Predictive modelling of response to neoadjuvant therapy in HER2+ breast cancer.

HER2-positive (HER2+) breast cancer accounts for 20-25% of all breast cancers. Predictive biomarkers of neoadjuvant therapy response are needed to better identify patients with early stage disease who may benefit from tailored treatments in the adjuvant setting. As part of the TCHL phase-II clinical trial (ICORG10-05/NCT01485926) whole exome DNA sequencing was carried out on normal-tumour pairs collected from 22 patients.

Value of Long-term Follow-up in Surgically Excised Lesions of Uncertain Malignant Potential in the Breast - Is 5 Years Necessary?

Introduction: B3 lesions are a heterogeneous group of breast lesions of uncertain malignant potential which usually require excision. The aim was to assess the efficacy of 5 years routine radiological or clinical follow-up of patients who had "high-risk" B3 lesions surgically excised, by analyzing recurrence and subsequent development of invasive/in-situ cancer.

Patients And Methods: A 10-year retrospective review from 2010 to 2019 was performed of B3 lesions diagnosed on core needle biopsy, including patients who proceeded to surgical excision with a high-risk lesion on final histology.

Steroid Ligands, the Forgotten Triggers of Nuclear Receptor Action; Implications for Acquired Resistance to Endocrine Therapy.

Purpose: There is strong epidemiologic evidence indicating that estrogens may not be the sole steroid drivers of breast cancer. We hypothesize that abundant adrenal androgenic steroid precursors, acting via the androgen receptor (AR), promote an endocrine-resistant breast cancer phenotype.

Experimental Design: AR was evaluated in a primary breast cancer tissue microarray ( = 844).

A Randomized Clinical Trial Evaluating the Efficacy and Quality of Life of Antibiotic-only Treatment of Acute Uncomplicated Appendicitis: Results of the COMMA Trial.

Objective: Evaluate the efficacy and quality of life associated with conservative treatment of acute uncomplicated appendicitis.

Summary Background Data: Conservative management with antibiotics only has emerged as a potential treatment option for acute uncomplicated appendicitis. However the reported failure rates are highly variable and there is a paucity of data in relation to quality of life.

Altered Steroid Milieu in AI-Resistant Breast Cancer Facilitates AR Mediated Gene-Expression Associated with Poor Response to Therapy.

Divergent roles for androgen receptor (AR) in breast cancer have been reported. Following aromatase inhibitor (AI) treatment, the conversion of circulating androgens into estrogens can be diminished by >99%. We wished to establish whether the steroid environment can dictate the role of AR and the implications of this for subsequent therapy.

Correction to: Nongenomic oestrogen signalling in oestrogen receptor negative breast cancer cells: a role for the angiotensin II receptor AT1.

After the publication of this work [1] errors were noticed in the total protein loading controls for Figs. 1C, 2B, 3B and 4B.

Epigenome-wide SRC-1-Mediated Gene Silencing Represses Cellular Differentiation in Advanced Breast Cancer.

Despite the clinical utility of endocrine therapies for estrogen receptor-positive (ER) breast cancer, up to 40% of patients eventually develop resistance, leading to disease progression. The molecular determinants that drive this adaptation to treatment remain poorly understood. Methylome aberrations drive cancer growth yet the functional role and mechanism of these epimutations in drug resistance are poorly elucidated.

Network analysis of SRC-1 reveals a novel transcription factor hub which regulates endocrine resistant breast cancer.

Steroid receptor coactivator 1 (SRC-1) interacts with nuclear receptors and other transcription factors (TFs) to initiate transcriptional networks and regulate downstream genes which enable the cancer cell to evade therapy and metastasise. Here we took a top-down discovery approach to map out the SRC-1 transcriptional network in endocrine resistant breast cancer. First, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) was employed to uncover new SRC-1 TF partners.

Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

Background: The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.

Methods: Baseline tumour biopsies were available from 74 patients with HER2-positive breast cancer who were enrolled in the phase II TCHL neoadjuvant study (ICORG 10-05) assessing TCH (docetaxel, carboplatin, trastuzumab) (n = 38) versus TCL (docetaxel, carboplatin, lapatinib) (n = 10) versus TCHL (docetaxel, carboplatin, trastuzumab, lapatinib) (n = 40), each for six cycles.

S100β as a serum marker in endocrine resistant breast cancer.

Background: Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer. However, its efficacy is limited by intrinsic and acquired resistance. Here the potential of S100β as a biomarker and inhibition of its signaling network as a therapeutic strategy in endocrine treated patients was investigated.

Should serum calcitonin be routinely measured in patients presenting with thyroid nodule?

Background: The European Thyroid Association recommends serum calcitonin measurement in thyroid nodule cases. In contrast, the American Thyroid Association is ambivalent. In this institution, thyroid nodules cases are subject to a multidisciplinary evaluation of the clinical history and examination, ultrasound and scintigraphy, CT scan and sometimes MRI scan, biochemistry and histopathology of biopsies.

Utility of repeat cytological assessment of thyroid nodules initially classified as benign: clinical insights from multidisciplinary care in an Irish tertiary referral centre.

Background: Fine needle aspiration biopsy (FNAB) is the tool of choice for evaluating thyroid nodules with the majority classified as benign following initial assessment. However, concern remains about false negative results and some guidelines have recommended routine repeat aspirates. We aimed to assess the utility of routine repeat FNAB for nodules classified as benign on initial biopsy and to examine the impact of establishing a multidisciplinary team for the care of these patients.

Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors.

Purpose: Acquired resistance to aromatase inhibitor (AI) therapy is a major clinical problem in the treatment of breast cancer. The detailed mechanisms of how tumor cells develop this resistance remain unclear. Here, the adapted function of estrogen receptor (ER) to an estrogen-depleted environment following AI treatment is reported.

Paradigms lost-an emerging role for over-expression of tight junction adhesion proteins in cancer pathogenesis.

Tight junctions (TJ) are multi-protein complexes located at the apicalmost tip of the lateral membrane in polarised epithelial and endothelial cells. Their principal function is in mediating intercellular adhesion and polarity. Accordingly, it has long been a paradigm that loss of TJ proteins and consequent deficits in cell-cell adhesion are required for tumour cell dissemination in the early stages of the invasive/metastatic cascade.

Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy.

Purpose: Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumor cells to evade therapy and colonize distant organs remain unclear. We sought to characterize global expression changes occurring with metastatic disease progression in the endocrine-resistant setting.

Experimental Design: Here, for the first time, RNAsequencing has been performed on matched primary, nodal, and liver metastatic tumors from tamoxifen-treated patients following disease progression.

Parathyroid adenoma in a patient with familial hypocalciuric hypercalcaemia.

A 57-year-old man with symptoms of fatigue, joint pains and insomnia was found to have hypercalcaemia secondary to hyperparathyroidism with a corrected calcium of 2.61 mmol/L (2.2-2.

Ductal barriers in mammary epithelium.

Tissue barriers play an integral role in the biology and pathobiology of mammary ductal epithelium. In normal breast physiology, tight and adherens junctions undergo dynamic changes in permeability in response to hormonal and other stimuli, while several of their proteins are directly involved in mammary tumorigenesis. This review describes first the structure of mammary ductal epithelial barriers and their role in normal mammary development, examining the cyclical changes in response to puberty, pregnancy, lactation and involution.

Global gene repression by the steroid receptor coactivator SRC-1 promotes oncogenesis.

Transcriptional control is the major determinant of cell fate. The steroid receptor coactivator (SRC)-1 enhances the activity of the estrogen receptor in breast cancer cells, where it confers cell survival benefits. Here, we report that a global analysis of SRC-1 target genes suggested that SRC-1 also mediates transcriptional repression in breast cancer cells.

A novel mechanism of regulating breast cancer cell migration via palmitoylation-dependent alterations in the lipid raft affiliation of CD44.

Introduction: Most breast cancer-related deaths result from metastasis, a process involving dynamic regulation of tumour cell adhesion and migration. The adhesion protein CD44, a key regulator of cell migration, is enriched in cholesterol-enriched membrane microdomains termed lipid rafts. We recently reported that raft affiliation of CD44 negatively regulates interactions with its migratory binding partner ezrin.

A comparison of intra-operative margin management techniques in breast-conserving surgery: a standardised approach reduces the likelihood of residual disease without increasing operative time.

Introduction: Breast-conserving surgery (BCS) is established as a standard treatment option for women with early-stage invasive breast cancers. Margin status predicts local disease recurrence. Up to 59 % of patients may undergo re-excision of their tumour cavity to establish clear margins.

Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration.

Cancer cell migration is an early event in metastasis, the main cause of breast cancer-related deaths. Cholesterol-enriched membrane domains called lipid rafts influence the function of many molecules, including the raft-associated protein CD44. We describe a novel mechanism whereby rafts regulate interactions between CD44 and its binding partner ezrin in migrating breast cancer cells.