Neuroendocrine tumours (NET) of the breast are rare. Diagnosis depends on close scrutiny of core- or excisional-biopsy specimens for characteristic growth patterns (papillary, nesting or mixed), which should trigger immunohistochemical staining for neuroendocrine markers (in particular chromogranin and synaptophysin). The diagnosis is confirmed if a) >50% of the tissue specimen demonstrate neuroendocrine markers and b) in-situ ductal carcinoma is identified and/or imaging modalities exclude extra-mammary sites. Our literature search including the non-English literature identified 66 articles with data on 123 cases, including our own. Oestrogen receptors are not diagnostic for NET's of the breast as they are found in tumours of non-mammary origin, too. Half of reported cases of neuroendocrine tumours have axillary lymph node involvement. Breast-conserving surgery (wide local excision ± axillary clearance) is commonly performed for suitable tumours. Chemotherapy regimens utilised are commonly either platinum- (as for small-cell cancers) or anthracycline-based (as for primary breast cancers). Best management remains unknown.

IntroductionThe automated breast volume scanner (ABVS) is the fi rst of its kind and utilises a large, 17 cm × 15 cm high-frequency ultrasound probe which sweeps across the whole breast generating images that can be reformatted into multiple planes and a 3D volume. ABVS will change breast ultrasound practice by: introducing operator standardisation, reproducibility and repeatability of measurement and interpretation; changing who acquires the volume set and how breast ultrasounds are reported; and allowing accurate comparison of previous and current examinations for screening and assessing treatment change. Methods Patients presented to the symptomatic clinic for conventional 2D ultrasound assessment with a variety of conditions. An additional ABVS was performed. Results Cases were classifi ed into: benign -for example, cysts, fi broadenomas, diabetic mastopathy; and malignant. Conclusion We present a review of our initial experience and highlight its advantages over conventional ultrasound, which include: improved mapping of lesions enabling more accurate future assessment and follow-up, and improved assessment of distortion over conventional 2D ultrasound. Further research is required to explore other potential benefi ts. Introduction A study of symptomatic breast units geographically spread over Ireland collected image quality, compression and radiation dose data from 18 mammography units; so how do these optimisation parameters compare nationally and internationally? The mean glandular dose (MGD) diagnostic reference level was proposed for the all-digital breast screening service [1] but not for the symptomatic breast service. Methods The quantitative and qualitative data were analysed using SPSS. Recommendations of MGD diagnostic reference levels were made at various levels for fi lm-screen mammography (FSM) and full-fi eld digital mammography (FFDM) units to match those levels published in worldwide. O2 Symptomatic breast services inResults MGDs received by symptomatic breast patients within Ireland are higher than those received in the all-digital Irish Breast Screening service, although the diff erences for FFDM are not substantial; 55 to 65 mm breast: 1.75 mGy (screening) versus 2.4 mGy (symptomatic) at the 95th percentile. The four-view routine mammography MGDs obtained in symptomatic breast units in Ireland are, however, substantially diff erent from other screening units with mixed FSM/FFDM modalities: 4.5 mGy (UK); 4.98 mGy (USA) versus 5.96 mGy (FFDM, symptomatic) and 9.63 mGy (FSM, symptomatic). Various reasons are proposed for the diff erences. Conclusion MGD diagnostic reference levels achieved in the screening service may be lower due to the exacting requirements for radiographer training, nonsurgical alteration of patient breasts and equipment quality assurance levels. Greater training of radiographers performing mammography in the symptomatic breast services is required to standardise mammographic projections with regard to MGDs delivered. Reference O3Correlations between shear wave elastog...

Background: Recently the FDA has withdrawn the indication for bevacizumab in metastatic breast cancer after several clinical studies failed to demonstrate an overall survival benefit. These studies however did report an increase in response rates to chemotherapy and improvement in progression free survival, suggesting a pattern of response to the drug followed by the development of resistance. We have little knowledge of the molecular mechanisms driving the development of resistance to bevacizumab. To better understand these mechanisms, we have conducted a window of opportunity study using a single cycle of bevacizumab with detailed pharmacodynamic assessments using gene expression arrays and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods: After ethical approval, 47 newly diagnosed locally advanced breast cancer patients were prospectively enrolled in this trial. Patients received single dose bevacizumab (15mg/ kg) 2 weeks prior to neoadjuvant chemotherapy and underwent core biopsies for gene expression and immunohistochemistry analysis and DCE-MRI scans before and 2 weeks after bevacizumab. 35 patients who had invasive ductal carcinoma together with good quality MRI scans and core biopsies before and after bevacizumab were included in this analysis. Pharmacokinetic (PK) modelling techniques were used to quantify PK parameters (Ktrans, kep, ve) from the DCE-MRI data. Gene expression profiling was performed using the Affymetrix Human Exon 1.0 ST arrays. Results: The majority of patients (28/35) showed a significant reduction in vessel permeability and blood flow of at least 30% following bevacizumab, with a mean decrease in the forward transfer constant (P < 0.0001) and the reverse rate constant kep (P < 0.0001). From gene expression and immunohistochemistry analyses, we identified several key metabolism-related genes that are significantly up-regulated after bevacizumab treatment, including pyruvate dehydrogenase kinase isozyme 1 (PDK1) (fig.1) and carbonic anhydrase 9 (CA9). In addition, we found a number of interesting genes that are down-regulated after bevacizumab treatment, including sulfatase-1 (SULF1), and cyclin E1 (CCNE1). Discussion: This study highlights that the combination of DCE-MRI and gene expression arrays can lead to an improved understanding of the molecular mechanisms governing response and resistance to anti-angiogenic therapy. Heterogeneity of response to bevacizumab was demonstrated, with some tumours showing increases or no change in Ktrans and others marked reductions, which may be of value in early stratification for therapy maintenance. Furthermore, the gene expression analysis showed activation of pathways, which could contribute to the development of resistance. For example, we observed significant up regulation of genes involved in regulating the switch from mitochondrial metabolism to glycolysis, such as PDK1. This suggests that using bevacizumab with the other targeted agents such as Dichloroacetate, a PDK1 inhibitor might be helpful in overcoming the development of resistance and ultimately lead to improved patient survival. Our preclinical studies strongly support this possibility. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-06-01.

Background: Anti-angiogenic therapy holds much promise for the treatment of breast cancer. In practice however, only a subset of patients who receive these drugs demonstrate a significant response to therapy. A key challenge therefore is to elucidate markers that are predictive of response to anti-angiogenic agents such as bevacizumab, and which would enable the selection of patients who would get the most benefit from these expensive therapies. Materials and Methods: We used high temporal resolution dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess tumor vascularity in 20 patients with primary breast cancer. Patients were imaged both before and two weeks after single dose Bevacizumab therapy (15mg/kg). Pharmacokinetic modelling techniques were used to quantify the volume transfer constant Ktrans, the rate constant kep, and the fractional volume of the extra-vascular extracellular space ve. Specifically, we used Tofts model with a population-based arterial input function (modified Fritz-Hansen) to model the contrast agent concentration time courses on a voxel-wise basis. Non-enhancing voxels were detected automatically with the use of a Bayesian noise model, and the corresponding pharmacokinetic parameter values for these voxels were set to zero. The median pharmacokinetic parameter values over the tumor volumes of interest were then computed both pre-and post Bevacizumab. Results: We found marked variation across patients in the baseline level and percentage change in median Ktrans, kep and ve following Bevacizumab. In particular, median Ktrans at baseline ranged form 0.12 to 0.88. Changes in median Ktrans varied from −97% to +19% across all patients, with an average change of −49%. Notably, we found a highly significant negative correlation (r = −0.92, P = 1e-08) between the absolute change in median Ktrans and the median Ktrans at baseline. In particular, tumors with a high median Ktrans at baseline demonstrated the greatest change in Ktrans following Bevacizumab therapy, whereas tumors with low median Ktrans at baseline demonstrated relatively little change in Ktrans. Discussion: Although Ktrans is a complex function of vessel permeability, surface area, and tumor blood flow, it has previously been demonstrated to be a reliable biomarker of response to anti-angiogenic therapy in a number of different cancers. Our results illustrate that therapy-induced changes in Ktrans can be predicted from the value of Ktrans at baseline, and hence DCE-MRI scans may enable the selection of primary breast cancer patients who show the greatest response to single-dose Bevacizumab therapy. Whether this will translate into longer term benefit and improvements in outcome for patients remains to be shown. The relationship between baseline and pre-/post-therapy change in Ktrans with the corresponding changes in gene expression is currently under study in a larger number of patients. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-02-07.

Background: Bevacizumab is an approved drug for advanced breast cancer alongside chemotherapy. To date there is no biomarker proven to be effective in patient stratification. To address this, a window of opportunity study was designed where bevacizumab is administered as a short-term first line treatment with a detailed pharmacodynamic assessment to identify the patients who are most likely to benefit from this therapy. This assessment consisted of Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) and gene expression analysis. Method: This is an on going two-centre, Phase II, non-randomised study. 43 locally advanced breast cancer patients aged >18 years, with performance status 0-1 who have adequate bone marrow, renal and liver functions have been enrolled. A single infusion of bevacizumab (15mg/kg) was given prior to commencement of neoadjuvant chemotherapy. DCE-MRI and core biopsies for exon gene array analysis were performed both at baseline and 2 weeks after bevacizumab. Pharmacokinetic modelling of DCE-MRI was used to quantify the volume transfer constant Ktrans, the rate constant kep, and the fractional volume of the extra-vascular extracellular space ve. The median pharmacokinetic parameter values over the tumour volumes of interest were then computed both pre-and post-bevacizumab. Results: Our initial gene expression analysis from 21 patients showed a high variability in the response. This was true for both single gene analysis and pathway signatures. In particular the expression fold changes of hypoxia and proliferation signatures after bevacizumab ranged from a minimum of 0.6 fold decrease to a maximum of 4.3 fold increase. Interestingly, fold changes in both these signatures were significantly positively correlated (Spearman rho=0.81, P<0.001). Changes in the proliferation signature were significantly inversely correlated with changes in mean and median ve (rho=-0.57, P<0.01 in both cases). Changes in the hypoxia signature were significantly inversely correlated with changes in mean and median kep (rho=-0.48, p=0.03 and rho=-0.58, p=0.007 respectively). Significantly over-represented pathways amongst genes up-regulated after bevacizumab were T-cell activation, inflammation, PDGF and apoptosis signalling. Discussion: Our initial results provide several potentially important avenues for further research, which may be useful in the identification of new therapeutic approaches. For example, the unexpected correlation of induction of hypoxia and proliferation in the same tumours has important implications for combination therapy. Furthermore, patients whose tumours showed the largest reduction in kep, a measure of vascular leakiness, also showed the greatest increase in hypoxia. In addition, patients who experienced the largest reduction in ve showed the highest fold change in proliferation. Although these results are preliminary and will need to be confirmed at study completion, they illustrate how the integrated analysis of DCE-MRI pharmacokinetic parameters and the corresponding gene expression profiles may enable an improved understanding of the mechanisms governing response and resistance to bevacizumab. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-28.