Evaluating Magnetic Seed Localization in Targeted Axillary Dissection for Node-Positive Early Breast Cancer Patients Receiving Neoadjuvant Systemic Therapy: A Comprehensive Review and Pooled Analysis.

De-escalation of axillary surgery is made possible by advancements in both neoadjuvant systemic therapy (NST) and in localisation technology for breast lesions. Magseed, developed in 2013 by Dr. Michael Douk of Cambridge, United Kingdom, is a wire-free localisation technology that facilitates the localisation and retrieval of lymph nodes for staging.

Unusual metastasis in BRCA mutated pancreatic cancer while on maintenance Olaparib: Two case reports and review of the literature.

The most common metastatic sites of pancreatic cancer are the liver, lymph nodes, peritoneum and lung. Here we report two cases of BRCA mutated pancreatic cancer that developed unusual metastasis while treatment with maintenance Olaparib and leading to rapid death. We hereby review the literature and address the possibility of a different nature and tumour biology of BRCA mutated cancer treated with PARP inhibitors.

Lobular Carcinomas Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma.

Purpose: Lobular carcinoma (LCIS) is a preinvasive lesion of the breast. We sought to define its genomic landscape, whether intralesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers. We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically advanced lesions from 24 patients [9 ductal carcinomas (DCIS), 13 invasive lobular carcinomas (ILC), and 5 invasive ductal carcinomas (IDC)].

Contralateral breast cancers: Independent cancers or metastases?

A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer.

Pleomorphic lobular carcinoma in situ of the breast: a single institution experience with clinical follow-up and centralized pathology review.

Purpose: The natural history of pleomorphic lobular carcinoma in situ (PLCIS) remains largely unknown.

Methods: A pathology database search (1995-2012) was performed to identify patients diagnosed with an LCIS variant. Patients with synchronous breast cancer and/or no evidence of pleomorphism were excluded.

Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.

Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers.

Clonal relationships between lobular carcinoma in situ and other breast malignancies.

Background: Recent evidence suggests that lobular carcinoma in situ (LCIS) can be a clonal precursor of invasive breast cancers of both the ductal and lobular phenotypes. We sought to confirm these findings with an extensive study of fresh frozen breast specimens from women undergoing mastectomy.

Methods: Patients with a history of LCIS presenting for therapeutic mastectomy were identified prospectively.

The Genomic Landscape of Male Breast Cancers.

Purpose: Male breast cancer is rare, and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of males with breast cancer is extrapolated from results in females with breast cancer. We sought to define whether male breast cancers harbor somatic genetic alterations in genes frequently altered in female breast cancers.

Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations.

Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related.

Biomarkers That Predict Sensitivity to Heat Shock Protein 90 Inhibitors.

Introduction: Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors.

Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships.

Purpose: Lobular carcinoma in situ (LCIS) has been proposed as a non-obligate precursor of invasive lobular carcinoma (ILC). Here we sought to define the repertoire of somatic genetic alterations in pure LCIS and in synchronous LCIS and ILC using targeted massively parallel sequencing.

Methods: DNA samples extracted from microdissected LCIS, ILC and matched normal breast tissue or peripheral blood from 30 patients were subjected to massively parallel sequencing targeting all exons of 273 genes, including the genes most frequently mutated in breast cancer and DNA repair-related genes.

Infiltrating epitheliosis of the breast: characterization of histological features, immunophenotype and genomic profile.

Aims: Infiltrating epitheliosis is a rare complex sclerosing lesion (CSL) of the breast, characterized by infiltrating ducts immersed in a scleroelastotic stroma and filled with cells having architectural and cytological patterns reminiscent of those of usual ductal hyperplasia. In this study we sought to define the molecular characteristics of infiltrating epitheliosis.

Methods And Results: Eight infiltrating epitheliosis, adjacent breast lesions (one usual ductal hyperplasia, one papilloma, one micropapillary ductal carcinoma in situ and one low-grade adenosquamous carcinoma), and corresponding normal breast tissue from each case were microdissected and subjected to massively parallel sequencing analysis targeting all coding regions of 254 genes mutated recurrently in breast cancer and/or related to DNA repair.

Lobular Carcinoma in Situ: A 29-Year Longitudinal Experience Evaluating Clinicopathologic Features and Breast Cancer Risk.

Purpose: The increased breast cancer risk conferred by a diagnosis of lobular carcinoma in situ (LCIS) is poorly understood. Here, we review our 29-year longitudinal experience with LCIS to evaluate factors associated with breast cancer risk.

Patients And Methods: Patients participating in surveillance after an LCIS diagnosis are observed in a prospectively maintained database.

In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer.

Detection of minor, genetically distinct subpopulations within tumors is a key challenge in cancer genomics. Here we report STAR-FISH (specific-to-allele PCR-FISH), a novel method for the combined detection of single-nucleotide and copy number alterations in single cells in intact archived tissues. Using this method, we assessed the clinical impact of changes in the frequency and topology of PIK3CA mutation and HER2 (ERBB2) amplification within HER2-positive breast cancer during neoadjuvant therapy.

Gene expression profiling of lobular carcinoma in situ reveals candidate precursor genes for invasion.

Purpose: Lobular carcinoma in situ (LCIS) is both a risk indicator and non-obligate precursor of invasive lobular carcinoma (ILC). We sought to characterize the transcriptomic features of LCIS and ILC, with a focus on the identification of intrinsic molecular subtypes of LCIS and the changes involved in the progression from normal breast epithelium to LCIS and ILC.

Methods: Fresh-frozen classic LCIS, classic ILC, and normal breast epithelium (N) from women undergoing prophylactic or therapeutic mastectomy were prospectively collected, laser-capture microdissected, and subjected to gene expression profiling using Affymetrix HG-U133A 2.

Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands.

Polymorphous low-grade adenocarcinoma (PLGA) is the second most frequent type of malignant tumor of the minor salivary glands. We identified PRKD1 hotspot mutations encoding p.Glu710Asp in 72.

PI3K pathway activation in high-grade ductal carcinoma in situ--implications for progression to invasive breast carcinoma.

Purpose: To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations.

Experimental Design: Eighty-nine cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of PIK3CA and AKT1 hotspot mutations.

Results: Alterations affecting the PI3K pathway were found in a subset of pure DCIS and DCIS adjacent to IBC.

ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.

Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases.

Is there a role for routine screening MRI in women with LCIS?

Women with lobular carcinoma in situ (LCIS) have an elevated breast cancer risk, yet the benefit of MRI screening is unclear. We examined cancer detection rates with mammography alone versus mammography plus MRI in this high-risk population. From a prospectively maintained, single-institution database, we identified 776 patients diagnosed with LCIS after the adoption of screening MRI in April 1999.

Progression from ductal carcinoma in situ to invasive breast cancer: revisited.

Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non-obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated.

Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer.

Purpose: HER2-amplified breast cancer is sometimes clinically insensitive to HER2-targeted treatment with trastuzumab. Laboratory models of resistance have causally implicated changes in HER2 expression and activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway. We conducted a prospective tissue acquisition study to determine if there is evidence for these lesions in metastatic tumors that have progressed on trastuzumab-containing therapy.

Impact of immunohistochemical analysis of sentinel lymph node biopsy on breast cancer management.

Background: Little evidence of the impact of immunohistochemical analysis (IHC) on the indications for adjuvant therapies is available. This study determined the modification rate of adjuvant chemotherapy and lymph node area radiotherapy using IHC and its impact on survival.

Patients And Methods: Between 2001 and 2005, 416 patients underwent surgery for invasive breast cancer with sentinel lymph node (SLN) biopsy.

Can the centrosome be a marker for DNA ploidy in breast cancer?

Background: The role of DNA ploidy in genomic instability of cancer cells and prognosis has been described in a number of studies. The role of the centrosome in cell cycle has also been reported.

Aim: In this study, we aimed to investigate the correlation between the centrosome and DNA ploidy in breast cancer in a search for a cytologic predictive and prognostic marker.

Genomic complexity and AKT dependence in serous ovarian cancer.

Unlabelled: Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of PI3 kinase/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed.