Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and ...epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER‐2 overexpression status for the period 2000–2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% 2000–2003 to 8.7% 2008–2011; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER‐2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER‐2‐positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12‐year period 2000–2011 and no increase in the proportion of young patients presenting with metastatic disease.
: The aim of core needle biopsy (CNB) is to diagnose a breast abnormality prior to open surgical excision. The radiology–pathology correlation helps in interpretation of pathologic findings and is ...greatly assisted by specimen radiology of all cores performed for calcifications, separation of cores containing calcification from those without, and the availability of the specimen radiograph to the pathologist at the time of reporting. The nature of the imaging abnormality should also be clearly conveyed. CNB is processed in a routine manner for paraffin embedding with preservation of sufficient material in the block for further studies as needed. Possible pitfalls include the loss of calcifications at the time of section cutting, calcium remained in the formalin of the specimen container, and failure to recognize calcium oxalate deposition in the CNB. The challenges of CNB interpretation are complicated by the availability of only limited material, but are generally similar to those encountered in open surgical excision specimens. This discussion focuses on high‐risk lesions and lesions that raise management issues. The most prudent approach for the pathologist is to provide sufficient information to prompt a surgical excision without overdiagnosing the lesion, thus placing the patient into the appropriate therapeutic algorithm.
Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of ...protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.
To the Editor: Dr Shet's letter raises an interesting question as to whether mucinous breast carcinoma is a distinct clinicopathologic entity or merely an umbrella term for mucin-producing papillary, ...solid papillary, and micropapillary tumors.
Lobular Carcinoma, Not Only a Classic Brogi, Edi; Murray, Melissa P.; Corben, Adriana D.
The breast journal,
09/2010, Volume:
16, Issue:
s1
Journal Article
Peer reviewed
: Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia are rare lesions, found incidentally in breast biopsies. They have been regarded traditionally as high‐risk lesions, but recent ...genetic evidence and follow‐up data indicates that they also constitute nonobligate precursors of invasive carcinoma. In addition to 16q deletion, a genetic alteration common across the spectrum of low‐grade mammary epithelial neoplasia, lobular lesions consistently demonstrate deletion or functional inactivation of the CDH1/E‐cadherin gene, with consequent loss of membranous immunoreactivity for the same antigen. The use of E‐cadherin in the evaluation of solid mammary carcinoma in situ with ambiguous morphology has identified variants of LCIS characterized by massive acinar expansion and necrosis with calcifications, and/or marked nuclear pleomorphism or signet ring cell formation. In contrast to classic LCIS, these rare lesions are detected mammographically and often occur in association with invasive carcinoma. Genetic analysis of these tumors has confirmed lobular lineage and demonstrated more extensive chromosomal alterations than in classic LCIS. A pleomorphic variant of invasive lobular carcinoma has also been described. Here, we summarize our evolving knowledge of in situ and invasive lobular neoplasia and highlight the implications for patient management.
Micro-Abstract There is a lack of predictive biomarkers that can help determine a subset of patients who might most benefit from treatment with heat shock protein 90 (HSP90) inhibitors. Results from ...this retrospective tissue analysis from advanced solid tumor patients (most with breast cancer) who were treated with various HSP90 inhibitors suggest that HER2 might be the only effective biomarker of sensitivity to HSP90 inhibitors.
The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic ...sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy.
Focal extravasated mucin (EM) with benign or atypical epithelium is a rare finding at breast core needle biopsy (CNB) and usually prompts surgical excision to rule out mucin‐producing carcinoma. In ...the largest detailed series to date, we assessed surgical outcomes in lesions yielding EM with atypical or nonatypical epithelium at CNB. With IRB approval, we retrospectively reviewed 28 consecutive atypical and nonatypical CNBs with EM that underwent surgical excision at our center over a 22‐year period. CNB imaging and pathologic findings were concordant if pathology sufficiently explained the radiologic features of the lesions. Pathologic findings in CNB and excision specimens were correlated. Statistical analysis was performed. CNBs sampled mammographic calcifications in 25/28 (89%) women and a mass in 3/28 (11%). All cases had concordant pathologic and imaging findings. At CNB, the epithelium associated with EM was atypical in 18/28 (64%) lesions and nonatypical in 10 (36%). Cancer (one mucinous carcinoma; three ductal carcinoma in situ) was present in 4/28 excision specimens (14%; 95% confidence intervals CI, 4%–33%). All carcinomas were in lesions with epithelial atypia at CNB (4/18; 22%; 95% CI, 6%–48%) versus none (0/10; 0%; 95% CI, 0%–31%) in nonatypical lesions at CNB; this difference was not statistically significant (p = 0.3). Surgery is warranted for lesions yielding EM with atypia at CNB due to the high (22%) prevalence of cancer. Our data suggest that surgical excision of lesions yielding EM without epithelial atypia at CNB may not be necessary provided that imaging and pathologic findings are concordant.
The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is ...functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes. In tumors, maintenance of the epichaperome network is vital for tumor survival, rendering them vulnerable to therapeutic interventions that target critical epichaperome network components. We discuss how the epichaperome empowers an approach for precision medicine cancer trials where a new target, biomarker, and relevant drug candidates can be correlated and integrated. We introduce chemical biology methods to investigate the heterogeneity of the chaperome in a given cellular context. Lastly, we discuss how ligand–protein binding kinetics are more appropriate than equilibrium binding parameters to characterize and unravel chaperome targeting in cancer and to gauge the selectivity of ligands for specific tumor-associated chaperome pools.
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