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1.
Breast ; 75: 103728, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38657322

ABSTRACT

INTRODUCTION: The Oncotype DX Breast RS test has been adopted in Scotland and has been the subject of a large population-based study by a Scottish Consensus Group to assess the uptake of the recurrence score (RS), evaluate co-variates associated with the RS and to analyse the effect it may have had on clinical practice. MATERIALS & METHODS: Pan-Scotland study between August 2018-August 2021 evaluating 833 patients who had a RS test performed as part of their diagnostic pathway. Data was extracted retrospectively from electronic records and analysis conducted to describe change in chemotherapy administration (by direct comparison with conventional risk assessment tools), and univariate/multivariate analysis to assess relationship between covariates and the RS. RESULTS: Chemotherapy treatment was strongly influenced by the RS (p < 0.001). Only 30 % of patients received chemotherapy treatment in the intermediate and high risk PREDICT groups, where chemotherapy is considered. Additionally, 55.5 % of patients with a high risk PREDICT had a low RS and did not receive chemotherapy. There were 17 % of patients with a low risk PREDICT but high RS who received chemotherapy. Multivariate regression analysis showed the progesterone receptor Allred score (PR score) to be a strong independent predictor of the RS, with a negative PR score being associated with high RS (OR 4.49, p < 0.001). Increasing grade was also associated with high RS (OR 3.81, p < 0.001). Classic lobular pathology was associated with a low RS in comparison to other tumour pathology (p < 0.01). Nodal disease was associated with a lower RS (p = 0.012) on univariate analysis, with menopausal status (p = 0.43) not influencing the RS on univariate or multivariate analysis. CONCLUSIONS: Genomic assays offer the potential for risk-stratified decision making regarding the use of chemotherapy. They can help reduce unnecessary chemotherapy treatment and identify a subgroup of patients with more adverse genomic tumour biology. A recent publication by Health Improvement Scotland (HIS) has updated guidance on use of the RS test for NHS Scotland. It suggests to limit its use to the intermediate risk PREDICT group. Our study shows the impact of the RS test in the low and high risk PREDICT groups. The implementation across Scotland has resulted in a notable shift in practice, leading to a significant reduction in chemotherapy administration in the setting of high risk PREDICT scores returning low risk RS. There has also been utility for the test in the low risk PREDICT group to detect a small subgroup with a high RS. We have found the PR score to have a strong independent association with high risk RS. This finding was not evaluated by the key RS test papers, and the potential prognostic information provided by the PR score as a surrogate biomarker is an outstanding question that requires more research to validate.


Subject(s)
Breast Neoplasms , Decision Support Systems, Clinical , Humans , Breast Neoplasms/genetics , Breast Neoplasms/drug therapy , Female , Scotland , Middle Aged , Retrospective Studies , Risk Assessment/methods , Aged , Adult , Neoplasm Recurrence, Local/genetics , Genomics , Receptors, Progesterone/metabolism
2.
Eur Radiol ; 26(2): 322-30, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26065395

ABSTRACT

OBJECTIVES: Patient-tailored treatments for breast cancer are based on histological and immunohistochemical (IHC) subtypes. Magnetic Resonance Imaging (MRI) texture analysis (TA) may be useful in non-invasive lesion subtype classification. METHODS: Women with newly diagnosed primary breast cancer underwent pre-treatment dynamic contrast-enhanced breast MRI. TA was performed using co-occurrence matrix (COM) features, by creating a model on retrospective training data, then prospectively applying to a test set. Analyses were blinded to breast pathology. Subtype classifications were performed using a cross-validated k-nearest-neighbour (k = 3) technique, with accuracy relative to pathology assessed and receiver operator curve (AUROC) calculated. Mann-Whitney U and Kruskal-Wallis tests were used to assess raw entropy feature values. RESULTS: Histological subtype classifications were similar across training (n = 148 cancers) and test sets (n = 73 lesions) using all COM features (training: 75%, AUROC = 0.816; test: 72.5%, AUROC = 0.823). Entropy features were significantly different between lobular and ductal cancers (p < 0.001; Mann-Whitney U). IHC classifications using COM features were also similar for training and test data (training: 57.2%, AUROC = 0.754; test: 57.0%, AUROC = 0.750). Hormone receptor positive and negative cancers demonstrated significantly different entropy features. Entropy features alone were unable to create a robust classification model. CONCLUSION: Textural differences on contrast-enhanced MR images may reflect underlying lesion subtypes, which merits testing against treatment response. KEY POINTS: • MR-derived entropy features, representing heterogeneity, provide important information on tissue composition. • Entropy features can differentiate between histological and immunohistochemical subtypes of breast cancer. • Differing entropy features between breast cancer subtypes implies differences in lesion heterogeneity. • Texture analysis of breast cancer potentially provides added information for decision making.


Subject(s)
Breast Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Entropy , Female , Humans , Image Enhancement/methods , Image Interpretation, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Middle Aged , Prospective Studies , Retrospective Studies
4.
Br J Cancer ; 110(7): 1744-7, 2014 Apr 02.
Article in English | MEDLINE | ID: mdl-24548861

ABSTRACT

BACKGROUND: A high percentage of stroma predicts poor survival in triple-negative breast cancers but is diminished in studies of unselected cases. We determined the prognostic significance of tumour-stroma ratio (TSR) in oestrogen receptor (ER)-positive male and female breast carcinomas. METHODS: TSR was measured in haematoxylin and eosin-stained tissue sections (118 female and 62 male). Relationship of TSR (cutoff 49%) to overall survival (OS) and relapse-free survival (RFS) was analysed. RESULTS: Tumours with ≥49% stroma were associated with better survival in female (OS P=0.008, HR=0.2-0.7; RFS P=0.006, HR=0.1-0.6) and male breast cancer (OS P=0.005, HR=0.05-0.6; RFS P=0.01, HR=0.87-5.6), confirmed in multivariate analysis. CONCLUSIONS: High stromal content was related to better survival in ER-positive breast cancers across both genders, contrasting data in triple-negative breast cancer and highlighting the importance of considering ER status when interpreting the prognostic value of TSR.


Subject(s)
Breast Neoplasms, Male/diagnosis , Breast Neoplasms/diagnosis , Receptors, Estrogen/metabolism , Tumor Burden , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms, Male/metabolism , Breast Neoplasms, Male/mortality , Breast Neoplasms, Male/pathology , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , Stromal Cells/pathology , Survival Analysis
5.
Eur Radiol ; 24(4): 921-6, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24326756

ABSTRACT

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Malignant breast masses classified as benign by quantitative SWE tend to have better prognostic features than those correctly classified as malignant. KEY POINTS: • 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.


Subject(s)
Breast Neoplasms/diagnostic imaging , Breast/pathology , Carcinoma, Ductal, Breast/diagnostic imaging , Carcinoma, Intraductal, Noninfiltrating/diagnostic imaging , Ultrasonography, Mammary/methods , Adult , Aged , Aged, 80 and over , Biopsy , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Elasticity Imaging Techniques , False Negative Reactions , Female , Humans , Middle Aged , Prognosis , Receptor, ErbB-2/analysis , Retrospective Studies , Young Adult
6.
Clin Pharmacol Ther ; 95(2): 216-27, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24060820

ABSTRACT

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-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: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; 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.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Cytochrome P-450 CYP2D6/genetics , Tamoxifen/therapeutic use , Aged , Antineoplastic Agents, Hormonal/pharmacokinetics , Breast Neoplasms/genetics , Female , Genetic Variation/genetics , Genotype , Humans , Menopause , Middle Aged , Pharmacogenetics/methods , Survival Analysis , Tamoxifen/pharmacokinetics , Treatment Outcome
7.
Br J Cancer ; 110(3): 565-72, 2014 Feb 04.
Article in English | MEDLINE | ID: mdl-24300977

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.


Subject(s)
Biomarkers, Tumor/biosynthesis , Breast Neoplasms/genetics , Early Detection of Cancer , Receptors, Progesterone/biosynthesis , Adult , Breast Neoplasms/pathology , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Prognosis , Receptor, ErbB-2/genetics , Receptors, Estrogen/metabolism , Receptors, Progesterone/genetics
8.
Clin Radiol ; 68(7): 704-7, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23518495

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.


Subject(s)
Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Lymph Nodes/pathology , Adult , Aged , Aged, 80 and over , Axilla , Biopsy, Fine-Needle/methods , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/surgery , Carcinoma, Intraductal, Noninfiltrating/surgery , Female , Humans , Image-Guided Biopsy/methods , Lymph Node Excision , Lymphatic Metastasis , Middle Aged , Ultrasonography, Interventional/methods
9.
Br J Cancer ; 108(4): 873-80, 2013 Mar 05.
Article in English | MEDLINE | ID: mdl-23412097

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.


Subject(s)
Breast Neoplasms/genetics , DNA, Neoplasm/analysis , Flow Cytometry/methods , Adult , Aged , Aged, 80 and over , Breast Neoplasms/classification , Breast Neoplasms/mortality , Female , Genes, p53 , Humans , Middle Aged , Mutation , Prognosis , Receptor, ErbB-2/analysis , Receptors, Progesterone/metabolism
10.
Eur J Surg Oncol ; 38(4): 302-6, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22285907

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Subject(s)
Breast Neoplasms/surgery , Carcinoma in Situ/surgery , Carcinoma, Ductal, Breast/surgery , Mastectomy, Segmental/statistics & numerical data , Neoplasm, Residual/surgery , Breast Neoplasms/pathology , Carcinoma in Situ/pathology , Carcinoma, Ductal, Breast/pathology , Databases, Factual , Decision Making , Female , Humans , Mastectomy, Segmental/adverse effects , Neoplasm, Residual/pathology , Prospective Studies , Reoperation , Retrospective Studies , Scotland , Treatment Outcome
11.
J Clin Pharm Ther ; 37(2): 173-81, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21592159

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Patients with sickle-cell disease (SCD) receiving chronic transfusions of red blood cells are at risk of developing serious adverse effects. Iron chelation therapy (ICT) helps eliminate iron overload by binding with plasma iron to form a non-toxic conjugate that can be safely excreted from the body. Two iron chelating agents are currently available in the United States: Deferoxamine (DFO) is an injectable formulation, and deferasirox (Exjade(®) ) is an oral suspension. This study compared the frequency of hospitalizations, persistence and compliance of patients with SCD from Medicaid programmes treated with DFO vs. deferasirox. METHODS: Health care claims from Medicaid Florida (1998-2007), Missouri (1993-2008) and New Jersey (1996-2008) were analysed. Patients with continuous enrolment for ≥6months prior to ICT initiation and ≥1 SCD diagnosis were included in the analysis. Patients were divided into four cohorts: patients treated with DFO (any-DFO group) and patients treated with deferasirox (any-deferasirox group); the latter was further divided into patients initiated on DFO and then switched to deferasirox (deferasirox switchers), and patients treated with deferasirox-only (deferasirox-only group). Frequency of hospitalization for crisis conditions related to SCD as well as length of stay pre- and post-ICT treatment initiation were assessed. Persistence was defined as time to drug discontinuation with ≥1 Rx gap, using Kaplan-Meier approach. Compliance was estimated using a medication possession ratio (MPR) based on the drug exposure approach. Adjusted analyses of persistence and compliance were also conducted. RESULTS: A total of 217 (mean age: 19·4years, 39·2 men), 275 (20·1years, 41·5% men), 105 (19·4years, 42·9% men) and 166 (20·4years, 41·6% men) patients were included in the any-DFO, any-deferasirox, deferasirox switchers and deferasirox-only groups, respectively. After ICT initiation, the any-deferasirox and deferasirox-only groups experienced a statistically significant reduction in the frequency of hospitalizations relative to pretreatment [any-deferasirox: from 0·09 to 0·06 hospitalizations per patient per month (pmpm), P=0·0105; deferasirox-only: from 0·11 to 0·07 hospitalizations pmpm, P=0·0188], whereas it remained stable in the any-DFO group at 0·08 hospitalizations pmpm (P=0·9483). The Kaplan-Meier rates of medication persistence assessed at 6 and 12months of follow-up were significantly lower for DFO patients (6 months: 0·34, 12months: 0·21) as compared to all deferasirox (0·51, 0·29, P=0·0002), deferasirox switchers (0·56, 0·37, P=0·0002) and deferasirox-only (0·47, 0·24, P=0·0176) patients. Similarly, compliance to treatment was significantly lower for patients treated with DFO (mean MPR: 0·64) compared with any-deferasirox (0·78, P<0·0001), deferasirox switchers (0·75, P=0·0002) and deferasirox-only (0·80, P<0·0001) patients. Adjusted analyses of persistence and compliance yielded similar results. WHAT IS NEW AND CONCLUSIONS: Based on a Medicaid population, patients treated with deferasirox were more compliant and persistent with their treatment than those treated with DFO. Frequency of hospitalizations was significantly reduced after treatment initiation for the any-deferasirox and deferasirox-only groups. Prospective studies controlling for potential clinical and treatment pattern differences between deferasirox and DFO patients are needed to assess whether the decreased hospitalizations after initiation of deferasirox are related to better treatment compliance.


Subject(s)
Anemia, Sickle Cell/drug therapy , Benzoates/therapeutic use , Deferoxamine/therapeutic use , Iron Chelating Agents/therapeutic use , Triazoles/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Benzoates/administration & dosage , Child , Child, Preschool , Cohort Studies , Deferasirox , Deferoxamine/administration & dosage , Female , Florida , Hospitalization/statistics & numerical data , Humans , Iron Chelating Agents/administration & dosage , Kaplan-Meier Estimate , Male , Medicaid , Medication Adherence , Middle Aged , Missouri , New Jersey , Retrospective Studies , Triazoles/administration & dosage , United States , Young Adult
12.
Clin Radiol ; 67(5): 417-9, 2012 May.
Article in English | MEDLINE | ID: mdl-22119100

ABSTRACT

AIM: To determine the diagnostic yield of each of three core passes when sampling abnormal lymph nodes in patients presenting with breast cancer. MATERIALS AND METHODS: All patients suspected of having breast cancer had axillary ultrasound as part of initial assessment. Radiologically abnormal nodes (cortical thickness >2.3mm or round shape) were biopsied with three passes of a 22 mm throw 14 G core biopsy needle and sent for histopathology in separate numbered pots. Data were collected prospectively, and analysis performed on the data of 55 consecutive patients who had positive nodes on at least one core biopsy needle pass. RESULTS: Of 55 patients with a positive node on core biopsy, tumour was noted in all three cores taken in 39 (70.9%). Lymph node metastasis was detected in 45 (81.8%) first core biopsies. With the first two cores taken, positive results were detected in 53 of 55 cases (96.4%). In both cases where tumour was only found on a third core biopsy pass, no lymph node tissue was present in the first two biopsy passes. CONCLUSION: Two well-directed 14 G core biopsy samples from an abnormal axillary node are adequate for diagnosis of breast cancer metastasis.


Subject(s)
Biopsy, Needle/methods , Breast Neoplasms/pathology , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Adult , Aged , Aged, 80 and over , Axilla , Female , Humans , Male , Middle Aged , Prospective Studies , Reproducibility of Results
13.
Oncogene ; 29(49): 6475-84, 2010 Dec 09.
Article in English | MEDLINE | ID: mdl-20818423

ABSTRACT

The RNA helicase p68 is a potent co-activator of p53-dependent transcription in response to DNA damage. Previous independent studies have indicated that p68 and the Δ133p53 isoforms, which modulate the function of full-length p53, are aberrantly expressed in breast cancers. Here we identify a striking inverse association of p68 and Δ133p53 expression in primary breast cancers. Consistent with these findings, small interfering RNA depletion of p68 in cell lines results in a p53-dependant increase of Δ133p53 in response to DNA damage, suggesting that increased Δ133p53 expression could result from downregulation of p68 and provide a potential mechanistic explanation for our observations in breast cancer. Δ133p53α, which has been shown to negatively regulate the function of full-length p53, reciprocally inhibits the ability of p68 to stimulate p53-dependent transcription from the p21 promoter, suggesting that Δ133p53α may be competing with p68 to regulate p53 function. This hypothesis is underscored by our observations that p68 interacts with the C-terminal domain of p53, co-immunoprecipitates 133p53α from cell extracts and interacts only with p53 molecules that are able to form tetramers. These data suggest that p68, p53 and 133p53α may form part of a complex feedback mechanism to regulate the expression of Δ133p53, with consequent modification of p53-mediated transcription, and may modulate the function of p53 in breast and other cancers that harbour wild-type p53.


Subject(s)
Breast Neoplasms/metabolism , DEAD-box RNA Helicases/metabolism , Tumor Suppressor Protein p53/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Promoter Regions, Genetic , Protein Interaction Domains and Motifs , Protein Isoforms/metabolism , RNA, Small Interfering/metabolism
14.
Br J Cancer ; 103(4): 475-81, 2010 Aug 10.
Article in English | MEDLINE | ID: mdl-20664587

ABSTRACT

BACKGROUND: This study assessed the impact of human epidermal growth factor receptor 2 (HER2) status on the outcomes in an unselected population of breast cancer patients who did not receive HER2-targeted therapy. METHODS: HER2 status by immunohistochemistry and fluorescence in situ hybridisation was compared with clinicopathological data, overall survival (OS) and disease-free survival (DFS) for all patients presenting with breast cancer over 3 years. RESULTS: In 865 patients (median follow up 6.02 years), HER2 positivity was identified in 13.3% of all cancers and was associated with higher tumour grade (P<10(-8)), lymphovascular invasion (P<0.001) and axillary nodal metastasis (P=0.003). There was a negative association with oestrogen-receptor (ER) and progesterone-receptor expression (P<10(-8)), but the majority (57%) of HER2+tumours were ER+HER2 positivity was associated with poorer OS (P=0.0046) and DFS (P=0.0001) confined to the lymph node-positive (LN+) and ER+ subgroups. CONCLUSION: HER2-positive cancers were less common in this population-based cohort than most selected series. The association of HER2 positivity with poor prognosis was confined to the ER+ and LN+ subgroups. The survival deficit for the 7.5% of patients with ER+/HER2+ cancer compared with ER+/HER2- patients points to a significant subgroup of women who may not (currently) be considered for HER2-directed therapy.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Survival Analysis
15.
Br J Cancer ; 102(4): 719-26, 2010 Feb 16.
Article in English | MEDLINE | ID: mdl-20104224

ABSTRACT

BACKGROUND: The deprivation gap for breast cancer survival remains unexplained by stage at presentation, treatment, or co-morbidities. We hypothesised that p53 mutation might contribute to the impaired outcome observed in patients from deprived communities. METHODS: p53 mutation status was determined using the Roche Amplichip research test in 246 women with primary breast cancer attending a single cancer centre and related to deprivation, pathology, overall, and disease-free survival. RESULTS: p53 mutation, identified in 64/246 (26%) of cancers, was most common in 10 out of 17 (58.8%) of the lowest (10th) deprivation decile. Those patients with p53 mutation in the 10th decile had a significantly worse disease-free survival of only 20% at 5 years (Kaplan-Meier logrank chi(2)=6.050, P=0.014) and worse overall survival of 24% at 5 years (Kaplan-Meier logrank chi(2)=6.791, P=0.009) than women of deciles 1-9 with p53 mutation (c.f. 56% and 72%, respectively) or patients in the 10th decile with wild-type p53 (no disease relapse or deaths). CONCLUSION: p53 mutation in breast cancer is associated with socio-economic deprivation and may provide a molecular basis, with therapeutic implications, for the poorer outcome in women from deprived communities.


Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Psychosocial Deprivation , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Breast Neoplasms/psychology , Female , Gene Frequency , Humans , Middle Aged , Mutation , Prognosis , Social Class , Survival Analysis
16.
J Clin Pathol ; 63(1): 88-9, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20026704

ABSTRACT

Fibrocystic disease is a common benign finding in the female breast and often presents as a palpable mass. It is much less commonly found in the male breast. A case is reported of a young man with female-type fibrocystic disease associated with papillary hyperplasia in the right breast.


Subject(s)
Breast/pathology , Fibrocystic Breast Disease/pathology , Adult , Fibrocystic Breast Disease/surgery , Follow-Up Studies , Humans , Hyperplasia/pathology , Hyperplasia/surgery , Male
18.
Clin Oncol (R Coll Radiol) ; 16(4): 248-54, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15214648

ABSTRACT

In the UK, cervical carcinoma is still the eleventh most common cause of cancer in women--it comprises 2% of all female cancers, and accounts for 927 deaths in 2002 alone. The most effective treatments to date are surgery in the form of loop excision of the transformation zone (LLETZ) for pre-invasive disease, LLETZ or simple hysterectomy with laparoscopic pelvic lymphadenectomy for International Federation of Gynecology and Obstetrics (FIGO) Stages IA1 and IA2 microinvasive carcinomas, and Wertheim's hysterectomy or Coelio-Schauta for FIGO Stage IB disease along with concurrent chemoradiotherapy in patents with at least FIGO Stage IB disease. However, radical trachelectomy, which involves a radical excision of the cervix with simultaneous laparoscopic or extraperitoneal lymphadenectomy, may be used selectively in patients with up to FIGO Stage IB1 cancers, as this may preserve fertility in younger women. This paper briefly discusses the role of human papilloma viruses (HPV) and human immunodeficiency virus (HIV) in the development of cervical pre-cancer, and some of the improvements in the techniques used in the cervical carcinoma screening programme. In addition, the diagnosis, staging, spread and prognostic factors involved in invasive cervical carcinoma are mentioned. We will also discuss the role of immunohistochemistry in the diagnosis of invasive cervical carcinoma and recent advances in the molecular pathology of cervical carcinomas.


Subject(s)
Uterine Cervical Dysplasia/diagnosis , Uterine Cervical Dysplasia/therapy , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/therapy , Female , HIV , Humans , Mass Screening/methods , Neoplasm Staging , Papillomaviridae , Prognosis , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/prevention & control , Uterine Cervical Neoplasms/virology , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/prevention & control , Uterine Cervical Dysplasia/virology
19.
Int J Gynecol Cancer ; 12(3): 308-11, 2002.
Article in English | MEDLINE | ID: mdl-12060454

ABSTRACT

This is an unusual presentation of a rare subtype of endometrial adenocarcinoma (villoglandular papillary carcinoma, VGPC) in a 71-year-old woman, which was initially diagnosed on cervical biopsy as being primary cervical VGPC. Loop excision failed to show any evidence of residual disease. Subsequent hysterectomy revealed a localized villoglandular carcinoma involving the uterine fundus and invading the inner one-third of the myometrium, the background endometrium was atrophic. The remaining cervix contained a focus of papillary forming endometrial type adenocarcinoma involving the surface epithelium and the superficial subepithelial glands. In conclusion, VGPC of cervix occurs mainly in young women and can be treated conservatively, pathologists should be cautious in making such a diagnosis in a postmenopausal woman before ruling out a primary endometrial origin.


Subject(s)
Adenocarcinoma, Papillary/diagnosis , Endometrial Neoplasms/diagnosis , Uterine Cervical Neoplasms/diagnosis , Adenocarcinoma, Papillary/surgery , Aged , Diagnosis, Differential , Endometrial Neoplasms/surgery , Epithelium/pathology , Female , Humans , Hysterectomy , Neoplasm Invasiveness , Uterine Cervical Neoplasms/surgery
20.
Histopathology ; 40(3): 245-52, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11895490

ABSTRACT

AIMS: We present the histopathological findings of a series of six cases of a benign uterine smooth muscle tumour with an unusual growth pattern. METHODS AND RESULTS: All cases have the appearances of the recently described dissecting (cotyledonoid) leiomyoma. In addition, three of these lesions demonstrate the features of intravenous leiomyomatosis with varying degrees of hydropic degeneration. CONCLUSIONS: This combination of phenotypes has not previously been described within the literature; therefore we propose that these are classified as examples of 'cotyledonoid hydropic intravenous leiomyomatosis', a new variant of unconventional leiomyoma.


Subject(s)
Leiomyoma/pathology , Leiomyomatosis/pathology , Uterine Neoplasms/pathology , Vascular Neoplasms/pathology , Adult , Female , Humans
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