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

Procedural fairness in judicial review of migration decisions: The evolution of a fundamental common law principle

Procedural fairness has undergone significant evolution from a moral limit on the exercise of power to a fundamental principle of the common law. The thesis explains and reconciles this evolution of procedural fairness in Australia in the context of judicial review of decisions made under the Migration Act 1958 (Cth). By historical analysis of the origins and development of the principles of procedural fairness, the thesis identifies values and concepts underlying those principles. The High Court’s current conception of fairness, as protecting individual rights and interests in the exercise of power, evolved from the idea that there is a morally correct and just way to decide things. The thesis explains how by judicial development the implication of the obligation to observe procedural fairness in Australia, in the context of migration decisions, was shaped and informed, expressly and implicitly, by these values and concepts. The thesis explains the basis for the current restatement of procedural fairness as a fundamental principle of the common law, the relationship between procedural fairness and the principle of legality, and the positioning of procedural fairness as a principle or presumption of statutory construction. The thesis suggests that the explanation rests in legal coherence, in particular defining the obligation to observe procedural fairness in terms of an implied limit on the exercise of statutory power. The thesis also suggests that the dual presumptions created by recognising procedural fairness as a fundamental principle buttressed by the principle of legality, practically deny the exclusion of the principles in all but a limited number of cases

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

The association of socioeconomic status on treatment strategy in patients with stage I and II breast cancer in the Netherlands

BACKGROUND: Previous studies have shown that socioeconomic status (SES) influences breast cancer therapy. However, these studies were performed in countries with unequal access to healthcare. Therefore, the aim of this study is to investigate whether SES also contributes to the likelihood of receiving a certain therapy in the Netherlands, a country with supposedly equal access to healthcare. MATERIALS AND METHODS: From the Netherlands Cancer Registry, 105,287 patients with newly diagnosed stage I or II breast cancer diagnosed between 2011 and 2018 were selected for analysis. SES was calculated from the average incomes of each postal code, which were divided into 10 deciles. Primary outcome was the effect of SES on the likelihood of undergoing surgery and secondary outcome was the effect of SES on the likelihood of the type of surgery. Both outcomes were corrected for patient, tumor, and hospital characteristics and were expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: SES did not affect the likelihood of a breast cancer patient to undergo surgery (OR 1.00 per 10% stratum). In contrast, increased age and higher tumor stage were the most important factors determining whether patients underwent surgery. Patients with higher SES were less likely to undergo mastectomy (OR 0.98). Additionally, more recently diagnosed patients were less likely to undergo mastectomy (OR 0.93 per year) while patients with higher tumor stage were more likely to undergo mastectomy (OR 3.42). CONCLUSION: SES does not affect whether a patient undergoes surgery; however, higher SES increased the likelihood of BCT

Expression of hypoxia-induced proteins in ductal carcinoma in situ and invasive cancer of the male breast

AIMS: The aim of this study was to determine the role of hypoxia in male breast carcinogenesis by evaluating the expression of the hypoxia-related proteins, hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase IX (CAIX) and glucose transporter-1 (Glut-1), in ductal carcinoma in situ (DCIS) of the male breast in relation to invasive cancer (IC). METHODS: Tumour tissue blocks of 18 cases of pure DCIS, 58 DCIS cases adjacent to IC (DCIS-AIC) and the 58 IC cases were stained by immunohistochemistry for HIF-1α, CAIX and Glut-1, and expression frequencies and patterns (diffuse and/or perinecrotic) were noted. RESULTS: HIF-1α overexpression was observed in 61.1% (11/18) of pure DCIS, in 37.9% (22/58) of DCIS-AIC and in 36.2% (21/58) of IC cases (not significant (n.s.)). CAIX overexpression was observed in 16.7% (3/18) of pure DCIS, in 37.9% (22/58) of DCIS-AIC and in 24.1% (14/58) of IC cases (n.s.). Glut-1 overexpression was observed in 61.1% (11/18) of pure DCIS, in 75.9% (44/58) of DCIS-AIC and in 62.1% (36/58) of IC cases (n.s.). Expression of hypoxia-related proteins was seen around necrosis in a little over one-third of DCIS cases, and often coincided with expression in adjacent IC when present. All these observations indicate that the hypoxia response is already at its maximum in the preinvasive DCIS stage. CONCLUSIONS: In conclusion, male DCIS frequently shows activated hypoxia response, comparable to male IC. This indicates that the activated hypoxia response previously seen in male IC is not a late bystander but likely a genuine carcinogenetic event

Hypoxia-Inducible Factor-1 as a Therapeutic Target in Endometrial Cancer Management

In the Western world, endometrial cancer (EC) is the most common malignant tumor of the female genital tract. Solid tumors like EC outgrow their vasculature resulting in hypoxia. Tumor hypoxia is important because it renders an aggressive phenotype and leads to radio- and chemo-therapy resistance. Hypoxia-inducible factor-1α (HIF-1α) plays an essential role in the adaptive cellular response to hypoxia and is associated with poor clinical outcome in EC. Therefore, HIF-1 could be an attractive therapeutic target. Selective HIF-1 inhibitors have not been identified. A number of nonselective inhibitors which target signaling pathways upstream or downstream HIF-1 are known to decrease HIF-1α protein levels. In clinical trials for the treatment of advanced and/or recurrent EC are the topoisomerase I inhibitor Topotecan, mTOR-inhibitor Rapamycin, and angiogenesis inhibitor Bevacizumab. Preliminary data shows encouraging results for these agents. Further work is needed to identify selective HIF-1 inhibitors and to translate these into clinical trials

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