Invasive lobular carcinoma of the breast: the increasing importance of this special subtype.

Invasive lobular carcinoma (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast cancer cases. ILCs are noted for their lack of E-cadherin function, which underpins their characteristic discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, tumours are luminal in molecular subtype, being oestrogen and progesterone receptor positive, and HER2 negative. Since last reviewing the lobular literature (McCart Reed et al., Breast Cancer Res 17:12, 2015), there has been a considerable increase in research output focused on this tumour type, including studies into the pathology and management of disease, a high-resolution definition of the genomic landscape of tumours as well as the evolution of several potential therapeutic avenues. There abounds a huge amount of new data, which we will review herein.

Breast Cancer Heterogeneity in Primary and Metastatic Disease.

Breast cancer encompasses a heterogeneous collection of neoplasms with diverse morphologies, molecular phenotypes, responses to therapy, probabilities of relapse and overall survival. Traditional histopathological classification aims to categorise tumours into subgroups to inform clinical management decisions, but the diversity within these subgroups remains considerable. Application of massively parallel sequencing technologies in breast cancer research has revealed the true depth of variability in terms of the genetic, phenotypic, cellular and microenvironmental constitution of individual tumours, with the realisation that each tumour is exquisitely unique. This poses great challenges in predicting the development of drug resistance, and treating metastatic disease. Central to achieving fully personalised clinical management is translating new insights on breast cancer heterogeneity into the clinical setting, to evolve the taxonomy of breast cancer and improve risk stratification.

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.

Delta troponin for the early diagnosis of AMI in emergency patients with chest pain.

OBJECTIVES: In patients presenting to the Emergency Department (ED) with potential acute myocardial infarction (AMI), elevated cardiac troponin (cTn) levels are indicative of myocardial necrosis. We assessed the accuracy of 'delta cTn' at 2h or 6h compared to the cTn concentration above the 99th percentile reference value for AMI in a prospective study of adult patients presenting to ED with symptoms suggestive of possible acute coronary syndrome. METHODS: Blood was sampled for cardiac troponin I (cTnI) on presentation, and at 2h and 6h following presentation using a sensitive assay (Beckman AccuTnI). All clinical endpoints were adjudicated by a cardiologist who was blinded to the 2h cTn assay result. RESULTS: Of the 874 patients, 70 (8%) were diagnosed with an AMI during their index presentation. The area under the ROC curve for diagnosing AMI at 2h was 0.89 [95%CI, 0.84-0.95] for absolute delta cTn versus 0.79 [95%CI 0.73-0.85] for the relative change. Specificity and PPV at 2h were optimized using a delta cTnI ≥ 0.03 µg/L (95.8% [95%CI 94.1-97.0] and 61.4% [95%CI 50.9-70.9] respectively). Sensitivity and NPV for AMI were optimized using the 99th percentile with the addition of a delta of<0.03 µg/L (97.1% [95%CI 90.2-99.2] and 99.7% [95%CI 99-99.9] respectively). CONCLUSIONS: An algorithm incorporating cTnI concentration and delta cTn values with a sensitive troponin assay allows accurate diagnosis of AMI within 2h from presentation and earlier rule-out of AMI in the majority of patients.

Examining renal impairment as a risk factor for acute coronary syndrome: a prospective observational study.

STUDY OBJECTIVE: This study seeks to examine whether the finding of an abnormal estimated glomerular filtration rate (eGFR) in the emergency department (ED) was associated with acute coronary syndrome in the population of patients presenting for investigation of chest pain. METHODS: We used prospectively collected data on adult patients presenting with suspected acute coronary syndrome to 2 EDs in Australia and New Zealand. Trained research nurses collected clinical data with a customized case report form. Creatinine measurements were taken on presentation, and the glomerular filtration rate ([GFR]; milliliters per minute per 1.73 m(2)) was estimated with the chronic kidney disease epidemiologic collaboration equation. The primary endpoint was acute coronary syndrome within 30 days of presentation, as adjudicated by cardiologists using standardized guidelines. Logistic regression analyses examined the relationship between eGFR and acute coronary syndrome. RESULTS: Acute coronary syndrome was diagnosed in 421 (21%) of the 1,968 patients recruited. Compared with patients with an eGFR greater than 90 mL/minute per 1.73 m(2), patients with an eGFR between 60 and 90 mL/minute per 1.73 m(2) and patients with an eGFR less than 60 mL/minute per 1.73 m(2) were 1.64 (95% confidence interval 1.10 to 2.44) and 1.70 (95% confidence interval 1.01 to 2.77) times more likely to receive a diagnosis of acute coronary syndrome after controlling for age, sex, hypertension, dyslipidemia, family history of cardiac disease, diabetes, patient history of cardiac disease, cardiac troponin level, and ECG findings. CONCLUSION: There is an independent association between eGFR and acute coronary syndrome risk in patients presenting to the ED with chest pain; this association is independent of age, traditional cardiac risk factors, medical history, troponin level, and ECG findings. Reduced eGFR should be considered an acute coronary syndrome risk factor, and clinicians should maintain high clinical suspicion for acute coronary syndrome in patients with abnormal renal function results regardless of whether they have known kidney disease, traditional acute coronary syndrome risk factors, or abnormal diagnostic test results. Risk stratification tools should include reduced eGFR as a high-risk feature.