Colin A Purdie

Ninewells Hospital, Dundee, Scotland, United Kingdom

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Publications (53)212.62 Total impact

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    ABSTRACT: Many human cancers contain mis-sense TP53 mutations that result in p53 protein accumulation. Although generally considered as a single class of mutations that abrogate wild-type function, individual TP53 mutations may have specific properties and prognostic effects. Tumours that contain mis-sense TP53 mutations show variable p53 stabilization patterns, which may reflect the specific mutation and/or aspects of tumour biology. We used immunohistochemistry on cell lines and human breast cancers with known TP53 mis-sense mutations and assessed the effects of each mutation with four structure/function prediction methods. Cell lines with mis-sense TP53 mutations show variable percentages of cells with p53 stabilization under normal growth conditions, ranging from approximately 50% to almost 100%. Stabilization is not related to structural or functional disruption, but agents that stabilize wild-type p53 increase the percentages of cells showing mis-sense mutant p53 accumulation in cell lines with heterogeneous stabilization. The same heterogeneity of p53 stabilization occurs in primary breast cancers, independent of the effect of the mutation on structural properties or functional disruption. Heterogeneous accumulation is more common in steroid receptor-positive or HER2-positive breast cancers and cell lines than in triple-negative samples. Immunohistochemcal staining patterns associate with Mdm2 levels, proliferation, grade and overall survival, whilst the type of mutation reflects downstream target activity. Inhibiting Mdm2 activity increases the extent of p53 stabilization in some, but not all, breast cancer cell lines. The data indicate that mis-sense mutant p53 stabilization is a complex and variable process in human breast cancers that associates with disease characteristics but is unrelated to structural or functional properties. That agents which stabilize wild-type p53 also stabilize mutant p53 has implications for patients with heterogeneous mutant p53 accumulation, where therapy may activate mutant p53 oncogenic function.
    The Journal of Pathology 03/2014; · 7.59 Impact Factor
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    ABSTRACT: Shear wave elastography (SWE) is a promising adjunct to greyscale ultrasound in differentiating benign from malignant breast masses. The purpose of this study was to characterise breast cancers which are not stiff on quantitative SWE, to elucidate potential sources of error in clinical application of SWE to evaluation of breast masses. Three hundred and two consecutive patients examined by SWE who underwent immediate surgery for breast cancer were included. Characteristics of 280 lesions with suspicious SWE values (mean stiffness >50 kPa) were compared with 22 lesions with benign SWE values (<50 kPa). Statistical significance of the differences was assessed using non-parametric goodness-of-fit tests. Pure ductal carcinoma in situ (DCIS) masses were more often soft on SWE than masses representing invasive breast cancer. Invasive cancers that were soft were more frequently: histological grade 1, tubular subtype, ≤10 mm invasive size and detected at screening mammography. No significant differences were found with respect to the presence of invasive lobular cancer, vascular invasion, hormone and HER-2 receptor status. Lymph node positivity was less common in soft cancers. Malignant breast masses classified as benign by quantitative SWE tend to have better prognostic features than those correctly classified as malignant. • Over 90 % of cancers assessable with ultrasound have a mean stiffness >50 kPa. • 'Soft' invasive cancers are frequently small (≤10 mm), low grade and screen-detected. • Pure DCIS masses are more often soft than invasive cancers (>40 %). • Large symptomatic masses are better evaluated with SWE than small clinically occult lesions. • When assessing small lesions, 'softness' should not raise the threshold for biopsy.
    European Radiology 12/2013; · 3.55 Impact Factor
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    ABSTRACT: Shear wave elastography (SWE) shows promise as an adjunct to greyscale ultrasound examination in assessing breast masses. In breast cancer, higher lesion stiffness on SWE has been shown to be associated with features of poor prognosis. The purpose of this study was to assess whether lesion stiffness at SWE is an independent predictor of lymph node involvement. Patients with invasive breast cancer treated by primary surgery, who had undergone SWE examination were eligible. Data were retrospectively analysed from 396 consecutive patients. The mean stiffness values were obtained using the Aixplorer(®) ultrasound machine from SuperSonic Imagine Ltd. Measurements were taken from a region of interest positioned over the stiffest part of the abnormality. The average of the mean stiffness value obtained from each of two orthogonal image planes was used for analysis. Associations between lymph node involvement and mean lesion stiffness, invasive cancer size, histologic grade, tumour type, ER expression, HER-2 status and vascular invasion were assessed using univariate and multivariate logistic regression. At univariate analysis, invasive size, histologic grade, HER-2 status, vascular invasion, tumour type and mean stiffness were significantly associated with nodal involvement. Nodal involvement rates ranged from 7 % for tumours with mean stiffness <50 kPa to 41 % for tumours with a mean stiffness of >150 kPa. At multivariate analysis, invasive size, tumour type, vascular invasion, and mean stiffness maintained independent significance. Mean stiffness at SWE is an independent predictor of lymph node metastasis and thus can confer prognostic information additional to that provided by conventional preoperative tumour assessment and staging.
    Breast Cancer Research and Treatment 12/2013; · 4.47 Impact Factor
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    ABSTRACT: Background:Progesterone receptor (PR) expression assessment in early invasive breast cancer remains controversial. This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer; particularly in oestrogen receptor (ER)-positive, lymph node (LN)-negative disease.Methods:A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years (2000-2004) underwent surgery for primary invasive breast cancer with curative intent. Prospective data collection included patient demographics, pathology, ER and PR expression, HER2 status, adjuvant chemotherapy and endocrine therapy. Progesterone receptor expression was compared with (all causes) overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS).Results:Overall survival was 71.0% and BCSS was 83.0% at median follow-up of 8.34 years. Absent PR expression was significantly associated with poorer prognosis for OS, BCSS and DFS (P<0.0001, log-rank), even within the ER-positive, LN-negative group (hazard ratio for BCSS 3.17, 95% CI 1.43-7.01) and was not influenced by endocrine therapy. Cox's regression analysis demonstrated that PR expression was an independent prognostic variable.Conclusion:Absence of PR expression is a powerful, independent prognostic variable in operable, primary breast cancer even in ER-positive, LN-negative patients receiving endocrine therapy. Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy.British Journal of Cancer advance online publication, 3 December 2013; doi:10.1038/bjc.2013.756 www.bjcancer.com.
    British Journal of Cancer 12/2013; · 5.08 Impact Factor
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    ABSTRACT: Background:Response of invasive breast cancer to neoadjuvant chemotherapy (NAC) is variable, and prediction of response is imperfect. We aimed to ascertain whether tissue stiffness in breast cancers, as assessed by shear-wave elastography (SWE) before treatment, is associated with response.Methods:We retrospectively compared pre-treatment tumour mean tissue stiffness, with post-treatment Residual Cancer Burden (RCB) scores and its components in 40 women with breast cancer treated by NAC using Pearson's correlation coefficient (CC), a general linear model and multiple linear regression. Subgroup analysis was carried out for luminal, HER2-positive and basal immuno-histochemical subtypes.Results:Statistically significant correlations were shown between stiffness and RCB scores and between stiffness and percentage tumour cellularity. The correlation between stiffness and percentage cellularity was strongest (CC 0.35 (P<0.0001) compared with CC 0.23 (P=0.004) for the RCB score). The results of a general linear model show that cellularity and RCB score maintain independent relationships with stiffness. By multiple linear regression, only cellularity maintained a significant relationship with stiffness.Conclusion:Pre-treatment tumour stiffness measured by SWE, has a statistically significant relationship with pathological response of invasive breast cancer to NAC.British Journal of Cancer advance online publication, 29 October 2013; doi:10.1038/bjc.2013.660 www.bjcancer.com.
    British Journal of Cancer 10/2013; · 5.08 Impact Factor
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    ABSTRACT: The International Tamoxifen Pharmacogenomics Consortium (ITPC) was established to address the controversy over CYP2D6 status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen treated patients (twelve globally-distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor (ER) positive breast cancer receiving 20 mg/day tamoxifen for 5 years, Criterion 1), CYP2D6 poor metabolizer status was associated with poorer Invasive Disease-Free Survival (IDFS: HR=1.25; 95% CI 1.06, 1.47; P=0.009). However, CYP2D6 was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (Criterion 2, n=2443; 49%; P=0.25) nor when no exclusions were applied (Criterion 3, n=4935; 99%; P=0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 23 September 2013 doi:10.1038/clpt.2013.186.
    Clinical Pharmacology &#38 Therapeutics 09/2013; · 6.85 Impact Factor
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    ABSTRACT: Human epidermal growth factor receptor 2 (HER2) testing is required for newly diagnosed breast cancer and advised for recurrent and metastatic breast cancer, to determine treatment planning using HER2-directed therapy in the neoadjuvant, adjuvant and advanced disease settings. Wide variation, nationally, in the turnaround time for HER2 testing may hinder equity of access for patients to both clinical trials and the timely implementation of HER2-directed therapy particularly in the neo-adjuvant setting. Process mapping from three recognised laboratories in the UK was applied to the logistics of HER2 testing in different geographic hub and spoke models. Consequently, recommendations for HER2 testing likely to facilitate access to clinical trials and timely patient care are presented.
    Journal of clinical pathology 09/2013; · 2.43 Impact Factor
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    ABSTRACT: INTRODUCTION: The clinical importance of internal mammary (IM) lymph node (LN) metastases in breast cancer remains unclear. The aim of this study was to determine the clinical value of opportunistic IMLN sampling at the time of free flap breast reconstruction using the IM recipient vessels and whether it affected the adjuvant treatment given. METHODS: A prospective study was conducted of IMLN exploration performed by a single surgeon as part of free flap breast reconstruction using IM recipient vessels. Patients where IMLNs were positive for metastatic disease were reviewed with the breast cancer multidisciplinary team for changes in therapy. RESULTS: 122 patients met the inclusion criteria, 111 of whom had immediate reconstructions. 63 patients had IMLNs excised, and of these 13 were positive for metastatic disease, all in immediate breast reconstructions. The adjuvant treatment given was changed in 1 patient with no axillary LN disease as a result of finding a positive IMLN. Positive IMLNs were significantly associated with larger tumours and axillary metastases, but not tumour location. All patients with positive IMLNs were alive at last follow-up with no local or distant recurrences, with mean disease-free survival of 20.5 months (5-56 months). CONCLUSION: Incidental IMLNs positive for metastatic disease were found in 13 of 122 free flap breast reconstructions and resulted in a change in adjuvant treatment in one patient. IMLNs found incidentally during recipient IM vessel exposure for free flap breast reconstruction therefore may upstage a patient's disease and influence the adjuvant treatment for their breast cancer and should therefore be submitted for pathological assessment.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 04/2013; · 2.56 Impact Factor
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    ABSTRACT: AIM: To assess whether an additional histopathological examination of ultrasound-guided core biopsy (USCB)/fine-needle aspiration (FNA) of abnormal axillary lymph nodes (ALN) can improve the preoperative diagnosis of axillary nodal metastasis. MATERIALS AND METHODS: Women with suspected invasive breast cancer and abnormal axillary ultrasound (AUS), but negative USCB on standard histopathological assessment were included. From the core biopsies six additional levels were sectioned for haematoxylin and eosin examination, and two levels were sectioned for immunohistochemistry with AE1/3. The presence of metastatic disease was noted. RESULTS: The USCB of 102 patients were submitted for additional histopathological examination, of whom 58 had screen-detected lesions and 44 had symptomatic lesions. Eighty underwent axillary surgery for invasive carcinoma (n = 74) or for ductal carcinoma in situ (DCIS) requiring mastectomy (n = 6). Twelve patients were found to have nodal disease with a mean of two nodes involved. The additional histopathological assessment of the nodal USCBs revealed tumour not seen at the standard examination in only three cases, which consisted of isolated tumour cells (n = 2) and micrometastasis (n = 1). All three patients underwent subsequent axillary node clearance; however, no upgrade of axillary disease was found at final histopathology. CONCLUSION: Additional histopathological examination of USCBs of radiologically abnormal ALN does not improve the preoperative diagnosis of axillary nodal metastasis in primary breast cancer and may lead to unnecessary axillary clearance.
    Clinical radiology 03/2013; · 1.65 Impact Factor
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    ABSTRACT: Background:Multiparameter flow cytometry is a robust and reliable method for determining tumour DNA content applicable to formalin-fixed paraffin-embedded (FFPE) tissue. This study examined the clinical and pathological associations of DNA content in primary breast cancer using an improved multiparametric technique.Methods:The FFPE tissue from 201 primary breast cancers was examined and the cancers categorised according to their DNA content using multiparametric flow cytometry incorporating differential labelling of stromal and tumour cell populations. Mathematical modelling software (ModFit 3.2.1) was used to calculate the DNA index (DI) and percentage S-phase fraction (SPF%) for each tumour. Independent associations with clinical and pathological parameters were sought using backward stepwise Binary Logistic Regression (BLR) and Cox's Regression (CR) analysis.Results:Tumours were grouped into four categories based on the DI of the tumour cell population. Low DI tumours (DI=0.76-1.14) associated with progesterone receptor-positive status (P=0.012, BLR), intermediate DI (DI=1.18-1.79) associated with p53 mutant tumours (P=0.001, BLR), high DI (DI1.80) tumours with human epidermal growth factor receptor 2 (HER2)-positive status (P=0.004, BLR) and 'multiploid tumours' (two or more tumour DNA peaks) did not show any significant associations. Tumours with high SPF% (10%) independently associated with poor overall survival (P=0.027, CR).Conclusion:Multiparametric flow analysis of FFPE tissue can accurately assess tumour DNA content. Tumour sub-populations associated with biomarkers of prognosis or likely response to therapy. The alterations in DNA content present the potential for greater understanding of the mechanisms underlying clinically significant biomarker changes in primary breast cancer.
    British Journal of Cancer 03/2013; 108(4):873-80. · 5.08 Impact Factor
  • The Breast Journal 10/2012; · 1.83 Impact Factor
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    ABSTRACT: Tissue microarray (TMA) is an established and valuable tool, particularly in translational research and clinical trials, allowing resource-efficient use, and high-throughput profiling, of large numbers of tumours. Despite this, there is little evidence, or guidance, on the optimum manufacture, use and assessment of TMAs. Here we review some of the literature, using breast cancer as an example, to highlight good practice and pitfalls in the design and manufacture of TMAs. Issues, such as the size, number, spacing and layout of cores, as well as the assessment and reporting of studies using TMAs are addressed. We make some suggestions regarding these challenges, and propose a checklist of features that should be considered in order to stimulate debate and improve the quality of data produced by TMA analysis.
    Journal of clinical pathology 10/2012; · 2.43 Impact Factor
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    ABSTRACT: The aim of this study was to assess the performance of shear wave elastography combined with BI-RADS classification of greyscale ultrasound images for benign/malignant differentiation in a large group of patients. One hundred and seventy-five consecutive patients with solid breast masses on routine ultrasonography undergoing percutaneous biopsy had the greyscale findings classified according to the American College of Radiology BI-RADS. The mean elasticity values from four shear wave images were obtained. For mean elasticity vs greyscale BI-RADS, the performance results against histology were sensitivity: 95% vs 95%, specificity: 77% vs 69%, Positive Predictive Value (PPV): 88% vs 84%, Negative Predictive Value (NPV): 90% vs 91%, and accuracy: 89% vs 86% (all P>0.05). The results for the combination (positive result from either modality counted as malignant) were sensitivity 100%, specificity 61%, PPV 82%, NPV 100%, and accuracy 86%. The combination of BI-RADS greyscale and shear wave elastography yielded superior sensitivity to BI-RADS alone (P=0.03) or shear wave alone (P=0.03). The NPV was superior in combination compared with either alone (BI-RADS P=0.01 and shear wave P=0.02). Together, BI-RADS assessment of greyscale ultrasound images and shear wave ultrasound elastography are extremely sensitive for detection of malignancy.
    British Journal of Cancer 06/2012; 107(2):224-9. · 5.08 Impact Factor
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    ABSTRACT: Sentinel node biopsy as a surgical method of axillary staging for early breast cancer has been widely accepted as an alternative to traditional four-node axillary node sampling, and is the recommended technique by the Association of Breast Surgery in the United Kingdom. In selected units axillary sampling has been compared with either radioisotope sentinel node or blue dye only techniques with comparable node positivity rates. There are no studies directly comparing combined method sentinel node biopsy (SNB) with conventional axillary (four) node sampling (ANS). Data for all patients undergoing axillary staging by axillary node sample or sentinel node biopsy were collected, including those proceeding to axillary clearance as a second procedure, but excluding those undergoing axillary clearance as a first procedure. From January 2005 to January 2011, 641 axillary staging procedures were performed (SNB n=231 (36.0%), ANS n=410 (64.0%)). Baseline tumour characteristics were similar for the two groups except for a higher frequency of breast conservation in the SNB group (95.6 vs. 75.6%; p<0.0001). The proportion of cases with positive nodes was higher in the SNB group (20.8 vs. 14.4%; p=0.042). In patients who had presented with symptomatic disease, there was a significantly higher node positivity rate with SNB (30.9%) than with ANS (15.5%; p=0.002), despite similar baseline characteristics in both groups. Combined method sentinel node biopsy is more sensitive at detecting low volume axillary disease than traditional four-node sample.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 05/2012; 38(8):662-9. · 2.56 Impact Factor
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    ABSTRACT: To compare the histologic prognostic feature of invasive breast cancer with mean stiffness as measured with shear-wave elastography. This retrospective study was exempted from ethical committee review. Patient consent for use of images for research was obtained. The study group comprised 101 consecutive women (age range, 38-91 years) with solid lesions identified during routine breast ultrasonography (US) performed between April 2010 and March 2011 and subsequently confirmed at histologic examination to be invasive cancers. Four elastographic images in two orthogonal planes were obtained of each lesion, and mean stiffness values were obtained from each image. Histologic findings following surgery were used for comparison, namely histologic grade, tumor type, invasive size, vascular invasion status, and lymph node status. Relationship between mean stiffness and histologic parameters was investigated by using a general linear model and multiple regression analysis. High histologic grade (P < .0001), large invasive size (P < .0001), lymph node involvement (P < .0001), tumor type (P < .0001), and vascular invasion (P = .0077) all showed statistically significant positive association with high mean stiffness values. Multiple linear regression indicated that invasive size is the strongest pathologic determinant of mean stiffness (P < .0001), with histologic grade also having significant influence (P = .022). In this study, breast cancers with higher mean stiffness values at shear-wave elastography had poorer prognostic features.
    Radiology 04/2012; 263(3):673-7. · 6.34 Impact Factor
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    ABSTRACT: Complete tumour excision in breast conserving surgery (BCS) is critical for successful outcome; involved circumferential resection margins are associated with increased disease recurrence. However, the importance of an involved anterior margin (IAM) is less clear. The purpose of this study was to review an aggressive approach to IAM and hence assess whether anterior margin re-excision (RE) yields clinical benefit. A review of prospectively collected clinical and pathology data was performed for all patients who underwent BCS between 2006 and 2010 through a single cancer centre. An involved margin was defined as < 1 mm clearance of invasive or in-situ breast cancer. 1667 patients underwent BCS for invasive and/or in-situ disease, of whom 114 underwent RE. A total of 170 involved margins were identified: most commonly the anterior (52 margins) followed by the posterior (39 margins) and inferior (31 margins) margin. Patients with IAM were more likely to have grade 3 invasive disease (p = 0.0323) but less likely to have residual disease found at re-excision (2/49 vs. 32/101 margins, p = 0.0033); there were no differences when in-situ characteristics were compared. RE of IAM after BCS rarely yields further disease; multi-disciplinary teams should consider whether further therapy for an IAM is required on a patient by patient basis.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 04/2012; 38(4):302-6. · 2.56 Impact Factor
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    ABSTRACT: Polo-like kinase-1 (PLK1) is a crucial driver of cell cycle progression and its down-regulation plays an important checkpoint role in response to DNA damage. Mechanistically, this is mediated by p53 which represses PLK1 expression through chromatin remodelling. Consistent with this model, cultured cells lacking p53 fail to repress PLK1 expression. This study examined PLK1 expression, p53 mutation and clinical outcome in breast cancer. Immunohistochemistry was performed using antibodies to PLK1, MDM2 and Ki67 on Tissue Micro-Array (TMA) slides of a cohort of 215 primary breast cancers. The TP53 gene (encoding p53) was sequenced in all tumour samples. Protein expression scored using the "Quickscore" method was compared with clinical and pathological data, including survival. Staining of PLK1 was observed in 11% of primary breast tumours and was significantly associated with the presence of TP53 mutation (P = 0.0063). Moreover, patients with both PLK1 expression and TP53 mutation showed a significantly worse survival than those with either PLK1 expression or TP53 mutation alone. There was also a close association of elevated PLK1 with triple negative tumours, considered to be poor prognosis breast cancers that generally harbour TP53 mutation. Further association was observed between elevated PLK1 levels and the major p53 negative regulator, MDM2. The significant association between elevated PLK1 and TP53 mutation in women with breast cancer is consistent with escape from repression of PLK1 expression by mutant p53. Tumours expressing elevated PLK1, but lacking functional p53, may be potential targets for novel anti-PLK1-targeted drugs.
    Breast cancer research: BCR 03/2012; 14(2):R40. · 5.87 Impact Factor
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    ABSTRACT: Prospective studies of biomarker status in primary and recurrent or metastatic breast cancer have confirmed the findings of historical retrospective studies which demonstrate that for biomarkers which influence routine clinical practice, Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal growth factor Receptor type 2 (HER2), biopsy of recurrent or metastatic disease is essential not only to confirm the presence of malignancy but to guide targeted medical therapy. Historically, discordance rates for the expression of receptors between primary and metastatic tumors, though variable, may have led to suboptimal treatment for a significant proportion of patients. While changes in PR are most common, changes in ER (positive to negative or less frequently negative to positive) and the less common changes in HER2 (usually gain of HER2 amplification) influence subsequent therapy for 1 in 6 patients and may thus impact upon survival. Recognition of the potential for heterogeneity within the primary, between metastatic sites and over time requires further prospective study in breast cancer where the comparability of metastases from multiple sites and the need to biopsy successive recurrences have been less well documented. Recent prospective studies confirm the retrospective evidence that optimal patient care requires appropriate biopsy and pathological assessment of recurrent or metastatic breast cancer.
    Cancer biomarkers: section A of Disease markers 01/2012; 12(6):231-9. · 0.97 Impact Factor
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    ABSTRACT: Migration Stimulating Factor (MSF) is a novel oncofetal biomarker previously identified in a number of human tumours. The aim of this study was to evaluate the possible association between MSF expression and disease progression in breast cancer. Archival breast tissues examined included malignant tumours (T; n=23), benign tumours or pathologies (B; n=8) and histologically normal breast from either reduction mammoplasties (NB; n=19) or from tumour patients (NB-T; n=18). Sections were stained with MSF-specific antibodies and assessed by consensus of 3-4 independent observers in terms of various MSF indices, which represented overall, epithelial and stromal MSF expression. MSF was heterogeneously expressed by epithelial and stromal cells, with significant inter-group quantitative differences in the sequence NB<NB-T=B<T The percentages of specimens in the various groups showing moderate or strong MSF expression were 0% (NB), 45% (NB-T), 50% (B), and 78% (T). MSF was also observed in ductal carcinoma in situ and in carcinoma tissue cores in microarrays. In both histologically normal tissues (NB, NB-T), MSF expression was inversely associated with patient age, and epithelial and stromal MSF indices were significantly and directly correlated; in contrast, such associations were not observed in tumours (B, T). MSF expression in T was not associated with its expression in the paired NB-T. These data indicate that MSF is a biomarker of early breast cancer and disease progression. Epithelial and stromal MSF may be differently regulated and may carry different diagnostic or prognostic value. MSF expression in histologically normal and benign tissues suggest the presence of “field cancerisation”, defined as the presence of predisposing genetic or epigenetic lesions which increase the risk of developing subsequent malignant lesions.
    Translational Medicine S1:003. doi:10.4172/2161-1025.S1-003. 01/2012; Translational Medic S1:003(Special Issue Title: Discovering Novel Biomarkers).
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    ABSTRACT: Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 may contribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-function properties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastro-intestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervous system (CNS) metastatic breast cancer is not known. In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53 determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres. We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation of complex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breast cancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealed evidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breast carcinoma to brain metastasis. Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cancer.
    British Journal of Cancer 12/2011; 106(2):397-404. · 5.08 Impact Factor

Publication Stats

430 Citations
212.62 Total Impact Points

Institutions

  • 2001–2014
    • Ninewells Hospital
      Dundee, Scotland, United Kingdom
  • 2010–2013
    • University of Dundee
      • Tayside Clinical Research Centre
      Dundee, SCT, United Kingdom
  • 2011
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada