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Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses. POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0–1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing. Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1–74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75–1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9–92·0) for patients in the POAI group and 90·4% (88·7–91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported. POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical–pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies. Cancer Research UK.

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors. Defects in homologous recombination (HR) are found in some triple negative breast cancers, suggesting they may be sensitive to PARP inhibitors. In this phase II clinical trial of the PARP inhibitor rucaparib, changes in Ki67 levels did not correlate with markers of HR deficiency but HR deficiency was detected in 69% of tumours, indicating that PARP inhibitors may be a useful treatment.

Reports of the presence of acrylamide in a range of fried and oven-cooked foods have caused worldwide concern because this compound has been classified as probably carcinogenic in humans. Here we show how acrylamide can be generated from food components during heat treatment as a result of the Maillard reaction between amino acids and reducing sugars. We find that asparagine, a major amino acid in potatoes and cereals, is a crucial participant in the production of acrylamide by this pathway.

Background: Excessive sodium intake is a major modifiable risk factor for cardiovascular disease, yet accurately assessing dietary sodium remains challenging due to food composition variability and inaccurate menu labeling. While menu labels are intended to guide consumers, discrepancies between reported and actual sodium content could undermine their effectiveness. Objective: To evaluate the accuracy of menu-declared sodium content in takeaway foods by comparing reported values with laboratory measurements. Design: A cross-sectional analysis of 39 takeaway food items from 23 outlets in Reading, UK. Sodium content was measured using Inductively Coupled Plasma – Mass Spectrometry (ICP-MS) and compared to menu-declared values. Results: Sodium content varied widely across food categories. Median sodium levels ranged from 0.1 g/100g (chips from fish & chips shop) to 1.6 g/100g (pizza), with some meals exceeding the 6 g/day recommended intake in a single serving. Curry dishes exhibited the greatest variability (2.3–9.4 g per dish). Significant discrepancies were found between menu-reported and measured sodium levels, with almost 50% of foods exceeding declared values. Conclusion: Take-away foods exhibit substantial sodium variability, and menu labels often fail to accurately reflect actual sodium content. These findings have implications for nutritional epidemiology, where inaccurate sodium estimates may misclassify intake, and for public health, as misleading labels could hinder sodium reduction efforts. It is therefore important that menu labels are not considered definitive but rather general indicators of sodium content and potentially other nutrients.

Reports of the presence of acrylamide in a range of fried and oven-cooked foods have caused worldwide concern because this compound has been classified as probably carcinogenic in humans. Here we show how acrylamide can be generated from food components during heat treatment as a result of the Maillard reaction between amino acids and reducing sugars. We find that asparagine, a major amino acid in potatoes and cereals, is a crucial participant in the production of acrylamide by this pathway.

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2–ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

Purpose Ki67 assessed at diagnosis (Ki67 baseline ) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki67 2week ) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki67 2week ) with recurrence-free survival. The aim was to define the association between Ki67 baseline and after aromatase inhibitor (AI) exposure ∆Ki67 2week and Ki67 2week with key prognostic and biologic factors utilising data from the POETIC study. Patients and methods In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks’ presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression. Results Established associations of Ki67 baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67 baseline . In control group Ki67 2week was 18% lower than Ki67 baseline (p < 0.001) when Ki67 2week was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki67 2week ) was 79.3% (IQR: −89.9 to −54.6) and 53.7% (IQR: −78.9 to −21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type. Conclusions The magnitude of this study allowed characterisation of relationships between Ki67 baseline , ∆Ki67 2week and Ki67 2week with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki67 2week or Ki67 2week is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies .

Inter‐observer concordance data for the HER2 category as assessed by a group of 16 specialist breast pathologists on 50 diagnostic core biopsies was compared with that produced by digital image analysis (DIA) using the HER2 APP, CE2797 (VP APP; Visiopharm, Hoersholm, Denmark). Comparing pathologists' consensus scores and DIA scores, 36 cases (73.5%) agreed. Fleiss' kappa statistic was 0.433 (indicative of moderate agreement). Cohen's weighted kappa was used to compare the scores of individual raters to consensus scores; for all 50 cases the kappa scores had a range between 0.412 and 0.854; the VP APP was ranked 12th of 17 raters (kappa score 0.638 indicating substantial agreement). Results for HER2‐low cases ( N  = 44) showed a kappa score range of 0.295 to 0.823; the VP APP ranked 12th of 17 (score 0.535 indicating moderate agreement). For high agreement cases the kappa score range was 0.664 to 1.000 for all HER2 scores ( N  = 24) and the VP APP scored 0.916 (indicating almost perfect agreement). For the HER2‐low scores ( N  = 20), the kappa score range was 0.506–1.000 and the VP APP scored 0.860 (almost perfect agreement). DIA of the proportions of tumour cells showing expression within each of the HER2 categories demonstrated that the majority of cases showing a low level of agreement between pathologists showed heterogeneity and/or a level of expression close to a cut‐point for decision making. This study demonstrates that the VP APP produces results that are extremely well‐aligned to those of expert pathologists in cases with good overall agreement, and in difficult cases its reproducibility will outperform that of the visual scorer. The results also suggest that use of the VP APP has the potential to reduce the proportion of cases referred for gene amplification testing by reducing the number of cases incorrectly classified as HER2 2+.

Background Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance. Methods Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI ( n  = 198) or no presurgical treatment (control n  = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67. Results High baseline ESR1 expression associated with better AI response in HER2+ tumours but not HER2− tumours. In HER2− tumours, baseline expression of 48 genes associated with poor antiproliferative response ( p  < 0.005) including PERP and YWHAQ , the two most significant, and the transcription co-regulators ( SAP130 , HDAC4 , and NCOA7 ) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling ( ERBB2-GS , RET/ GDNF-GS , and IGF-1-GS ), and immune activity ( STAT1-GS ) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2− and HER2+ patients. Conclusions There is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors. Trial registration ISRCTN, ISRCTN63882543 , registered on 18 December 2007.

Intestinal epithelial cells migrate from the base of the crypt to the villi where they are shed. However, little is known about the cell shedding process. We have studied the role of apoptosis and wound healing mechanisms in cell shedding from human small intestinal epithelium. A method preparing paraffin sections of human small intestine that preserves cell shedding was developed. A total of 14 417 villus sections were studied. The relationship of cell shedding to leukocytes (CD45), macrophages (CD68) and blood vessels (CD34) were studied by immunohistochemistry. Apoptotic cells were identified using the M30 antibody against cleaved cytokeratin 18 and an antibody against cleaved caspase-3. Potential wound healing mechanisms were studied using antibodies against Zona Occludens-1 (ZO-1) and phosphorylated myosin light chains (MLCs). We found that 5.3% of villus sections contained a shedding cell. An eosin-positive gap was often seen within the epithelial monolayer beneath shedding cells. Shedding was not associated with leukocytes, macrophages or blood vessels. Cells always underwent apoptosis during ejection from the monolayer. Apoptotic bodies were never seen in the monolayer but morphologically normal cells that were positive for M30 or cleaved caspase-3 were often seen. ZO-1 protein was usually (41/42) localized to the apical pole of cells neighboring a shedding event. Phosphorylated MLCs could be identified in 50% of shedding events. In conclusion, cell shedding is associated with apoptosis though it remains unclear whether apoptosis initiates shedding. It is also associated with phosphorylation of MLCs; a process associated previously with wound healing.