Development and Validation of a HER2-Low Focused Immunohistochemical Scoring System With High-Interobserver Concordance: The Australian HER2-Low Breast Cancer Concordance Study.

The DESTINY Breast-04 trial revealed survival advantages of trastuzumab deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ immunohistochemistry [IHC], without amplification). Although this trial applied the 2018 Americal Society of Clinial Oncology (ASCO)/College of American Pathologists (CAP) HER2 IHC scoring criteria, the subjectivity and imprecision in IHC scoring have raised concerns that patients' treatment may be misaligned. Our group of 9 experienced breast pathologists collated a deidentified set of 60 breast cancer core biopsies from 3 laboratories, evaluated with the Ventana 4B5 HER2 assay and mostly scored locally as HER2 0 or 1+. Based on ASCO/CAP 2018 criteria and our extensive experience of reporting HER2 IHC, we specified scoring conventions for cancers with low levels of HER2 protein expression, articulating specific scoring pitfalls. Each pathologist then reviewed digitized whole slide images of the IHC slides and scored the HER2 expression for each case. At a subsequent consensus workshop, we reviewed the cases jointly to establish consensus scores for each case and determine the percentage of HER2 expressing tumor cells. Consensus was reached on all cases, with 40 classified as 1+ and 3 as 2+ (not amplified), totaling 43 (71.7%) HER2-low cancers. The remaining cases were HER2 0. In 93.3% of cases (56/60), the consensus score matched with the majority opinion of pathologists' independent scores. Seven (41.2%) of the 17 cases reported locally as HER2 0 were classified as HER2 low. Conversely, among 32 cases with local scores of 1+, 7 (21.8%) were reclassified as ultralow or null. Individual pathologists' accuracy in matching the consensus scores ranged from 73.3% to 91.67% (mean, 80.74%). Among HER2-low cancers those in which <20% of the tumor cells expressed HER2 had the lowest concordance levels. Observers Cohen's κ coefficients for concordance were excellent for 4, good in 1, and moderate in the 4 observers. This reference set of cases with expert consensus HER2 scores will be invaluable for peer training and development of our national external quality assurance program for HER2-low cancers. For assessing breast cancers at the low end of HER2 protein expression, our targeted scoring criteria and explicit instruction on pitfalls improved pathologists' accuracy and concordance.

Artificial intelligence-based digital scores of stromal tumour-infiltrating lymphocytes and tumour-associated stroma predict disease-specific survival in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is known to have a relatively poor outcome with variable prognoses, raising the need for more informative risk stratification. We investigated a set of digital, artificial intelligence (AI)-based spatial tumour microenvironment (sTME) features and explored their prognostic value in TNBC. After performing tissue classification on digitised haematoxylin and eosin (H&E) slides of TNBC cases, we employed a deep learning-based algorithm to segment tissue regions into tumour, stroma, and lymphocytes in order to compute quantitative features concerning the spatial relationship of tumour with lymphocytes and stroma. The prognostic value of the digital features was explored using survival analysis with Cox proportional hazard models in a cross-validation setting on two independent international multi-centric TNBC cohorts: The Australian Breast Cancer Tissue Bank (AUBC) cohort (n = 318) and The Cancer Genome Atlas Breast Cancer (TCGA) cohort (n = 111). The proposed digital stromal tumour-infiltrating lymphocytes (Digi-sTILs) score and the digital tumour-associated stroma (Digi-TAS) score were found to carry strong prognostic value for disease-specific survival, with the Digi-sTILs and Digi-TAS scores giving C-index values of 0.65 (p = 0.0189) and 0.60 (p = 0.0437), respectively, on the TCGA cohort as a validation set. Combining the Digi-sTILs feature with the patient's positivity status for axillary lymph nodes yielded a C-index of 0.76 on unseen validation cohorts. We surmise that the proposed digital features could potentially be used for better risk stratification and management of TNBC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Comparison of breast cancer HER-2 receptor testing with immunohistochemistry and in situ hybridization.

PURPOSE: Human epidermal growth factor receptor-2 (HER2) status can be tested with immunohistochemistry (IHC) and in situ hybridization (ISH). The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 testing guidelines suggest initial HER2 testing using IHC and further testing IHC equivocal cases with ISH. However, many institutions perform both IHC and ISH on the same specimen. This study aims to analyze the concordance between HER2 IHC and ISH in order to evaluate the benefit of repeating HER2 testing on the same breast cancer specimens. METHOD: Patients diagnosed with invasive breast cancer through BreastScreen NSW Sydney West program between January 2018 and December 2020 were identified and their HER2 IHC and HER2 ISH results on core needle biopsy (CNB) and surgical excisions (SE) were retrospectively collected. Specimens with both IHC and ISH results were then analyzed for agreement and concordance using unweighted kappa values. Equivocal IHC (2+) cases were excluded from concordance analysis. RESULTS: Overall, there were 240 invasive breast cancer specimens (CNB and SE) with both IHC and ISH recorded. Concordance between HER2 IHC and ISH was 100% (95% CI: 96.2-100%; κ = 1.00 (P < 0.001)). Of the IHC equivocal cases (n = 146), 94.5% were ISH negative. CONCLUSION: There was perfect positive concordance and agreement between non-equivocal IHC and ISH results. This reinforces that IHC alone can be utilized reliably for testing HER2 status of non-equivocal cases consistent with the 2018 ASCO/CAP guidelines.

Should low-risk DCIS lose the cancer label? An evidence review.

BACKGROUND: Population mammographic screening for breast cancer has led to large increases in the diagnosis and treatment of ductal carcinoma in situ (DCIS). Active surveillance has been proposed as a management strategy for low-risk DCIS to mitigate against potential overdiagnosis and overtreatment. However, clinicians and patients remain reluctant to choose active surveillance, even within a trial setting. Re-calibration of the diagnostic threshold for low-risk DCIS and/or use of a label that does not include the word 'cancer' might encourage the uptake of active surveillance and other conservative treatment options. We aimed to identify and collate relevant epidemiological evidence to inform further discussion on these ideas. METHODS: We searched PubMed and EMBASE databases for low-risk DCIS studies in four categories: (1) natural history; (2) subclinical cancer found at autopsy; (3) diagnostic reproducibility (two or more pathologist interpretations at a single time point); and (4) diagnostic drift (two or more pathologist interpretations at different time points). Where we identified a pre-existing systematic review, the search was restricted to studies published after the inclusion period of the review. Two authors screened records, extracted data, and performed risk of bias assessment. We undertook a narrative synthesis of the included evidence within each category. RESULTS: Natural History (n = 11): one systematic review and nine primary studies were included, but only five provided evidence on the prognosis of women with low-risk DCIS. These studies reported that women with low-risk DCIS had comparable outcomes whether or not they had surgery. The risk of invasive breast cancer in patients with low-risk DCIS ranged from 6.5% (7.5 years) to 10.8% (10 years). The risk of dying from breast cancer in patients with low-risk DCIS ranged from 1.2 to 2.2% (10 years). Subclinical cancer at autopsy (n = 1): one systematic review of 13 studies estimated the mean prevalence of subclinical in situ breast cancer to be 8.9%. Diagnostic reproducibility (n = 13): two systematic reviews and 11 primary studies found at most moderate agreement in differentiating low-grade DCIS from other diagnoses. Diagnostic drift: no studies found. CONCLUSION: Epidemiological evidence supports consideration of relabelling and/or recalibrating diagnostic thresholds for low-risk DCIS. Such diagnostic changes would need agreement on the definition of low-risk DCIS and improved diagnostic reproducibility.

Ductal Carcinoma in Situ: Molecular Changes Accompanying Disease Progression.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC), whereby if left untreated, approximately 12% of patients develop invasive disease. The current standard of care is surgical removal of the lesion, to prevent potential progression, and radiotherapy to reduce risk of recurrence. There is substantial overtreatment of DCIS patients, considering not all DCIS lesions progress to invasive disease. Hence, there is a critical imperative to better predict which DCIS lesions are destined for poor outcome and which are not, allowing for tailored treatment. Active surveillance is currently being trialed as an alternative management practice, but this approach relies on accurately identifying cases that are at low risk of progression to invasive disease. Two DCIS-specific genomic profiling assays that attempt to distinguish low and high-risk patients have emerged, but imperfections in risk stratification coupled with a high price tag warrant the continued search for more robust and accessible prognostic biomarkers. This search has largely turned researchers toward the tumor microenvironment. Recent evidence suggests that a spectrum of cell types within the DCIS microenvironment are genetically and phenotypically altered compared to normal tissue and play critical roles in disease progression. Uncovering the molecular mechanisms contributing to DCIS progression has provided optimism for the search for well-validated prognostic biomarkers that can accurately predict the risk for a patient developing IDC. The discovery of such markers would modernize DCIS management and allow tailored treatment plans. This review will summarize the current literature regarding DCIS diagnosis, treatment, and pathology.

Concordance between core needle biopsy and surgical excision for breast cancer tumor grade and biomarkers.

PURPOSE: Histopathological biomarkers guide breast cancer management. Testing histopathological biomarkers on both core needle biopsy (CNB) and surgical excision (SE) in patients who are treated with upfront surgery is unnecessary and costly if there is high concordance between the two. This study investigated the concordance between CNB and SE for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor-2 (HER2), tumor grade and Ki-67. METHODS: Histopathological biomarker information were retrospectively collected from preoperative CNB and SE on patients diagnosed with breast cancer through the BreastScreen Sydney West program over a four-year period between January 2017 and December 2020. Data were then analyzed to calculate percentage of agreement and concordance using kappa values for ER, PR, HER2, tumor grade and Ki-67. RESULTS: A total of 504 cases of invasive breast cancers were analyzed. There was substantial level of concordance for ER 96.7% (κ = 0.687) and PR 93.2% (κ = 0.69). Concordance for HER2 negative (IHC 0, IHC 1 +) or positive (IHC 3 +) tumor on CNB was 100% (κ = 1.00). Grade and Ki-67 showed moderate level of concordance, 72.6% (κ = 0.545) and 70.5% (κ = 0.453), respectively. CONCLUSION: ER, PR and HER2 show high level of concordance. CNB is reliable in determining histopathological biomarkers for ER, PR positive and HER2 positive or negative tumors indicating that retesting these on SE may not be necessary.

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

PURPOSE: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS: Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS: 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. CONCLUSION: Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.

Interobserver concordance in visual assessment of Ki67 immunohistochemistry in surgical excision specimens from patients with lymph node-negative breast cancer.

PURPOSE: This study aimed to determine the interobserver concordance of two methods for proliferation assessment in breast cancer using Ki67 immunohistochemistry. METHODS: Ki67 was independently assessed in randomly selected tumour samples from patients with lymph node-negative breast cancer using two different methods: either cell counting or visual estimation of hot spot areas. For hot spot cell counting, positive and negative cell numbers were recorded for total cell counts of 300-500, 500-800 and 800-1000 cells. Visual estimation involved allocation of a score from 1 to 5 using a visual scale to estimate percentage positivity. Interobserver agreement for hot spot counting was calculated using a two-way fixed effects intraclass correlation model, and by using Cohen's kappa measure for visual assessment. Prognostic concordance between the two methods was also calculated using Cohen's kappa. RESULTS: Samples from 96 patients were included in this analysis. Interobserver agreement for hot spot cell counting was excellent (> 0.75) across all three cell count ranges, with correlation coefficients of 0.88 (95% CI 0.84-0.92), 0.87 (95% CI 0.82-0.91) and 0.89 (95% CI 0.85-0.92), respectively. Interobserver agreement with visual estimation was greatest for hot spots compared with areas of intermediate or low proliferation, with kappa scores of 0.49, 0.42 and 0.40, respectively. Both assessment methods demonstrated excellent prognostic agreement. CONCLUSIONS: Interobserver and prognostic concordance in Ki67 immunohistochemistry assessments was high using either hot spot cell counting or visual estimation, further supporting the utility and reproducibility of these cost-efficient methods to assess proliferation.

Electronic medical record implementation in tertiary care: factors influencing adoption of an electronic medical record in a cancer centre.

BACKGROUND: Electronic Medical Records (EMRs) are one of a range of digital health solutions that are key enablers of the data revolution transforming the health sector. They offer a wide range of benefits to health professionals, patients, researchers and other key stakeholders. However, effective implementation has proved challenging. METHODS: A qualitative methodology was used in the study. Interviews were conducted with 12 clinical and administrative staff of a cancer centre at one-month pre-launch and eight clinical and administrative staff at 12-months post-launch of an EMR. Data from the interviews was collected via audio recording. Audio recordings were transcribed, de-identified and analysed to identify staff experiences with the EMR. RESULTS: Data from the pre-implementation interviews were grouped into four categories: 1) Awareness and understanding of EMR; 2) Engagement in launch process; 3) Standardisation and completeness of data; 4) Effect on workload. Data from the post-launch interviews were grouped into six categories: 1) Standardisation and completeness of data; 2) Effect on workload; 3) Feature completeness and functionality; 4) Interaction with technical support; 5) Learning curve; 6) Buy-in from staff. Two categories: Standardisation and completeness of data and effect on workload were common across pre and post-implementation interviews. CONCLUSION: Findings from this study contribute new knowledge on barriers and enablers to the implementation of EMRs in complex clinical settings. Barriers to successful implementation include lack of technical support once the EMR has launched, health professional perception the EMR increases workload, and the learning curve for staff adequately familiarize themselves with using the EMR.

Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1.

BACKGROUND: Metaplastic breast carcinoma encompasses a heterogeneous group of tumours with differentiation into squamous and/or spindle, chondroid, osseous or rhabdoid mesenchymal-looking elements. Emerging immunotherapies targeting Programmed Death Ligand 1 (PD-L1) and immune-suppressing T cells (Tregs) may benefit metaplastic breast cancer patients, which are typically chemo-resistant and do not express hormone therapy targets. METHODS: We evaluated the immunohistochemical expression of PD-L1 and FOXP3, and the extent of tumour infiltrating lymphocytes (TILs) in a large cohort of metaplastic breast cancers, with survival data. RESULTS: Metaplastic breast cancers were significantly enriched for PD-L1 positive tumour cells, compared to triple-negative ductal breast cancers (P < 0.0001), while there was no significant difference in PD-L1 positive TILs. Metaplastic breast cancers were also significantly enriched for TILs expressing FOXP3, with FOXP3 positive intra-tumoural TILs (iTILs) associated with an adverse prognostic outcome (P = 0.0226). Multivariate analysis identified FOXP3 iTILs expression status as an important independent prognostic factor for patient survival. CONCLUSIONS: Our findings indicate the clinical significance and prognostic value of FOXP3, PD-1/PD-L1 checkpoint and TILs in metaplastic breast cancer and confirm that a subset of metaplastics may benefit from immune-based therapies.

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications.

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Developing an Intranet-Based Lymphedema Dashboard for Breast Cancer Multidisciplinary Teams: Design Research Study.

BACKGROUND: A large quantity of data is collected during the delivery of cancer care. However, once collected, these data are difficult for health professionals to access to support clinical decision making and performance review. There is a need for innovative tools that make clinical data more accessible to support health professionals in these activities. One approach for providing health professionals with access to clinical data is to create the infrastructure and interface for a clinical dashboard to make data accessible in a timely and relevant manner. OBJECTIVE: This study aimed to develop and evaluate 2 prototype dashboards for displaying data on the identification and management of lymphedema. METHODS: The study used a co-design framework to develop 2 prototype dashboards for use by health professionals delivering breast cancer care. The key feature of these dashboards was an approach for visualizing lymphedema patient cohort and individual patient data. This project began with 2 focus group sessions conducted with members of a breast cancer multidisciplinary team (n=33) and a breast cancer consumer (n=1) to establish clinically relevant and appropriate data for presentation and the visualization requirements for a dashboard. A series of fortnightly meetings over 6 months with an Advisory Committee (n=10) occurred to inform and refine the development of a static mock-up dashboard. This mock-up was then presented to representatives of the multidisciplinary team (n=3) to get preliminary feedback about the design and use of such dashboards. Feedback from these presentations was reviewed and used to inform the development of the interactive prototypes. A structured evaluation was conducted on the prototypes, using Think Aloud Protocol and semistructured interviews with representatives of the multidisciplinary team (n=5). RESULTS: Lymphedema was selected as a clinically relevant area for the prototype dashboards. A qualitative evaluation is reported for 5 health professionals. These participants were selected from 3 specialties: surgery (n=1), radiation oncology (n=2), and occupational therapy (n=2). Participants were able to complete the majority of tasks on the dashboard. Semistructured interview themes were categorized into engagement or enthusiasm for the dashboard, user experience, and data quality and completeness. CONCLUSIONS: Findings from this study constitute the first report of a co-design process for creating a lymphedema dashboard for breast cancer health professionals. Health professionals are interested in the use of data visualization tools to make routinely collected clinical data more accessible. To be used effectively, dashboards need to be reliable and sourced from accurate and comprehensive data sets. While the co-design process used to develop the visualization tool proved effective for designing an individual patient dashboard, the complexity and accessibility of the data required for a cohort dashboard remained a challenge.

Axillary reverse mapping in patients with breast cancer: Is it oncologically safe?

BACKGROUND: Axillary reverse mapping (ARM) is a technique used to identify the lymphatics draining the arm. The aim of this study was to examine the prevalence and predictors of ARM node metastases in breast cancer patients undergoing an axillary lymph node dissection (ALND). METHODS: A total of 87 patients were enrolled in this study. Patent V Blue dye was injected in the upper arm for ARM node localization. All patients had an ALND with the identified ARM node removed and sent separately for histologic analysis. RESULTS: Of 67 (77%) patients in whom an ARM node was identified, 49 (73%) were negative and 18 (27%) were positive for metastases on final histopathology. Positive ARM node status was significantly associated with advanced axillary disease, and larger primary cancers. Patients requiring a completion ALND due to a positive sentinel lymph node biopsy (SLNB) with non-suspicious ARM nodes during surgery did not have ARM node metastases. CONCLUSIONS: There is a high risk of ARM node involvement, approximately a quarter, in patients with preoperatively known lymph node metastases from breast cancer. However, it may be safe to preserve a clinically non-suspicious ARM node in patients with a positive SLNB who require a completion ALND. J. Surg. Oncol. 2016;113:726-731. © 2016 Wiley Periodicals, Inc.

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer.

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families.

The heterogeneity of multiple case breast cancer families that do not carry mutations in BRCA1 or BRCA2 (non-BRCA1/2 families) poses a challenge to the identification of breast cancer susceptibility genes. The aim of this study was to determine whether intrafamilial concordance in breast cancer pathology could identify subgroups of non-BRCA1/2 families with consistent genotypic features. Invasive breast cancers were reviewed from 84 individuals belonging to 30 multiple-case families; BRCA1 (n = 9), BRCA2 (n = 10), and non-BRCA1/2 (n = 11). Hierarchical cluster analysis based on histopathology and age at first diagnosis was then used to specify three subgroups designated Clusters 1-3. The genomic features of non-BRCA1/2 families were examined by genome wide linkage and FGFR2 SNP genotyping, according to whether they showed cluster-concordant or cluster-mixed familial pathology. The majority of pathogenic BRCA1 mutation carriers (80%) fell into a single cluster. In contrast pathogenic BRCA2 mutation carriers were distributed across all three clusters and within families, cluster groups were also generally mixed. Most non-BRCA1/2 mutation carriers belonged to Cluster 3 (71%). Genome wide linkage data from five non-BRCA1/2 Cluster 3-concordant families were compared with four mixed cluster non-BRCA1/2 families. This revealed a number of distinct linkage peaks, including some regions previously associated with breast cancer susceptibility. The distribution of low risk alleles in FGFR2 was not different between these two subgroups (P = 0.237). The pattern of breast cancer pathology concordance amongst family members may assist the investigation of breast cancer susceptibility in multiple case families.

Diagnostic evaluation of papillary lesions of the breast on core biopsy.

The management of asymptomatic intraductal papillary lesions of the breast diagnosed on core biopsy poses a challenge for patients and clinicians, as the distinction between common benign lesions and atypical or malignant varieties may be difficult without formal excision. The aim of this study was to determine whether a combination of histopathologic and biomarker features could be used to accurately identify benign papillary lesions on core biopsy. An inclusive group of 127 excised papillary lesions was characterized by detailed histopathologic review and immunohistochemical staining for the basal markers cytokeratin 5/6 (CK5/6) and P63 and the proliferation marker Ki67. Comparison of benign, atypical, and malignant lesions revealed that the combination of broad, sclerotic fibrovascular cores, and epithelial CK5/6 staining was most commonly seen in benign papillomas. Ki67 staining revealed striking intralesional heterogeneity, but there was no difference between the high scores of benign, atypical, or malignant lesions (P=0.173). In a non-overlapping set of 42 cases, a binary classifier specifying benign lesions on the basis of thick fibrovascular cores and epithelial CK5/6 staining on core biopsy gave an overall misclassification rate of 4/42 (10%) when compared with the final excision diagnosis. Misclassified cases included 2/27 lesions ultimately diagnosed as benign and 2/2 atypical papillomas. All malignant lesions (n=13) were correctly assigned. The combined assessment of fibrovascular core thickness and CK5/6 staining on core biopsy distinguished benign from malignant papillary lesions, but did not separate benign from atypical cases. This approach may form a useful addition to the clinicopathologic evaluation of papillary lesions of the breast.

Factors Influencing Implementation of an Electronic Medical Record in a Tertiary Cancer Centre.

BACKGROUND: EMRs are one of a range of digital health solutions that are key enablers of the data revolution transforming the health sector. They offer a wide range of benefits to health professionals, patients and other key stakeholders. However, effective implementation has proved challenging. METHOD: A qualitative methodology was used in the study. Interviews were conducted with members of a cancer team 12 months post-implementation of an EMR. Data from the interviews was collected via audio recording. Audio recordings were transcribed, de-identified and analyzed to identify the experiences of staff with the EMR. FINDINGS: Data was categorized in to six categories: 1) Standardisation of documentation and completeness of data; 2) Effect on workload; 3) Feature completeness and functionality; 4) Interaction with technical support; 5) Learning curve; 6) Buy-in from staff. CONCLUSIONS & IMPLICATIONS: Findings from this study contribute new knowledge on barriers and enablers to the implementation of EMRs in complex clinical settings. Barriers to successful implementation include lack of technical support, perceived increase in workload and a learning curve to fully familiarize with the feature set of the EMR.

Fine needle aspiration biopsy cytology of phyllodes tumour and fibroadenoma: A cytomorphological study of 104 cases.

BACKGROUND: The cytomorphological features in the distinction between phyllodes tumour (PT) and fibroadenoma (FA) on fine needle aspiration biopsy (FNAB) remains challenging because of the biphasic nature of these lesions and the rarity of PT. METHODS: FNAB smears of histologically confirmed PT (N = 26) and FA (N = 78) cases were retrieved from a retrospective database interrogation from the Department of Cytology/Tissue Pathology, ICPMR Pathology West (Cerner Millennium) in Westmead Hospital. For each case, two smears were selected, de-identified and independently reviewed by four observers comprising two cytologists and two cytopathologists. Cytological parameters examined included detailed evaluation of smear cellularity, epithelial and stromal components as well as the smear background. RESULTS: The cytological features of moderate to marked stromal cellularity and stromal nuclear atypia were more evident in PT than in FA, identified by three out of four observers. The epithelial characteristics, presence of macrophages, multinucleated giant cells and blood vessels showed no statistically significant differences in the distinction between the two lesions. CONCLUSION: The results of this study indicate that in all of the cytological features assessed for PT and FA, no single cytological feature was found to be statistically significant in identifying PT across all observers. This reflects the overlap of cytological features seen in these lesions. FNAB cytology cannot reliably distinguish FA and PT.

Profiling differential microRNA expression between in situ, infiltrative and lympho-vascular space invasive breast cancer: a pilot study.

Ductal carcinoma in situ (DCIS), invasive breast cancer (IBC) and lympho-vascular invasion (LVI) represent distinct stages in breast cancer progression with different clinical implications. Altered microRNA (miRNA) expression may play a role in mediating the progression of DCIS to IBC and LVI. The aim of this pilot study was to investigate whether differential miRNA expression could play a role in breast cancer progression. Cancer cells from DCIS, IBC and LVI were microdissected from formalin fixed paraffin embedded (FFPE) tissue of five breast cancer samples. MiRNA profiling of extracted RNA was performed using the TaqMan® Array Human MicroRNA Cards A and B v3.0. Candidate miRNAs and gene targets were validated by qPCR. 3D culture of MCF10A, MCF10DCIS.com and T47D cells were used as models for normal, DCIS and IBC. Immunohistochemistry of candidate genes was performed on FFPE 3D cell cultures as well as on tissue microarray which included cores of DCIS and IBC samples. MiR-150, miR-126 and miR-155 were found to be more highly expressed in IBC and LVI compared to DCIS. Gene targets of these miRNAs, RhoA, PEG10 and MYB, were found to be more highly expressed in DCIS compared to IBC by qPCR and in MCF10A and MCF10DCIS.com cells compared to T47D cells by immunohistochemistry. There was no difference in intensity of staining of RhoA by immunohistochemistry in DCIS versus IBC samples on tissue microarray. In this pilot study, we found evidence to support a potential role for variation in miRNA levels in the transition from DCIS to IBC.

Carcinoma in situ of the breast in New South Wales, Australia: Current status and trends over the last 40 year.

BACKGROUND: The incidence of non-invasive breast cancer has increased substantially over time. We aim to describe temporal trends in the incidence of carcinoma in situ of the breast in New South Wales (NSW), Australia. METHODS: Descriptive study of trends in the incidence of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) in women who received a diagnosis from 1972 to 2012, recorded in the NSW Cancer Registry. RESULTS: Carcinoma in situ as a proportion of all breast cancer was 0.4% during the prescreening period 1972 to 1987 and is currently 14.1% (2006 to 2012). Among 10,810 women diagnosed with DCIS, incidence across all ages rose from 0.15 per 100,000 during 1972 to 1983 to 16.81 per 100,000 over 2006 to 2012, representing a 100-fold increase (IRR 113.10; 95% CI 81.94 to 156.08). Among women in the target age group for screening (50-69 years) incidence rose from 0.27 per 100,000 to 51.96 over the same period (IRR 195.50; 95% CI 117.26 to 325.89). DCIS incidence peaks in women aged 60-69 years. DCIS incidence has not stabilized despite screening being well established for over 20 years, and participation rates in the target age range remaining stable. CONCLUSIONS: Our findings raise questions about the value of the increasing detection of DCIS and aggressive treatment of these lesions, especially among older women, and support trials of de-escalated treatment.