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Sarah E Pinder

Publications and source records attributed to Sarah E Pinder.

At least 19 recordsLinked to original sources
PubMed2006

Non-operative breast pathology: lobular neoplasia.

Lobular neoplasia is a relatively uncommon lesion, which is frequently diagnosed in biopsy specimens taken for other reasons. Although the histological features of this lesion are well known, its biological significance as a "risk indicator" or "breast cancer precursor" has been a matter of debate. This review provides an update on recent clinicopathological and molecular data on lobular neoplasia and how these have changed the way these lesions are perceived and, most importantly, managed. Furthermore, the current recommendations for the management of lobular neoplasia diagnosed on core needle biopsies proposed in the National Health Service Breast Cancer Screening guidelines are discussed.

Biomarkers, Tumor↗
PubMed2006

MYC amplification in breast cancer: a chromogenic in situ hybridisation study.

AIMS: To analyse the correlation between MYC amplification and various clinicopathological features and outcome in a cohort of 245 patients with invasive breast carcinoma treated with surgery followed by anthracycline-based chemotherapy. Given the high prevalence of MYC amplification in tumours of BRCA1 mutation carriers and the similarities between these and sporadic "basal-like" carcinomas, the prevalence of MYC amplification in "basal-like" breast carcinomas was investigated. METHODS: MYC gene copy number was assessed on tissue microarrays containing duplicate cores of 245 invasive breast carcinomas by means of chromogenic in situ hybridisation using SpotLight C-MYC amplification probe and chromosome 8 centromeric probe (CEP8). Signals were evaluated at 400x magnification; 30 morphologically unequivocal neoplastic cells in each core were counted for the presence of the gene and CEP8 probes. RESULTS: Amplification was defined as a MYC:CEP8 ratio >2. Signals for both MYC and CEP8 were assessable in 196/245 (80%) tumours. MYC amplification was found in 19/196 cases (9.7%) and was not associated with tumour size, histological grade, positivity for oestrogen receptor, progesterone receptor, HER2, epidermal growth factor, cytokeratins 14, 5/6 and 17, MIB1 or p53. Only 4% of basal-like carcinomas showed MYC amplification, compared to 8.75% and 10.7% of luminal and HER2 tumours respectively. On univariate analysis, MYC amplification displayed a significant association with shorter metastasis-free and overall survival and proved to be an independent prognostic factor on multivariate survival analysis. CONCLUSION: MYC amplification is not associated with "basal-like" phenotype and proved to be an independent prognostic factor for breast cancer patients treated with anthracycline-based chemotherapy.

Anthracyclines↗
PubMed2006

A consensus prognostic gene expression classifier for ER positive breast cancer.

BACKGROUND: A consensus prognostic gene expression classifier is still elusive in heterogeneous diseases such as breast cancer. RESULTS: Here we perform a combined analysis of three major breast cancer microarray data sets to hone in on a universally valid prognostic molecular classifier in estrogen receptor (ER) positive tumors. Using a recently developed robust measure of prognostic separation, we further validate the prognostic classifier in three external independent cohorts, confirming the validity of our molecular classifier in a total of 877 ER positive samples. Furthermore, we find that molecular classifiers may not outperform classical prognostic indices but that they can be used in hybrid molecular-pathological classification schemes to improve prognostic separation. CONCLUSION: The prognostic molecular classifier presented here is the first to be valid in over 877 ER positive breast cancer samples and across three different microarray platforms. Larger multi-institutional studies will be needed to fully determine the added prognostic value of molecular classifiers when combined with standard prognostic factors.

Breast Neoplasms↗
PubMed2006

Bcl-2 is a prognostic marker in breast cancer independently of the Nottingham Prognostic Index.

PURPOSE: Prognostication of breast cancer using clinicopathologic variables, although useful, remains imperfect. Many reports suggest that gene expression profiling can refine the current approach. Alternatively, it has been shown that panels of proteins assessed by immunohistochemistry might also be useful in this regard. We evaluate the prognostic potential of a panel of markers by immunohistochemistry in a large case series to establish if either a single marker or a panel could improve the prognostic power of the Nottingham Prognostic Index (NPI). We validated the results in an independent series. EXPERIMENTAL DESIGN AND RESULTS: The expression of 13 biomarkers was evaluated in 930 breast cancers on a tissue microarray. Eight markers [estrogen receptor (ER), progesterone receptor (PR), Bcl-2, cyclin E, p53, MIB-1, cytokeratin 5/6, and HER2] showed a significant association with survival at 10 years on univariate analysis. On multivariate analysis that included these eight markers and the NPI, only the NPI [hazard ratio (HR), 1.35; 95% confidence interval (95% CI), 1.16-1.56; P = 0.0005], ER (HR, 0.59; 95% CI, 0.39-0.88; P = 0.011), and Bcl-2 (HR, 0.68; 95% CI, 0.46-0.99; P = 0.055) were significant. In a subsequent multivariate analysis that included the NPI, ER, and Bcl-2, only Bcl-2 (HR, 0.62; 95% CI, 0.44-0.87; P = 0.006) remained independent of NPI (HR, 1.50; 95% CI, 1.16-1.56; P = 0.004). In addition, Bcl-2, used as a single marker, was more powerful than the use of a panel of markers. Based on these results, an independent series was used to validate the prognostic significance of Bcl-2. ER and PR were also evaluated in this validation series. Bcl-2 (HR, 0.83; 95% CI, 0.71-0.96; P = 0.018) retained prognostic significance independent of the NPI (HR, 2.04; 95% CI, 1.67-2.51; P < 0.001) with an effect that was maximal in the first 5 years. CONCLUSION: Bcl-2 is an independent predictor of breast cancer outcome and seems to be useful as a prognostic adjunct to the NPI, particularly in the first 5 years after diagnosis.

Adult↗
PubMed2006

Interobserver reproducibility in the diagnosis of flat epithelial atypia of the breast.

Columnar cell lesions (CCLs) of the breast with low-grade/monomorphic-type cytologic atypia are being identified increasingly in biopsies performed owing to mammographic microcalcifications. The WHO Working Group on the Pathology and Genetics of Tumours of the Breast recently introduced the term 'flat epithelial atypia' (FEA) for these lesions. However, the ability of pathologists to reproducibly diagnose FEA and to distinguish it from CCLs without atypia has not been previously evaluated. Eight pathologists with an interest in breast pathology participated in a study to address this issue. The study reference pathologist provided the other seven study pathologists with a Powerpoint tutorial that included written criteria for, and representative images of, FEA and CCLs without atypia (ie, columnar cell change and columnar cell hyperplasia). Following review of the tutorial, the study pathologists examined images in Powerpoint format from 30 CCLs and were instructed to categorize each as either 'FEA' or 'not atypical'. Overall agreement among the eight pathologists was 91.8% (95% CI, 84.0-96.9%), and the multi-rater kappa value was 0.83 (95% CI, 0.67-0.94), which is within the 'excellent agreement' range. Agreement was slightly better for determining absence of FEA (92.8%: 95% CI, 84.1-97.4%), than for determining its presence (90.4%: 95% CI, 79.9-96.7%). We conclude that the diagnosis of FEA and its distinction from CCLs without atypia is highly reproducible with the use of available diagnostic criteria.

Breast↗
PubMed2006

Is mammographic spiculation an independent, good prognostic factor in screening-detected invasive breast cancer?

OBJECTIVE: The aim of this study was to review the prognostic significance of pathologic and radiologic factors for screening-detected invasive breast cancers of any size. MATERIALS AND METHODS: The patient group was a consecutive series of 470 screening-detected invasive breast cancers that were diagnosed between 1988 and 1998. Data regarding tumor type, grade, maximum invasive diameter, lymph node status, and the presence or absence of vascular invasion were recorded, as were the mammographic features of the lesion. Survival was ascertained from hospital records and a cancer registry. Differences in survival were assessed using Kaplan-Meier survival curves with a log-rank test for difference. The significance of any correlations was assessed using the chi-square test and the chi-square test for trend. Multivariate analysis used a Cox proportional hazards model. RESULTS: At univariate analysis, large invasive size, the presence of definite vascular invasion, high histologic grade, and nodal involvement were associated with poorer breast-cancer-specific survival. Mammographic spiculation (the presence of either a spiculated mass or distortion) was associated with more prolonged breast-cancer-specific survival. The presence or absence of mammographic comedo calcification did not influence breast-cancer-specific survival. In a Cox multivariate analysis that included those factors significant in univariate analysis, size, grade, nodal stage, and mammographic spiculation maintained their prognostic significance. CONCLUSION: Mammographic spiculation is an independent, good prognostic factor for screening-detected invasive breast cancer. The mechanism of how mammographic spiculation confers a beneficial prognostic effect is not clear.

Aged↗
PubMed2005

Total loss of MHC class I is an independent indicator of good prognosis in breast cancer.

Tumours can be recognised by CTL and NK cells. CTL recognition depends on expression of MHC Class I loaded with peptides from tumour antigens. In contrast, loss of MHC Class I results in NK activation. In our study a large set of samples from patients with primary operable invasive breast cancer was evaluated for the expression of MHC Class I heavy and light by immunohistochemical staining of 439 breast carcinomas in a tissue microarray. Forty-seven percent (206 of 439) of breast carcinomas were considered negative for HLA Class I heavy chain (HC10), whereas lack of anti-beta2m-antibody staining was observed in 39% (167 of 424) of tumours, with only 3% of the beta2m-negative tumours expressing detectable HLA Class I heavy chain. Correlation with patient outcome showed direct relationship between patient survival and HLA-negative phenotype (log rank = 0.004). A positive relationship was found between the intensity of expression of MHC Class I light and heavy chains expression and histological grade of invasive tumour (p < 0.001) and Nottingham Prognostic Index (p < 0.001). To investigate whether HLA Class I heavy and light chains expression had independent prognostic significance, Cox multivariate regression analysis, including the parameters of tumour size, lymph node stage, grade and intensity of HC10 and anti-beta2m staining, was carried out. In our analysis, lymph node stage (p < 0.001), tumour grade (p = 0.005) and intensity of MHC Class I light and heavy chains expression were shown to be independent prognostic factors predictive of overall survival (p-values HC10 = 0.047 and beta2m = 0.018).

Adult↗
PubMed2005

High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses.

Recent studies on gene molecular profiling using cDNA microarray in a relatively small series of breast cancer have identified biologically distinct groups with apparent clinical and prognostic relevance. The validation of such new taxonomies should be confirmed on larger series of cases prior to acceptance in clinical practice. The development of tissue microarray (TMA) technology provides methodology for high-throughput concomitant analyses of multiple proteins on large numbers of archival tumour samples. In our study, we have used immunohistochemistry techniques applied to TMA preparations of 1,076 cases of invasive breast cancer to study the combined protein expression profiles of a large panel of well-characterized commercially available biomarkers related to epithelial cell lineage, differentiation, hormone and growth factor receptors and gene products known to be altered in some forms of breast cancer. Using hierarchical clustering methodology, 5 groups with distinct patterns of protein expression were identified. A sixth group of only 4 cases was also identified but deemed too small for further detailed assessment. Further analysis of these clusters was performed using multiple layer perceptron (MLP)-artificial neural network (ANN) with a back propagation algorithm to identify key biomarkers driving the membership of each group. We have identified 2 large groups by their expression of luminal epithelial cell phenotypic characteristics, hormone receptors positivity, absence of basal epithelial phenotype characteristics and lack of c-erbB-2 protein overexpression. Two additional groups were characterized by high c-erbB-2 positivity and negative or weak hormone receptors expression but showed differences in MUC1 and E-cadherin expression. The final group was characterized by strong basal epithelial characteristics, p53 positivity, absent hormone receptors and weak to low luminal epithelial cytokeratin expression. In addition, we have identified significant differences between clusters identified in this series with respect to established prognostic factors including tumour grade, size and histologic tumour type as well as differences in patient outcomes. The different protein expression profiles identified in our study confirm the biologic heterogeneity of breast cancer and demonstrate the clinical relevance of classification in this manner. These observations could form the basis of revision of existing traditional classification systems for breast cancer.

Breast Neoplasms↗
PubMed2005

High-resolution analysis of 16q22.1 in breast carcinoma using DNA amplifiable probes (multiplex amplifiable probe hybridization technique) and immunohistochemistry.

Loss of the chromosomal material at 16q22.1 is one of the most frequent genetic aberrations found in both lobular and low-grade nonlobular invasive carcinoma of the breast, indicating the presence of a tumour suppressor gene (TSG) at this region in these tumours. However, the TSG (s) at the 16q22.1 in the more frequent nonlobular carcinomas is still unknown. Multiplex Amplifiable Probe Hybridisation (MAPH) is a simple, accurate and a high-resolution technique that provides an alternative approach to DNA copy-number measurement. The aim of our study was to examine the most likely candidate genes at 16q22.1 using MAPH assay combined with protein expression analysis by immunohistochemistry. We identified deletion at 16q22.1 that involves some or all of these genes. We also noticed that the smallest region of deletion at 16q22.1 could be delineated to a 3 Mb region centromeric to the P-cadherin gene. Apart from the correlation between E-cadherin protein expression and its gene copy number, no correlation was detected between the expression of E2F-4, CTCF, TRF2 or P-cadherin with their gene's copy number. In the malignant tissues, no significant loss or decrease of protein expression of any gene other than E-cadherin was seen in association with any specific tumour type. No expression of VE-cadherin or Ksp-cadherin was detected in the normal and/or malignant tissues of the breast in these cases. However, there was a correlation between increased nuclear expression of E2F-4 and tumours with higher histological grade (p = 0.04) and positive lymph node disease (p = 0.02), suggesting that it may have an oncogenic rather than a tumour suppressor role. The malignant breast tissues also showed abnormal cytoplasmic cellular localisation of CTCF, compared to its expression in the normal parenchymal cells. In conclusion, we have demonstrated that MAPH is a potential technique for assessment of genomic imbalances in malignant tissues. Although our results support E-cadherin as the TSG in invasive lobular carcinoma, they argue against the candidacy of E2F-4, CTCF, TRF2, P-cadherin, Ksp-cadherin and VE-cadherin as TSGs in breast cancer.

Antigens, CD↗
PubMed2005

Selective use of post-mastectomy flap irradiation in high-risk breast cancer patients.

The incidence of local recurrence after mastectomy can be reduced by chest wall radiotherapy. However, only a minority of patients are at substantial risk. No UK national guidelines exist for the use of mastectomy flap radiotherapy. This study evaluated a protocol, whereby only high-risk patients were treated with post-mastectomy flap radiotherapy; identified histologically by grade, vascular invasion and nodal status. All women treated by simple mastectomy for invasive breast cancer at the Nottingham Breast Unit from January 1993 to December 1995 were studied (n=292). Postoperative flap radiotherapy was given to 147 high-risk women (50.3%). Median follow-up was 76 months. Overall, 12 women (4.1%) developed a chest wall recurrence; six were single spot recurrences and the remaining six were either multiple spot (n=3) or field change (field change dermal invasion, n=3). The chest wall recurrence rate was 2.7% in those treated with radiotherapy. A low rate of local recurrence has been achieved with selective use of mastectomy flap radiotherapy.

Adult↗
PubMed2005

Estrogen receptor-negative breast carcinomas: a review of morphology and immunophenotypical analysis.

Estrogen receptor (ER)-negative breast cancers are a group of tumors with poor prognosis and fewer cancer prevention and treatment strategies compared to ER-positive tumors. The aim of this study was to assess the morphological characteristics and immunohistochemical profile of ER-negative tumors and thus to understand the biological behavior and unique nature. In total, 291 consecutive ER-negative cases available from our primary breast cancer series were examined. Hematoxylin- and eosin-stained sections of all the cases were studied for several morphological parameters and their immunophenotype profile. These findings were correlated with patient and tumor characteristics and survival data. ER-negative tumors constituted 30% of the primary operable breast cancer series. The majority of tumors were grade 3 (94%) and the commonest histological types were ductal/no specific type (85%), and atypical medullary carcinoma (8%). High-grade comedo-type necrosis, lymphoid stroma, central necrosis/fibrosis and pushing margins were the most common morphological features. The presence of a pushing margin showed a significant relation to androgen receptor negativity, absence of epidermal growth factor receptor expression and negative lymph nodes. Lymphoid stroma and comedo-necrosis correlated with higher tumor grade. ER-negative breast cancers are a distinct group of tumors with several common morphological features. Grade 3 histology, pushing margin, lymphoid stroma, comedo-type necrosis and central fibrosis/necrosis are the dominant morphological findings. The presence of a pushing margin appears to have a significant correlation with negative lymph node status. ER-negative tumors show a higher expression of p53, CerbB2 and epidermal growth factor receptor compared to ER-positive breast cancer. These unique features support the concept that ER-negative tumors are a morphologically and phenotypically distinct entity and provide a rationale for the study and use of newer promising agents in the treatment of ER-negative breast cancer.

Actins↗
PubMed2005

Columnar cell lesions of the breast: the missing link in breast cancer progression? A morphological and molecular analysis.

Columnar cell lesions (CCLs) of the breast are a spectrum of lesions that have posed difficulties to pathologists for many years, prompting discussion concerning their biologic and clinical significance. We present a study of CCL in context with hyperplasia of usual type (HUT) and the more advanced lesions ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. A total of 81 lesions from 18 patients were subjected to a comprehensive morphologic review based upon a modified version of Schnitt's classification system for CCL, immunophenotypic analysis (estrogen receptor [ER], progesterone receptor [PgR], Her2/neu, cytokeratin 5/6 [CK5/6], cytokeratin 14 [CK14], E-cadherin, p53) and for the first time, a whole genome molecular analysis by comparative genomic hybridization. Multiple CCLs from 3 patients were studied in particular detail, with topographic information and/or showing a morphologic spectrum of CCL within individual terminal duct lobular units. CCLs were ER and PgR positive, CK5/6 and CK14 negative, exhibit low numbers of genetic alterations and recurrent 16q loss, features that are similar to those of low grade in situ and invasive carcinoma. The molecular genetic profiles closely reflect the degree of proliferation and atypia in CCL, indicating some of these lesions represent both a morphologic and molecular continuum. In addition, overlapping chromosomal alterations between CCL and more advanced lesions within individual terminal duct lobular units suggest a commonality in molecular evolution. These data further support the hypothesis that CCLs are a nonobligate, intermediary step in the development of some forms of low grade in situ and invasive carcinoma.

Biomarkers, Tumor↗
PubMed2004

Do poor-prognosis breast tumours express membrane cofactor proteins (CD46)?

UNLABELLED: CD46 or membrane cofactor protein (MCP) is a complement regulatory protein that has been identified on all nucleated cells and which protects them from attack by autologous complement. Breast carcinomas are reported to consistently express CD46. AIM AND METHODS: Our previous immunohistochemical study showed that in breast carcinomas, loss of CD59 and CD55 correlated with poor survival. This study aimed to investigate the prognostic significance of CD46 on breast tumours using a rabbit polyclonal anti-CD46 antibody with a standard immunohistochemistry method. A total of 510 breast tissues from patients with primary operable breast cancer diagnosed between 1987 and 1992 had previously been included in tissue microarrays. They included patients 70 years of age or less (mean = 54 years) with a long-term follow-up (median = 82 months). RESULTS: Immunohistochemical study revealed that 507/510 (99.4%) of breast tumours expressed CD46. Strong immunoreactivity was exhibited by 136/510 (27%) tumours, while moderate and weak staining was observed in 43% and 29% of tumours, respectively. Intensity of CD46 expression was significantly associated with tumour grade (p < 0.05), histological type of tumour (p < 0.001) and tumour recurrence (p < 0.05). There was no correlation with lymph node stage or the presence of vascular invasion, nor with patient age or menopausal status. Interestingly, as most tumours expressed CD46, it would appear that poor-prognosis tumours that lose CD55 and CD59 still express CD46. CONCLUSION: Breast tumours express high levels of CD46 that correlates with tumour grade and recurrence. It is therefore likely that loss of CD55 and CD59 could be compensated by expression of CD46. However, loss of CD55 and CD59, even for tumours that still express CD46, is still associated with a poor prognosis. This may suggest that CD46 alone can protect from complement lysis but that loss of CD55 and CD59 are associated with other roles in immune regulation.

Adult↗
PubMed2004

Loss of CD55 is associated with aggressive breast tumors.

PURPOSE: CD55 is a complement regulatory protein expressed by cells to protect them from bystander attack by complement. CD55 is overexpressed on some tumor cell lines, and in colorectal carcinomas, it has been shown to be an indicator of poor prognostic. EXPERIMENTAL DESIGN: A large set of samples (480) from patients with primary operable breast cancer followed for 4-192 months were included in the present study. The prognostic significance of CD55 was then investigated in these tumors using an anti-CD55 monoclonal antibody (RM1) that we raised against a synthetic peptide and a standard immunohistochemistry method. RESULTS: Ninety-five percent of the breast carcinomas expressed CD55 (RM1) with intensity ranging from weak (51%) to strong (6%). High expression of CD55 was significantly associated with low-grade (grades 1 or 2; P = 0.001), lymph node negativity (P = 0.031), and good prognosis tumors (Nottingham Prognostic Index < 3.4; P < 0.001). Survival analysis showed CD55 overexpression was associated with a more favorable outcome and loss of CD55 being associated with poor survival (P = 0.001). Intensity of CD55 expression was significantly correlated (P = 0.002) with intensity of CD59 expression (as shown in a previous study) in these series of patients. CONCLUSIONS: In conclusion, we found that loss of both CD55 and CD59 in breast carcinomas is associated with a worse prognosis.

Animals↗
PubMed2004

Expression of luminal and basal cytokeratins in human breast carcinoma.

We have examined basal and luminal cell cytokeratin expression in 1944 cases of invasive breast carcinoma, using tissue microarray (TMA) technology, to determine the frequency of expression of each cytokeratin subtype, their relationships and prognostic relevance, if any. Expression was determined by immunocytochemistry staining using antibodies to the luminal cytokeratins (CKs) 7/8, 18 and 19 and the basal markers CK 5/6 and CK 14. Additionally, assessment of alpha-smooth muscle actin (SMA) and oestrogen receptor status (ER) was performed. The vast majority of the cases showed positivity for CK 7/8, 18 and 19 indicating a differentiated glandular phenotype, a finding associated with good prognosis, ER positivity and older patient age. In contrast, basal marker expression was significantly related to poor prognosis, ER negativity and younger patient age. Multivariate analysis showed that CK 5/6 was an independent indicator for relapse free interval. We were able to subgroup the cases into four distinct phenotype categories (pure luminal, mixed luminal/basal, pure basal and null), which had significant differences in relation to the biological features and the clinical course of the disease. Tumours classified as expressing a basal phenotype (the combined luminal plus basal and the pure basal) were in a poor prognostic subgroup, typically ER negative in most cases. These findings provide further evidence that breast cancer has distinct differentiation subclasses that have both biological and clinical relevance.

Actins↗
PubMed2004

Expression of E2F-4 in invasive breast carcinomas is associated with poor prognosis.

The E2F family of transcription factors plays a key role in the control of cellular proliferation and apoptosis. Some family members act as oncogenes and others act as tumour suppressor genes (TSGs), behaviour which appears to be tissue-specific. E2F-4 is a member of the E2F family, located at chromosome band 16q22.1, that shows frequent deletion in breast cancer, suggesting that it may function as a TSG in breast carcinogenesis. In the present study, the expression of E2F-4 was assessed immunohistochemically on paraffin wax sections from 265 breast carcinomas and expression was compared with both clinicopathological variables and disease outcome in an attempt to identify its possible role as a TSG and to assess its prognostic value, if any, in breast cancer. E2F-4 protein expression was detected in the nuclei and in the cytoplasm of normal and malignant breast epithelial cells. In the malignant tissues, no significant loss or decrease of expression was seen in association with any specific tumour type. There was a correlation between increased nuclear expression of E2F-4 and indicators of poor prognosis including larger tumour size (p = 0.000), grade 3 lesions (p = 0.033), lymph node stage (p = 0.037), and poorer Nottingham prognostic index group (p = 0.003). Increased immunoreactivity was also seen in association with the development of recurrent disease (p = 0.004), distant metastasis (p = 0.001), and poorer outcome including poorer overall survival time (p = 0.002) and shorter disease-free interval (p = 0.001). In multivariate analysis, E2F-4 was of independent prognostic significance along with grade and lymph node stage. These results suggest that E2F-4 may play a role in breast cancer progression and that increased nuclear expression is associated with more advanced tumours with poor outcomes. E2F-4 appears to have an oncogenic role rather than a tumour suppressor role in breast carcinogenesis and, hence, it is not the gene targeted by 16q22.1 loss in breast carcinoma.

Adult↗