Role of sentinel lymph node biopsy in early breast cancer.

Current literature has suggested that sentinel lymph node biopsy may replace axillary dissection as the nodal staging procedure of choice in early breast cancer. The aim of this study is to evaluate the effectiveness and accuracy of sentinel lymph node biopsy using methylene blue dye in predicting axillary nodal status in early breast cancer with clinically impalpable axillary lymph nodes. In the period between June 2005 and May 2009, 50 patients with early breast cancer and clinically impalpable axillary lymph nodes, underwent sentinel lymph node biopsy using methylene blue dye followed by completion of axillary dissection in the same setting after taking a written consent from the patients. Of the included 50 patients, sentinel lymph node biopsy was successful in 48 patients (96.0%). Accuracy of sentinel lymph node biopsy was 95.8%, sensitivity was 90.0%, false negative rate was 6.7%, negative predictive value was 93.3%.

Breast cancer in women aged 25 years and younger.

OBJECTIVE: To evaluate breast cancer characteristics in women aged 25 years and younger. METHODS: This was a retrospective, nested, within-cases matched study. The study design was based on a two-phase protocol. In the first phase, stage, grade, histologic subtype, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status were compared between 28 patients (aged 25 years and younger) and 685 older premenopausal women (aged older than 25 years) with breast cancer. The second phase aimed to determine whether young patients exhibited worse prognosis when compared with older premenopausal women. RESULTS: Young patients presented at a more advanced stage (P=.012) and exhibited a higher grade (P=.018). No significant differences were noted regarding histologic subtype, estrogen receptor, and progesterone receptor status. Genetic testing for BRCA1 and BRCA2 mutations was performed in 12 of 28 young patients and mutations were found in 25% of them. Moreover, young women presented poorer overall survival (hazard ratio [HR] 4.30, 95% confidence interval [CI] 1.09-17.03) than their older counterparts, matched by histologic subtype, stage, and grade; a similar pattern was noted regarding relapse-free survival (HR 8.28, 95% CI 2.24-30.60). CONCLUSION: Breast cancer diagnosis in women aged 25 years and younger is uncommon; however, these patients present at a more advanced stage, with a higher grade, and exhibit poorer survival.

Pathology of invasive breast disease.

Invasive breast cancers constitute a heterogeneous group of lesions. Although the most common types are ductal and lobular, this distinction is not meant to indicate the site of origin within the mammary ductal system. The main purpose of the identification of specific types of invasive breast carcinoma is to refine the prediction of likely behavior and response to treatment also offered by the other major prognostic factors, including lymph node stage, histologic grade, tumor size, and lymphovascular invasion.

Promoter methylation of RASSF1A modulates the effect of the microtubule-targeting agent docetaxel in breast cancer.

Docetaxel is one of the most commonly used chemotherapeutic agents in breast cancer. To avert from significant toxicities with no clinical benefit, identification of predictive markers for response is one of the most important unsolved clinical needs. Therefore, the potential associations of RASSF1A hypermethylation and response to docetaxel-based chemotherapy were evaluated, and the underlying mechanism was studied. The expression of RASSF1A in breast cancer cell lines and tissues of normal breast, ductal carcinoma in situ (DCIS), and breast cancer (n=45) was analyzed by immunohistochemistry and western blot analysis. Immunohistochemical staining showed that the expression of RASSF1A was frequently lost in primary breast cancers and human breast cancer cell lines, while normal breast tissues or DCIS displayed moderate to strong expression. Furthermore, quantitative methylation analysis of the RASSF1A promoter region in 45 primary breast cancers revealed that RASSF1A was frequently methylated in primary breast cancers (≥20% methylation in 53% of the patients), and prospective analysis in patients with locally advanced or recurrent breast cancer showed that the mean level of methylation of RASSF1A was significantly higher in patients who did not respond to docetaxel-based chemotherapy (30.6±8.5%) than patients with partial or complete response (20.1±11.2%, p=0.042). Finally, in vitro studies showed that RASSF1A had cooperative activity in suppression of cancer cell growth and proliferation by enhancing docetaxel-induced cell cycle arrest. Our results suggest that hypermethylated RASSF1A is an important modulating factor for the efficacy of docetaxel-based chemotherapy in breast cancer.

Yield of selective magnetic resonance imaging in preoperative workup of newly diagnosed breast cancer patients planned for breast conserving surgery.

The role of routine preoperative magnetic resonance imaging (MRI) in newly diagnosed breast cancer patients planned for breast conserving surgery is presently being debated. In our medical center we practice selective use of preoperative MRI; we sought to examine the yield of MRI in this highly selected group of patients. A retrospective study of all newly diagnosed breast cancer patients presenting between January 2007 and July 2010 to the Tel Aviv Sourasky Medical Center (Tel Aviv, Israel) was completed. Patients planned for breast conserving surgery who underwent preoperative MRI were included in this study. Patients and tumor characteristics, indication for MRI, findings on MRI, consequent workup, and impact on surgical treatment were recorded. Association between preoperative characteristics and yield of MRI was examined. During the study period, 105 patients that were candidates for breast conserving surgery underwent preoperative evaluation with MRI. Use of breast MRI increased over time. Rates of mastectomy were stable throughout the study years. Dense mammogram was the most frequent (51, 68%) indication for MRI. Additional suspicious findings were found in 41 (39%) patients, prompting further workup including 36 biopsies in 25 patients, of which 22 (61%) were with cancer. These additional findings prompted a change in the surgical plan in a third of the patients. In most patients (92; 88%) clear margins were achieved. Limiting the use of MRI in the preoperative workup of breast cancer patients to a selected group of patients can increase the yield of MRI.

Current management practice of breast borderline lesions--need for further research and guidelines.

BACKGROUND: Breast borderline lesions are usually diagnosed on needle biopsies of imaging abnormalities. The natural history of these lesions is unclear, and the literature is divided on appropriate management. It was hypothesized that management varies among surgeons and may be associated with surgeon and practice characteristics. METHODS: A survey of 477 members of the American Society of Breast Surgeons was completed. Results were analyzed according to various surgeon and practice characteristics. RESULTS: Most respondents recommended routine excision for atypical ductal and lobular hyperplasia. Excision of radial scars and papillomas was much more variable, with only 50% recommending routine excision. Results differed by surgical dedication to breast surgery and fellowship training. Management of atypical ductal or lobular hyperplasia found at the margin varied significantly. The lack of a routine tumor board, low breast case volume, and low percentage of breast cases were associated with routine excision in these cases. CONCLUSIONS: Breast borderline lesions pose a clinical dilemma, with practice varying greatly among surgeons.

The adjacent vessel sign on breast MRI: new data and a subgroup analysis for 1,084 histologically verified cases.

OBJECTIVE: The adjacent vessel sign (AVS) is a descriptor for differentiating malignant from benign breast lesions on breast MRI (bMRI). This investigation was designed to verify the previous reports on the diagnostic accuracy of AVS and to assess correlation between AVS, histopathological diagnosis, lesion size and lesion grade. MATERIALS AND METHODS: This study was approved by the local ethical committee. Experienced radiologists evaluated 1,084 lesions. The exclusion criteria were no histological verification after bMRI and breast interventions that were done up to one year before bMRI (surgery, core biopsy, chemo- or radiation therapy). The native and dynamic contrast-enhanced T1-weighted series were acquired using standardized protocols. The AVS was rated positive if a vessel leading to a lesion could be visualized. Prevalence of an AVS was correlated with the lesions' size, grade and histology using Chi-square-tests. RESULTS: The AVS was significantly associated with malignancy (p < 0.001; sensitivity: 47%, specificity: 88%, positive-predictive-value [PPV]: 85%). Malignant lesions > 2 cm more often presented with an AVS than did those malignant lesions < 2 cm (p < 0.0001; sensitivity: 65%, PPV: 90%). There was no correlation of the AVS with the tumor grade. The prevalence of an AVS didn't significantly differ between invasive lobular carcinomas versus ductal carcinomas. In situ cancers were less frequently associated with an AVS (p < 0.001). CONCLUSION: The adjacent vessel sign was significantly associated with malignancy. Thus, it can be used to accurately assess breast lesions on bMRI. In this study, the AVS was particularly associated with advanced and invasive carcinomas.

Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT).

BACKGROUND: Patients with breast cancer brain metastasis are a heterogeneous group in relation to tumor biology and outcome. MATERIALS AND METHODS: The group of 222 breast cancer patients with brain metastasis was divided into three biological subgroups. The propensity of biological subtypes for metastases to the brain and survivals depending on biological subtype, recursive partitioning analysis of Radiation Therapy Oncology Group (RPA RTOG) prognostic class and the use of systemic treatment after whole-brain radiotherapy were assessed. RESULTS: The rate of patients with triple-negative, human epidermal growth factor receptor 2 (HER2)-positive and luminal breast cancer with brain metastases was 28%, 53% and 19%, respectively. Median survival from brain metastases in triple-negative, HER2-positive and luminal subtype was 3.7, 9 and 15 months, respectively. Median survival from brain metastases in RPA RTOG prognostic class I, II and III was 15, 11 and 3 months, respectively. In the luminal and in the triple-negative subtype, systemic therapy prolonged survival from 3 to 14 months and from 3 to 4 months, respectively. In HER2-positive subtype, median survival without further treatment, after chemotherapy and after chemotherapy with targeted therapy were 3, 8 and 11 months, respectively. CONCLUSIONS: HER2-positive and triple-negative breast cancers have special predilection for metastases to the brain. Survival from brain metastases depended on performance status and the use of systemic treatment.

Decreasing trend of tumor size and downstaging in breast cancer in Iran: results of a 15-year study.

The aim of this cross-sectional study was to show the characteristics of breast cancer across a period of 15 years according to pathological records in Tehran, Iran. In the year 1985, a 20-year study was designed and developed in five major hospitals in Tehran to study the burden and characteristics of breast cancer in Iran. This study is based on the data collected from 1986 through 2000. SPSS version 13 was used for statistical analysis. In this study, 1612 female breast cancer records were reviewed. The mean age of patients was 47.95+/-12.42 years with a median of 47 years. Over the study period, the proportion of tumors diagnosed at T2 increased with a decline in the proportion of T3 cases. Similarly, the percentage of stage II cases at diagnosis increased, whereas stage III decreased. We detected a decrease in tumor size and downstaging of female breast cancer in Tehran, Iran. This can be attributed to the overall improvement in the level of health in Iran and also educational activities that teach women how to perform breast self-exam and when and why to ask for breast examination.

Breast cancer and cyclin D1 gene polymorphism in Turkish women.

BACKGROUND: Cyclin D1 protein plays an important part in regulating the progress of the cell during the G(1) phase of the cell cycle. It has been suggested that G870A polymorphism at the exon4/intron4 splicing region of the CCND1 gene may play a role in tumorigenesis and invasiveness. PATIENTS AND METHODS: A case-control study was performed to test the association between G870A polymorphisms in the CCND1 gene and breast cancer risk and cancer progression. For this purpose, 38 patients with breast cancer and 64 healthy women controls were included in the study. The CCND1 G870A polymorphisms in our study groups were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using peripheral blood samples. RESULTS: A significant difference was found in the distribution of the GG, AG and AA genotypes between the patient group and the control group (p=0.021). A lower risk (odds ratio 0.435, 95% confidence interval 0.223-0.846) was found to be associated with heterozygote AG individuals when compared with homozygote allele carriers in breast cancer. The cyclin D1 A870G genotype was associated with capsular invasion (p=0.02). CONCLUSION: The risk of breast cancer development and prognosis may be associated with genetic variation in the CCND1 genotype, which may be used as a biomarker for further studies.

Risk-benefit analysis of preoperative breast MRI in patients with primary breast cancer.

AIM: To analyse and compare the risks and benefits of preoperative breast MRI (BMRI) in patients with primary breast cancer (PBC), and to determine the influence of mammographic breast density (BD) and histological tumour type (TT). MATERIALS AND METHODS: One hundred and nineteen patients who underwent preoperative bilateral breast MRI for staging of PBC during a 1-year period from July 2005 to August 2006 were prospectively evaluated. Changes in clinical management due to BMRI findings were recorded. MRI-detected lesions were correlated with histology. Additional MRI-detected malignant lesions and spared additional biopsies because of negative MRI in case of unclear ultrasound findings were determined as beneficial for the patient. Biopsies of benign MRI detected lesions were defined as disadvantageous. The influence of BD (ACR 1-4) and TT on the change in clinical management and patient benefit was evaluated. RESULTS: The findings of the BMRI examinations changed the clinical management in 48 patients (40.3%). Seventeen women underwent mastectomy instead of breast conservation, eight patients underwent extended excision, 21 additional lesions were clarified by MRI intervention, and two ultrasound-detected lesions were not biopsied because of negative MRI. Histologically malignant additional or extended biopsies (n=34) and two cases of spared biopsies resulted in 36 (30.3%) women who benefited from preoperative BMRI. Twelve patients (10.1%) had additional biopsies of MRI-detected benign lesions, and therefore, had an unfavourable outcome due to BMRI. The change in clinical management and patient benefit were independent of BD and TT (p>0.05). CONCLUSION: Preoperative BMRI was beneficial for 30.3% of 119 patients with PBC. The percentage of additional biopsies of benign lesions (10.1%) seems acceptable.

Down-regulation of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma involves promoter methylation and associates with metastasis.

FEZ1/LZTS1 is a tumor suppressor gene located in chromosomal band 8p22, and methylation has been identified as a mechanism for its loss of function in tumors. Chromosomal deletion at 8p22 is also frequent in breast cancer. We therefore examined whether LZTS1 plays a role in breast cancer. We analyzed expression of LZTS1 at both the RNA and protein levels, and promoter methylation in a number of primary tumors and cell lines from breast cancer. We also examined the association between LZTS1 expression and different clinicopathological parameters of breast cancer. We found that the expression of LZTS1 mRNA was reduced in 25 of 50 (50%) primary tumors and 29 of 30 (97%) breast cancer cell lines. Immunohistochemical staining showed that LZTS1 protein was absent or down-regulated in 72 (72%) of 100 primary breast carcinomas. Reduced expression of LZTS1 at either the RNA or protein level was significantly correlated with lymph node metastases (P < 0.05). DNA methylation analysis revealed that the LZTS1 gene was frequently methylated in both cell lines and primary tumors from breast cancer, and the extent of DNA methylation was correlated with reduced expression of the gene. These findings suggest that LZTS1 plays a role in the development and progression of breast cancer at least through promoter methylation-mediated transcriptional downregulation.

Significance of pathological evaluation for lymphatic vessel invasion in invasive breast cancer.

BACKGROUND: Lymphatic vessel invasion (LVI) has been conventionally assessed on hematoxylin-eosin (HE) stained sections, but this assessment tends to be subjective. The aim of this study is to investigate the significance of LVI in invasive breast cancers, primarily using immunohistochemical lymphatic endothelial markers. METHODS: We studied 69 invasive breast carcinoma cases. Using D2-40 and podoplanin, we investigated the distribution of lymphatic vessels around the tumor and LVI, and they were compared with the HE sections. The correlation between LVI, lymph node metastasis and disease free survival (DFS) was also investigated. RESULTS: Lymphatic vessels were most frequently seen outside the tumor (86%), whereas lymphatic vessels were not seen in the central zone of the tumor. LVI was found in 22 cases, of which nineteen was seen in the peripheral zone (87%). For both HE and lymphatic markers, the rates of mild LVI tended to be high. The concordance rate between D2-40 and podoplanin was 94.2% (65/69). LVI assessed on HE sections was corresponded to 54/69 cases (78.2%) using either D2-40 or podoplanin. There were 25 axillary lymph node positive cases. Lymph node metastasis significantly correlated with LVI assessed by HE section, but did not correlate with LVI assessed by the lymphatic markers. The tumor recurred in 19 cases during the mean follow-up period of 47.5 months. Disease free survival was significantly better for LVI negative cases on HE analysis, and LVI negative or mildly positive by any staining procedure. CONCLUSION: The lymphatic endothelium markers, D2-40 and podoplanin, are very useful for detecting LVI, but careful examination by routine HE sections may be enough for routine practice. Moderate or marked degree of LVI may be of value to predict survival.

False-positive and false-negative cases of fine-needle aspiration cytology for palpable breast lesions.

BACKGROUND: Fine-needle aspiration cytology (FNA) is less traumatic and technically easy to apply to small breast tumors. METHODS: A total of 382 cases of palpable breast lesions that had undergone fine needle aspiration and histopathologic diagnosis were reviewed with an emphasis on the rate of false positive diagnoses in benign breast lesions. RESULTS: A diagnosis of " malignant " was made in 98 of the 382 specimens (25.6%). The predictive value for malignancy was 97.9%. The sensitivity, specificity, and accuracy of FNA were 86.3%, 98.2%, and 93.2%, respectively, when the " suspicious " group was considered positive for malignancy. The histologic subtypes of the 4 false-positive cases were epithelial proliferative lesions, ductal or lobular hyperplasia. None of these 4 cases were definitely diagnosed as " malignant " by radiological studies. Four false-negative cases by FNA were suspicious for malignancy radiologically. There was no specific pathological subtype associated with false-negative status on FNA in this study. CONCLUSION: Palpable breast tumors can be definitively diagnosed based on a combination of physical examination, radiological studies and FNA, when the radiological studies concur with the diagnosis by FNA.

Central quadrantectomy with resection of the nipple-areola complex compared with mastectomy in patients with retroareolar breast cancer.

Appropriate surgery in women with retroareolar breast cancer should allow resection of the cancer with wide free margins and an acceptable cosmetic result. The aim of this study was to compare breast conservation surgery (BCS) to mastectomy for treatment of retroareolar breast cancer. In a prospective nonrandomized study, 69 women with retroareolar breast cancers underwent either central quadrantectomy (n=33) with complete removal of the nipple-areola complex or mastectomy (n=36). Two of 33 (6%) patients scheduled for BCS had a secondary mastectomy and immediate reconstruction due to involved margins. After a median follow-up of 42 month (range 17-99 months) in the BCS group and 43 months (range 16-118 months) in the mastectomy group local and regional recurrences as well as systemic disease were comparable between both groups. The postoperative cosmetic result after BCS as evaluated by the patients was rated as excellent in 80% and good in 20% with no poor result. BCS followed by radiation therapy is a feasible alternative to mastectomy in patients with retroareolar breast cancer.

Early- and late-onset breast cancer types among women in the United States and Japan.

BACKGROUND: Although differences in breast cancer incidence among Occidental and Asian populations are often attributed to variations in environmental exposures and/or lifestyle, fewer studies have systematically examined the effect of age-related variations. METHODS: To further explore age-related geographic breast cancer variations, we compared age-specific incidence patterns among cases of female invasive breast cancer from the Surveillance, Epidemiology, and End Results (SEER) program and the Osaka Cancer Registry (1978-1997). RESULTS: In SEER, there were 236,130 Whites, 21,137 Blacks, and 3,304 Japanese-Americans in Hawaii with invasive breast cancer. In Osaka, there were 25,350 cases. Incidence rates per 100,000 woman-years ranged from 87.6 among Whites to 21.8 in Osaka. Age-specific incidence rates increased rapidly until age 50 years for all race/ethnicity groups, and then continued to increase more slowly for Whites, Blacks, and Japanese-Americans in Hawaii but plateaud for Osaka. Age-specific incidence rates in SEER reflected bimodal (early-onset and late-onset) breast cancer populations, whereas Osaka had only an early-onset age distribution. These age-specific differences in incidence among SEER and Osaka persisted after adjustment for calendar-period and birth-cohort effects using age-period-cohort models. CONCLUSIONS: Results confirm striking age-specific differences among Occidental and native Japanese breast cancer populations, probably due to complex age-related biological and/or environmental variations among Occidental and Asian breast cancer populations.

COX-2 expression in lobular in situ neoplasia of the breast: correlation with histopathological grading system according to the Tavassoli classification.

AIMS: There is considerable evidence to link cyclooxygenase (COX)-2 to the development of cancer. The aim of this study was to assess COX-2 expression and its subcellular localization in lobular in situ neoplasia (LIN) of the breast and to verify differences in COX-2 expression between different grades of lesions according to the Tavassoli classification. METHODS AND RESULTS: We analysed the expression of COX-2 protein by immunohistochemistry in tissue samples of 51 LIN lesions classified into three grades according to the Tavassoli classification. COX-2 immunostaining was observed in 78.4% of LIN samples and showed a prevalent membranous rather than cytoplasmic pattern. COX-2 was expressed in 16/17 (94.1%) LIN1, 22/25 (88%) LIN2 and 2/9 (22.2%) LIN3. As regards COX-2 expression, a statistically significant difference was found between LIN1 and LIN3 (P = 0.001) and between LIN2 and LIN3 (P =0.001). No difference was found between LIN1 and LIN2. Moreover, a significant negative correlation was found between LIN grade and COX-2 expression (P < 0.0001). CONCLUSIONS: COX-2 is highly expressed in LIN, supporting a role for this protein in the early stage of breast carcinogenesis, representing the rationale for using COX-2 selective inhibitors in the earliest stages of breast cancer.

Cell blocks of breast FNAs frequently allow diagnosis of invasion or histological classification of proliferative changes.

Two major limitations of breast fine needle aspiration (FNA) compared with core needle biopsies (CNB) are the inability to determine whether a cancer is invasive and to classify proliferative lesions. We studied 40 consecutive "rapid cell blocks" from breast FNAs with surgical pathology follow-up to test whether cell blocks can overcome these limitations. Of 25 carcinomas, invasion could be identified in the cell block sections in 11 (44%). One cystosarcoma phyllodes was suspected based on the cell block sections. Cell blocks from 12 of 14 benign breast FNAs showed sufficient cells to assign a histologic diagnosis of no hyperplasia (1 case, confirmed on follow-up) and usual hyperplasia (11 cases; confirmed in eight of 11 on follow-up). Specific histologic diagnoses included intraductal papilloma (2 cases), and in situ lobular neoplasia (2 cases). Cell blocks complement smears and monolayers and appear to overcome major limitations of breast FNA.

The cytoskeleton regulatory protein hMena (ENAH) is overexpressed in human benign breast lesions with high risk of transformation and human epidermal growth factor receptor-2-positive/hormonal receptor-negative tumors.

PURPOSE: hMena (ENAH), a cytoskeleton regulatory protein involved in the regulation of cell motility and adhesion, is overexpressed in breast cancer. The aim of this study was to define at what stage of breast carcinogenesis hMena is overexpressed and to correlate hMena overexpression with established prognostic factors in breast cancer, focusing on human epidermal growth factor receptor-2 (HER-2). EXPERIMENTAL DESIGN: hMena expression was assessed immunohistochemically in a prospective cohort of cases (n = 360) encompassing a highly representative spectrum of benign breast diseases associated with different risk of transformation, in situ, invasive, and metastatic tumors. Correlations with conventional pathologic and prognostic variables, such as proliferation index, hormonal receptor status, and HER-2 overexpression, were also evaluated. In vitro experiments were done to study the effect of neuregulin-1 and Herceptin treatments on hMena expression. RESULTS: hMena protein is undetectable in normal breast and is weakly expressed in a small percentage of low-risk benign diseases (9%), but displays a progressive and significant increase of positivity in benign lesions at higher risk of transformation (slightly increased risk 43%; moderate increased risk 67%), in in situ (72%), invasive (93%), and metastatic breast cancer (91%). A significant direct correlation with tumor size (P = 0.04), proliferation index (P < 0.0001), and HER-2 overexpression (P < 0.0001) and an inverse relationship with estrogen (P = 0.036) and progesterone receptors (P = 0.001) are found in invasive carcinomas. In vitro experiments show that neuregulin-1 up-regulates, whereas Herceptin down-regulates, hMena expression. CONCLUSIONS: Our data provide new insights into the relevance of actin-binding proteins in human breast carcinogenesis and indicate hMena overexpression as a surrogate indicator in breast disease management.