Prophylactic Mastectomy in BRCA1/2 Mutation Carriers and Women at Risk of Hereditary Breast Cancer: Long-Term Experiences at the Rotterdam Family Cancer Clinic

Background BRCA1/2 mutation carriers and women from a hereditary breast(/ovarian) cancer family have a highly increased risk of developing breast cancer (BC). Prophylactic mastectomy (PM) results in the greatest BC risk reduction. Long-term data on the efficacy and sequels of PM are scarce. Methods From 358 high-risk women (including 236 BRCA1/2 carriers) undergoing PM between 1994 and 2004, relevant data on the occurrence of BC in relation to PM, complications in relation to breast reconstruction (BR), mutation status, age at PM and preoperative imaging examination results were extracted from the medical records, and analyzed separately for women without (unaffected, n = 177) and with a BC history (affected, n = 181). Results No primary BCs occurred after PM (median follow-up 4.5 years). In one previously unaffected woman, metastatic BC was detected almost 4 years after PM (primary BC not found). Median age at PM was younger in unaffected women (P < .001), affected women more frequently were 50% risk carriers (P < .001). Unexpected (pre)malignant changes at PM were found in 3% of the patients (in 5 affected, and 5 unaffected women, respectively). In 49.6% of the women opting for BR one or more complications were registered, totaling 215 complications, leading to 153 surgical interventions (71%). Complications were mainly related to cosmetic outcome (36%) and capsular formation (24%). Conclusions The risk of developing a primary BC after PM remains low after longer follow-up. Preoperative imaging and careful histological examination is warranted because of potential unexpected (pre)malignant findings. The high complication rate after breast reconstruction mainly concerns cosmetic issues

Genetic counselling and the intention to undergo prophylactic mastectomy: effects of a breast cancer risk assessment

Scientific reports suggest that women at risk for familial breast cancer may benefit from prophylactic mastectomy. However, few data are available about how women decide upon this clinical option, and in particular, what role an objective risk assessment plays in this. The purpose of the present study is to assess whether this objective risk information provided in genetic counselling affects the intention for prophylactic mastectomy. Additionally, the (mediating) effects of breast cancer worry and perceived risk are investigated. A total of 241 women completed a questionnaire before and after receiving information about their familial lifetime breast cancer risk in a genetic counselling session. Path analysis showed that the objective risk information had a corrective effect on perceived risk (β=0.38; P=0.0001), whereas the amount of breast cancer worry was not influenced by the counselling session. The objective risk information did not directly affect the intention for prophylactic mastectomy. The intention was influenced by perceived risk after counselling (β=0.23; P=0.002), and by the precounselling levels of perceived risk (β=0.27; P=0.00025) and breast cancer worry (β=0.32; P=0.0001), that is, higher levels of perceived risk and breast cancer worry imply a stronger intention for prophylactic mastectomy. A personal history of breast cancer did not directly influence the intention for prophylactic mastectomy, but affected women who had undergone a mastectomy as surgical treatment were more positively inclined to have a prophylactic mastectomy than women who had had breast-conserving therapy. The impact of objective risk information on the intention for prophylactic mastectomy is limited and is mediated by perceived risk. Important determinants of the intention for prophylactic mastectomy were precounselling levels of breast cancer worry and perceived risk, suggesting that genetic counselling is only one event in the entire process of decision making. Therefore, interventions aimed at improving decision making on prophylactic mastectomy should explicitly address precounselling factors, such as personal beliefs and the psychological impact of the family medical history

The pathology of familial breast cancer: The pre-BRCA1/BRCA2 era - historical perspectives

A proportion of breast carcinomas develop as a result of a genetic predispostion to the disease. Prior to cloning of the BRCA1 and BRCA2 genes a limited number of studies were carried out to identify specific histopathological characteristics of hereditary breast cancer. These studies are the subject of this review. The main finding was the association of the (atypical) medullary type of breast cancer with a family history; the most important caveat being that medullary breast cancer is found more frequently in young patients. In view of the frequent bilateral occurrence of lobular cancer, this histologic type is also likely to be associated with a predisposing genetic defect. Future investigations will have to test this hypothesis. In addition to mutations in the BRCA1 and BRCA2 genes, there are as yet unidentified genetic defects predisposing to breast cancer development, and histopathology may well help in identifying these genes in the future

Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan

INTRODUCTION: Although breast carcinoma (BC) is the most common malignancy affecting Jordanian females and the affected population in Jordan is younger than that in the West, no information is available on its biological characteristics. Our aims in this study are to evaluate the expression of estrogen receptor (ER) and progesterone receptor (PR) and Her-2/neu overexpression in BC in Jordan, and to compare the expression of these with other prognostic parameters for BC such as histological type, histological grade, tumor size, patients' age, and number of lymph node metastases. METHOD: This is a retrospective study conducted in the Department of Pathology at Jordan University of Science and Technology. A confirmed 91 cases of BC diagnosed in the period 1995 to 1998 were reviewed and graded. We used immunohistochemistry to evaluate the expression of ER, PR, and Her-2. Immunohistochemical findings were correlated with age, tumor size, grade and axillary lymph node status. RESULTS: Her-2 was overexpressed in 24% of the cases. The mean age of Her-2 positive cases was 42 years as opposed to 53 years among Her-2 negative cases (p = 0.0001). Her-2 expression was inversely related to ER and PR expression. Her-2 positive tumors tended to be larger than Her-2 negative tumors with 35% overexpression among T3 tumors as opposed to 22% among T2 tumors (p = 0.13). Her-2 positive cases tended to have higher rates of axillary metastases, but this did not reach statistical significance. ER and PR positive cases were seen in older patients with smaller tumor sizes. CONCLUSION: Her-2 overexpression was seen in 24% of BC affecting Jordanian females. Her-2 overexpression was associated with young age at presentation, larger tumor size, and was inversely related to ER and PR expression. One-fifth of the carcinomas were Her-2 positive and ER negative. This group appears to represent an aggressive form of BC presenting at a young age with large primary tumors and a high rate of four or more axillary lymph node metastases

Evaluation of models to predict BRCA germline mutations

The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66–2.67) for Penn, 1.74 (95% CI 1.48–2.04) for Myriad, 1.35 (95% CI 1.19–1.53) for Manchester and 1.68 (95% CI 1.39–2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study

Retroperitoneal Castleman's tumor and paraneoplastic pemphigus: report of a case and review of the literature

BACKGROUND: Castleman's disease is a rare lymphoproliferative syndrome. Its etiology and pathogenesis are unclear. The disease can be occasionally associated with a paraneoplastic pemphigus (PNP), an autoimmune mucocutaneous disorder commonly seen in neoplasms of lymphocytic origin. CASE PRESENTATION: We present a case of a 63-year old male patient who was referred for surgical treatment of a lately diagnosed retroperitoneal pelvic mass. The patient had been already treated for two years due to progressive diffuse cutaneous lesions histologically consistent with lichen ruber verucosus and pemphigus vulgaris. Intraoperatively a highly vascularized solid mass occupying the small pelvis was resected after meticulous vascular ligation and hemostasis. After surgery and following immunosuppressive treatment a clear remission of the skin lesions was observed. CONCLUSION: Castleman's tumor should be always suspected when a retroperitoneal mass is combined with PNP. In a review of the literature we found 37 additional cases. Complete surgical resection of the tumor can be curative in most of the cases

Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma

The current model for breast cancer progression proposes independent “low‐grade (LG) like” and “high‐grade (HG) like” pathways but lacks a known precursor to HG cancer. We applied low coverage whole genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. 14/20 isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG‐like CNA than LG DCIS (eg. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent “low‐grade like” and “high‐grade like” pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH could be more clinically significant than LG DCIS, requiring biomarkers for personalising management