Breast: Ductal carcinoma

Review on Breast: Ductal carcinoma, with data on clinics, and the genes involved

Histopathological Features of Early Onset Indonesian Breast Cancer Pointing to Brca1/2 Germline Mutations

Background: Breast cancer under 40 years concerns a relatively small subgroup of cases that tend to display a more aggressive phenotype. Compatible with this, early age of onset has been known as one of clinical characteristic of hereditary breast cancers associated with germline BRCA1 or BRCA1 mutations. As early onset breast cancer is frequent in Indonesia, we investigated the histopathological and immunohistochemical characteristics of early onset (< 40 years) Indonesian breast cancer patients, as such features can be used to distinguish between BRCA and non-BRCA germline mutation carriers among these young women.Method: Thirty-five formalin-fixed and paraffin-embedded tissue sections of young women (mean 36 years, range 22-40 years) who underwent surgical resection at the Department of Surgery of the Sardjito Hospital Yogyakarta were examined for pathological features, estrogen and progesterone receptor status, proliferation as determined by Ki67 labeling, EGFR and CK5/6 and the presence of HER-2/neu and p53 protein. Additionally, mutation analysis for BRCA1 and BRCA2 was performed in 30 young women. The control group consisted ofcarcinomas from women above 50 years (mean 59.02, range 50-80 years).Result: Carcinomas occurring in women aged below 40 years were more often advanced stage and higher proliferating (p=0.006). Among the early onset breast cancer patients, ductal type, grade 3, ER and HER-2/neu negativity, high Ki67 index and CK5/6 and EGFR positivity were typical for BRCA1 patients. Unfortunately, there were no typical phenotypical features for BRCA2 carriers. However, grade I and lobular cases were never BRCA1/2 germline mutated.Conclusion: Early onset Indonesian breast cancer shows increased proliferation compared to late onset patients. Within the early onset group, the strongest features pointing to a sporadic cancer seem to be grade I and lobular differentiation. Features increasing the chance of a germline BRCA1/2 mutation are CK5/6 and EGFR expression, p53 accumulation and high proliferation as measured by Ki67 labeling. This is potentially useful to optimize selection of early onset breast cancer patients for BRCA1/2 mutation testing

Histopathological Features of Early Onset Indonesian Breast Cancer Pointing to Brca1/2 Germline Mutations

Background: Breast cancer under 40 years concerns a relatively small subgroup of cases that tend to display a more aggressive phenotype. Compatible with this, early age of onset has been known as one of clinical characteristic of hereditary breast cancers associated with germline BRCA1 or BRCA1 mutations. As early onset breast cancer is frequent in Indonesia, we investigated the histopathological and immunohistochemical characteristics of early onset (< 40 years) Indonesian breast cancer patients, as such features can be used to distinguish between BRCA and non-BRCA germline mutation carriers among these young women.Method: Thirty-five formalin-fixed and paraffin-embedded tissue sections of young women (mean 36 years, range 22-40 years) who underwent surgical resection at the Department of Surgery of the Sardjito Hospital Yogyakarta were examined for pathological features, estrogen and progesterone receptor status, proliferation as determined by Ki67 labeling, EGFR and CK5/6 and the presence of HER-2/neu and p53 protein. Additionally, mutation analysis for BRCA1 and BRCA2 was performed in 30 young women. The control group consisted ofcarcinomas from women above 50 years (mean 59.02, range 50-80 years).Result: Carcinomas occurring in women aged below 40 years were more often advanced stage and higher proliferating (p=0.006). Among the early onset breast cancer patients, ductal type, grade 3, ER and HER-2/neu negativity, high Ki67 index and CK5/6 and EGFR positivity were typical for BRCA1 patients. Unfortunately, there were no typical phenotypical features for BRCA2 carriers. However, grade I and lobular cases were never BRCA1/2 germline mutated.Conclusion: Early onset Indonesian breast cancer shows increased proliferation compared to late onset patients. Within the early onset group, the strongest features pointing to a sporadic cancer seem to be grade I and lobular differentiation. Features increasing the chance of a germline BRCA1/2 mutation are CK5/6 and EGFR expression, p53 accumulation and high proliferation as measured by Ki67 labeling. This is potentially useful to optimize selection of early onset breast cancer patients for BRCA1/2 mutation testing.Keywords: breast cancer, early onset, histopathology, immunohistochemistry, BRCA1, BRCA

The Microanatomic Location of Metastatic Breast Cancer in Sentinel Lymph Nodes Predicts Nonsentinel Lymph Node Involvement

Background: The majority of sentinel node (SN) positive breast cancer patients do not have additional non-SN involvement and may not benefit from axillary lymph node dissection (ALND). Previous studies in melanoma have suggested that microanatomic localization of SN metastases may predict non-SN involvement. The present study was designed to assess whether these criteria might also be used to be more restrictive in selecting breast cancer patients who would benefit from an ALND. Methods: A consecutive series of 357 patients with invasive breast cancer and a tumorpositive axillary SN, followed by an ALND, was reviewed. Microanatomic SN tumor features (subcapsular, combined subcapsular and parenchymal, parenchymal, extensive localization, multifocality, and the penetrative depth from the SN capsule) were evaluated for their predictive value for non-SN involvement. Results: Non-SN metastases were found in 136/357 cases (38%). Microanatomic location and penetrative depth of SN metastases were significant predictors for non-SN involvement (<0.001); limited penetrative depth was associated with a low frequency of non-SN involvement with a minimal of 10%. Conclusions: Microanatomic location and penetrative depth of breast cancer SN metastases predict non-SN involvement. However, based on these features no subgroup of patients could be selected with less than 10% non-SN involvement

Number of apoptotic cells as a prognostic marker in invasive breast cancer

Apoptosis plays an important role in tumorigenesis. Tumour growth is determined by the rate of cell proliferation and cell death. We counted the number of apoptotic cells in haematoxylin and eosin (H&E)-stained tumour sections in series of 172 grade I and II invasive breast cancers with long-term follow-up. The number of apoptotic cells in ten high-power fields were converted to the number of apoptotic cells per mm2to obtain the apoptotic index (AI). The AI showed a positive correlation to the mitotic activity index (MAI) (P = 0.0001), histological grade (P< 0.0001) and worse tumour differentiation. Patients with high AI showed shorter overall survival than patients with low AI in the total group as well as in the lymph node-positive group. Tumour size, MAI, lymph node status and AI were independent prognostic indicators in multivariate analysis. The AI was shown to be of additional prognostic value to the MAI in the total patients group as well as in the lymph node-positive group. The correlation between the AI and the MAI points to linked mechanisms of apoptosis and proliferation. Since apoptotic cells can be counted with good reproducibility in H&E-stained tumour sections, the AI may be used as an additional prognostic indicator in invasive breast cancer. © 2000 Cancer Research Campaig

Expression of BNIP3 in invasive breast cancer: correlations with the hypoxic response and clinicopathological features

<p>Abstract</p> <p>Background</p> <p>Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is a pro-apoptotic member of the Bcl-2 family induced under hypoxia. Low or absent expression has recently been described in human tumors, including gastrointestinal tumors, resulting in poor prognosis. Little is known about BNIP3 expression in invasive breast cancer. The aim of the present study was to investigate the expression of BNIP3 in invasive breast cancer at the mRNA and protein level in correlation with the hypoxic response and clinicopathological features.</p> <p>Methods</p> <p>In 40 cases of invasive breast cancer, BNIP3 mRNA <it>in situ </it>hybridization was performed on frozen sections with a digoxigenin labeled anti-BNIP3 probe. Paraffin embedded sections of the same specimens were used to determine protein expression of BNIP3, Hypoxia Inducible Factor 1 alpha (HIF-1α) and its downstream targets Glucose Transporter 1 (Glut-1) and Carbonic Anhydrase (CAIX) by immunohistochemistry.</p> <p>Results</p> <p>BNIP3 mRNA was expressed in 16/40 (40%) of the cases and correlated with BNIP3 protein expression (p = 0.0218). Neither BNIP3 protein nor mRNA expression correlated with expression of HIF-1α expression or its downstream targets. Tumors which showed loss of expression of BNIP3 had significantly more often lymph node metastases (82% vs 39%, p = 0.010) and showed a higher mitotic activity index (p = 0.027). BNIP3 protein expression was often nuclear in normal breast, but cytoplasmic in tumor cells.</p> <p>Conclusion</p> <p>BNIP3 expression is lost in a significant portion of invasive breast cancers, which is correlated with poor prognostic features such as positive lymph node status and high proliferation, but not with the hypoxic response.</p

Expression of hypoxia-inducible factor-1α and cell cycle proteins in invasive breast cancer are estrogen receptor related

BACKGROUND: The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator of the cellular response to hypoxia. Previous studies showed that concentrations of its subunit HIF-1α, as a surrogate for HIF-1 activity, are increased during breast carcinogenesis and can independently predict prognosis in breast cancer. During carcinogenesis, the cell cycle is progressively deregulated, and proliferation rate is a strong prognostic factor in breast cancer. In this study we undertook a detailed evaluation of the relationships between HIF-1α and cell cycle-associated proteins. METHODS: In a representative estrogen receptor (ER) group of 150 breast cancers, the expression of HIF-1α, vascular endothelial growth factor, the ER, HER-2/neu, Ki-67, cyclin A, cyclin D(1), p21, p53, and Bcl-2 was investigated by immunohistochemistry. RESULTS: High concentrations (5% or more) of HIF-1α were associated with increased proliferation as shown by positive correlations with Ki-67 (P < 0.001) and the late S–G2-phase protein cyclin A (P < 0.001), but not with the G1-phase protein cyclin D(1). High HIF-1α concentrations were also strongly associated with p53 positivity (P < 0.001) and loss of Bcl-2 expression (P = 0.013). No association was found between p21 and HIF-1α (P = 0.105) in the whole group of patients. However, the subgroup of ER-positive cancers was characterized by a strong positive association between HIF-1α and p21 (P = 0.023), and HIF-1α lacked any relation with proliferation. CONCLUSION: HIF-1α overexpression is associated with increased proliferation, which might explain the adverse prognostic impact of increased concentrations of HIF-1α in invasive breast cancer. In ER-positive tumors, HIF-1α is associated with p21 but not against proliferation. This shows the importance of further functional analysis to unravel the role of HIF-1 in late cell cycle progression, and the link between HIF-1, p21, and ER

Loss of expression of FANCD2 protein in sporadic and hereditary breast cancer

Fanconi anemia (FA) is a recessive disorder associated with progressive pancytopenia, multiple developmental defects, and marked predisposition to malignancies. FA is genetically heterogeneous, comprising at least 12 complementation groups (A–M). Activation of one of the FA proteins (FANCD2) by mono-ubiquitination is an essential step in DNA damage response. As FANCD2 interacts with BRCA1, is expressed in proliferating normal breast cells, and FANCD2 knockout mice develop breast tumors, we investigated the expression of FANCD2 in sporadic and hereditary invasive breast cancer patients to evaluate its possible role in breast carcinogenesis. Two tissue microarrays of 129 and 220 sporadic breast cancers and a tissue microarray containing 25 BRCA1 germline mutation-related invasive breast cancers were stained for FANCD2. Expression results were compared with several clinicopathological variables and tested for prognostic value. Eighteen of 96 (19%) sporadic breast cancers and two of 21 (10%) BRCA1-related breast cancers were completely FANCD2-negative, which, however, still showed proliferation. In the remaining cases, the percentage of FANCD2-expressing cells correlated strongly with mitotic index and percentage of cells positive for the proliferation markers Ki-67 and Cyclin A. In immunofluorescence double staining, coexpression of FANCD2 and Ki-67 was apparent. In survival analysis, high FANCD2 expression appeared to be prognostically unfavorable for overall survival (p = 0.03), independent from other major prognosticators (p = 0.026). In conclusion, FANCD2 expression is absent in 10–20% of sporadic and BRCA1-related breast cancers, indicating that somatic inactivating (epi)genetic events in FANCD2 may be important in both sporadic and hereditary breast carcinogenesis. FANCD2 is of independent prognostic value in sporadic breast cancer

Lympho-vascular invasion in BRCA related breast cancer compared to sporadic controls

<p>Abstract</p> <p>Background</p> <p>Germline mutations in the BRCA1 gene predispose to the development of breast cancer, exhibiting a specific histological phenotype. Identification of possible hallmarks of these tumors is important for selecting patients for genetic screening and provides inside in carcinogenetic pathways.</p> <p>Since BRCA1-associated breast cancers have pushing borders that prevent them from easily reaching vessels and are often of the medullary (like) type that is known to have a low rate of lympho-vascular invasion (LVI), we hypothesized that absence of LVI could characterize BRCA1 related breast cancer.</p> <p>Methods</p> <p>A population of 68 BRCA1 related invasive breast cancers was evaluated for LVI by an experienced breast pathologist blinded to mutation status, and compared to a control group matched for age, grade and tumor type.</p> <p>Results</p> <p>LVI was present in 25.0% of BRCA1 related cases, compared to 20.6% of controls (P = 0.54, OR = 1.29, CI 0.58-2.78).</p> <p>Conclusion</p> <p>LVI is frequent in BRCA1 germline mutation related breast cancers, but seems to occur as often in sporadic controls matched for age, grade and tumor type. Apparently, these hereditary cancers find their way to the blood and lymph vessels despite their well demarcation and often medullary differentiation.</p