| 1. |
- Corvigno, Sara, et al.
(författare)
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High density of stroma-localized CD11c-positive macrophages is associated with longer overall survival in high-grade serous ovarian cancer.
- 2020
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 159:3, s. 860-868
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Pre-clinical studies have identified marker- and tumor compartment-defined functionally distinct macrophage subsets. Our study analyzes marker-defined macrophage subsets in different tumor compartments of high-grade serous ovarian cancer (HGSC).METHODS: A discovery cohort (N = 113) was subjected to immunohistochemistry (IHC) analyses. CD68-positivity was confirmed for CD11c-, CD80- and CD163-positive cells. Subset-marker-positive cells were scored in the total tumor and in four tumor compartments. Correlation analyses investigated co-expression of subsets, relationship to CD8+ cells and survival associations. A validation cohort (N = 121) was used to confirm selected findings from the discovery cohort.RESULTS: CD163-positve cells was the most abundant subtype in all compartments. CD11c and CD163 subsets were strongly correlated with each other in stroma and epithelial areas, whereas CD80 and CD163 were correlated in epithelial areas. CD80 and CD11c in perivascular areas showed low correlations. Strong associations were detected between CD8 and CD80 in the tumor epithelium-dominated areas, and between CD8 and CD11c in stroma areas. High stromal CD11c density was associated with a longer median overall survival in the discovery cohort (HR 0.39; CI 95%, 0.23-0.68; p = 0.001) and in the validation cohort (HR 0.46; CI 95%, 0.22-0.93; p = 0.03).CONCLUSIONS: Our study supports the existence of clinically relevant marker- and localization defined macrophage subsets in HGSC, which are independently regulated. Moreover, it suggests stromal CD11c as a novel prognostic marker in HGSC.
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| 2. |
- Johansson, Ida, et al.
(författare)
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Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker
- 2012
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Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 14:1
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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.
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| 3. |
- Kimbung, Siker, et al.
(författare)
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Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer
- 2016
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 22:1, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis. Experimental Design: A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested. Results: Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by down-regulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors. Conclusions: Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer. (C)2015 AACR.
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| 4. |
- Nilsson, Cecilia, et al.
(författare)
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High proliferation is associated with inferior Outcome in male breast cancer patients
- 2013
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Ingår i: Modern Pathology. - : Nature Publishing Group. - 0893-3952 .- 1530-0285. ; 26:1, s. 87-94
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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
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| 5. |
- Nilsson, Cecilia, et al.
(författare)
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Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact
- 2013
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Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 52:1, s. 102-109
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Tidskriftsartikel (refereegranskat)abstract
- 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 andgt;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.
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| 6. |
- Strand, Carina, et al.
(författare)
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The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naive women with N0/N1 primary breast cancer
- 2013
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Ingår i: SpringerPlus. - : Springer Science and Business Media LLC. - 2193-1801. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naive breast cancer patients. Methods/design: In the present study, including 1,854 patients, Ki67 was used in the index (KiGE), since it is the generally accepted proliferation marker in clinical routine. The low KiGE-group was defined as histological grade 1 patients and grade 2 patients which were ER-positive and had low Ki67 expression. All other patients made up the high KiGE-group. The KiGE-index separated patients into two groups with different prognosis. In multivariate analysis, KiGE was significantly associated with disease-free survival, when adjusted for age at diagnosis, tumor size and adjuvant endocrine treatment (hazard ratio: 3.5, 95% confidence interval: 2.6-4.7, P<0.0001). Discussion: We have confirmed a prognostic index based on a proliferation marker (Ki67), histological grade, and ER for identification of a low-risk group of patients with N0/N1 primary breast cancer. For this low-risk group constituting 57% of the patients, with a five-year distant disease-free survival of 92%, adjuvant chemotherapy will have limited effect and may be avoided.
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