.
(författare)
-
Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker
- 2012
-
Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- 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). less thanbrgreater than less thanbrgreater thanMethods: 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. less thanbrgreater than less thanbrgreater thanResults: 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. less thanbrgreater than less thanbrgreater thanConclusions: 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.
|
|
| 15. |
- Johansson, Ida, et al.
(författare)
-
High-resolution genomic profiling of male breast cancer reveals differences hidden behind the similarities with female breast cancer
- 2011
-
Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 129:3, s. 747-760
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 16. |
- Koliadi, Anthoula, et al.
(författare)
-
Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer
- 2010
-
Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 49:6, s. 816-820
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 17. |
- Koliadi, Anthoula
(författare)
-
The Prognostic Impact of Proliferation Markers in Breast Cancer with Emphasis on Cyclin B1 and PPH3
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
|
|
| 18. |
- Nilsson, Cecilia, 1971-
(författare)
-
Characterization of Male Breast Cancer : From Molecule to Clinical Outcome
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
|
|
| 19. |
- Nilsson, Cecilia, et al.
(författare)
-
High proliferation is associated with inferior Outcome in male breast cancer patients
- 2013
-
Ingår i: Modern Pathology. - : Nature Publishing Group. - 0893-3952 .- 1530-0285. ; 26:1, s. 87-94
-
Tidskriftsartikel (refereegranskat)abstract
- 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 male breast cancer into molecular subgroups with different prognoses, the clinical importance of proliferation 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 study proliferation 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 of patients 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 for breast cancer death, whereas cyclin D1 overexpression halves the risk. The clinical utility of these proliferation markers needs further elucidation. Modern Pathology (2013) 26, 87-94; doi:10.1038/modpathol.2012.145; published online 24 August 2012
|
|
| 20. |
- Nilsson, Cecilia, et al.
(författare)
-
Similarities and differences in the characteristics and primary treatment of breast cancer in men and women - a population based study (Sweden)
- 2011
-
Ingår i: Acta Oncologica. - 1651-226X .- 0284-186X. ; 50:7, s. 1083-1088
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
