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Background: oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. Methods: all available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67 2wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. Findings: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 2wk (p2wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. Interpretation: our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. Funding: Cancer Research UK (CRUK/07/015).

Background Approximately 5,000 patients undergo breast reconstruction annually in the United Kingdom ( 2:1 ratio of immediate versus delayed respectively). Whilst skin sparing mastectomy is an accepted modality for local control in appropriately selected patients, nipple preservation remains controversial. In over 1,800 peer reviewed nipple sparing mastectomy (NSM) cases, the local event rate attributable to NAC preservation following NSM (therapeutic and prophylactic) is 0.16% with no evidence of deleterious impact on disease free survival. This study aims to evaluate in a selected cohort of patients, the oncological safety and aesthetic outcome of nipple- sparing mastectomy and immediate breast reconstruction (IBR). We highlight the surgical technique used and propose in/exclusion criteria. Material and Methods: Patients were identified retrospectively from our Institution's electronic patient records and WinPath™ database by searching clinical codes corresponding to NSM & IBR, performed by the senior authors (IJL and RD) between January 2004 and December 2008. Pre-operative selection criteria included: 100% pre-operative lesion characterisation; 5mm margin acceptance; submission of separate nipple core specimens for paraffin block histological assessment and re-excision of all involved/close margins. Follow-up data was verified from patients’ case notes, histo- pathological review and standardised photographic views. Endpoints include: local recurrence rate, disease free survival, peri-operative NAC subcutaneous tissue loss and validated aesthetic outcome measures. Results*: 84 patients underwent NSM & IBR for invasive disease. The mean age was 52.1 years and a median follow-up of 38 months. IBR utilised autologous tissue (latissimus dorsi or transverse rectus abdominus musculocutaneous flaps) with/without implant prosthesis. There was one case of local recurrence (1.2%) in a patient who declined re-excision of close/involved margins and no recorded breast cancer related deaths. Peri-operative complication rates were within the national mastectomy breast reconstruction audit outcome guidelines. Conclusion: In this cohort of patients, nipple sparing mastectomy and immediate breast reconstruction achieves comparable oncological outcomes with excellent aesthesis relative to traditional ablative procedures for local control. Nipple preservation although not evaluated independently does enhance cosmetic outcomes. *(Preliminary analysis) Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-16-16.

Background. Latissimus dorsi breast reconstruction has problems with scars at the donor site and on the reconstructed breast. We report the feasibility and aesthetic results of Envelope Mastectomy and Immediate Reconstruction (EMIR), which utilises a single lateral mammary fold incision. Patients and methods. Between 2001 and 2002, 20 EMIRs were performed in 19 patients, one as a staged bilateral procedure. Twenty consecutive patients, matched for body habitus, who had undergone standard latissimus dorsi breast reconstruction by the same surgeon from 1996 to 2000 were used as controls. Patient satisfaction was assessed using a validated Body Image Scale. Standard post-operative photographs were scored by three independent observers. Results. Length of stay and complication rates were equivalent between both groups. Cosmetic self-assessment scores on the Body Image Scale and scores by the independent observers were satisfactory for both groups but no statistically significant difference was observed between groups. Conclusions. EMIR is a technically feasible and cosmetically acceptable method of immediate breast reconstruction.

Normal human breast tissue maintained as xenografts in female Balb/c (nu/nu) athymic mice is capable of metabolising N-nitrosodimethylamine (NDMA) to active intermediates that will react with DNA. Administration of NDMA to mice with slow-release implants of 17 beta-oestradiol which provide human physiological (luteal phase) circulating oestrogen levels and increase cell proliferation in the xenograft (Laidlaw et al., 1992), leads to an apparent increase in the extent of reaction with DNA compared to controls without oestrogen implants. In mice with oestrogen implants, measurements of the amounts of the promutagenic lesion, O6-methyl-2'-deoxyguanosine formed in DNA clearly indicated a dose related increase in the extent of reaction. Detection of O6-methyl-2'-deoxyguanosine using immunohistochemical procedures revealed that the nuclei of cells of the glandular epithelium, supportive tissue and adipose tissue, in decreasing order of prevalence, were positively stained for the presence of this DNA lesion. Epithelial cells, which are the putative target cells for carcinogenesis in the breast, are therefore prone to promutagenic damage as a result of exposure to an environmental nitrosamine. Images Figure 2 Figure 3

Astronomical Telescopes and Instrumentation, 2002, Waikoloa, Hawai'i, United States, Series: Proceedings of SPIE; no. 4855

We report here the results of experiments investigating the effects of oestradiol (E2)and progesterone (Pg) alone or in combination upon human breast epithelial cell proliferation together with steroid receptor, growth factor and growth factor receptor expression.

In order to resolve the question of which ovarian steroid stimulates normal human mammary epithelial cell proliferation, we have implanted pieces of normal human breast tissue subcutaneously into athymic nude mice. These mice were then treated with slow-release pellets containing estradiol (E2) or progesterone (P) such that serum levels of E2 and P were increased to those seen in normal women. The proliferative activity of the tissue implants was assessed by uptake of tritiated thymidine and steroid receptor expression was measured immunocytochemically. Insertion of a 2 mg E2 pellet 14 days after tissue implantation increased the thymidine labeling index (TLI) from a median of 0.4% (n = 34) to a median of 2.1% after 7 days (n = 43; P < 0.001 by Mann Whitney U test). In contrast, treatment with a P pellet (4 mg) had no effect upon the TLI whereas P (4 mg) in combination with E2 (2 mg) had no effect over and above that of E2 alone. There was a significant correlation between the increase in TLI and either the E2 content of the pellets (P < 0.001 by linear regression) or the serum E2 levels achieved (P < 0.001). Expression of the P receptor was increased 15- to 20-fold by E2 treatment. We conclude that E2 is sufficient to stimulate human breast epithelial cell proliferation at physiologically relevant concentrations and that P does not affect proliferation either alone or after E2 priming.

Introduction Involved margins in breast-conserving surgery (BCS) are associated with increased risk of local recurrence. In our institution, it is our practice to remove extra adjacent margins of tissue at the time of primary operation if the surgeon feels that tumour excision is incomplete. The aim of this study was to determine the proportion of necessary versus unnecessary intra-operative extra margin excisions and to determine whether there is any patient or pathological factors associated with making a correct decision. Methods Retrospective study of patient records and pathology reports, for 100 consecutive patients undergoing BCS for primary breast cancer at our institution, from 2011-2012. Statistical analysis was performed using Student’s t-test, chi-squared test and a logistic regression model. Results 66% of all patients had extra tissue removed for suspected involved or close margins. The decision to take extra tissue was correct in 48%. As a result, further surgery was prevented in 53% of these patients. Appropriate extra margin excision was significantly associated with younger patient age (P Conclusions Removing the entire tumour with adequate margins in BCS prevents subjecting a patient to further surgery. Conversely, unnecessarily removing uninvolved extra tissue at primary operation in an attempt to prevent re-operation, may impact negatively on breast cosmesis and increases the workload for the Pathologist. This study suggests that older patients, those with small tumours and invasive as opposed to in situ disease are more likely to have extra margins removed unnecessarily. Larger scale studies may help to clarify how we can select patients more accurately for intra-operative margin excision. Disclosure All authors have declared no conflicts of interest.

Objective To determine the identification and the percentage of the false negative of the sentinel nodes in patients with early breast cancer Hospital La Linea, during the period 2007 to 2010. Methods We collect fifty patients with early breast cancer, without clinical and ultrasonographic involvement of axillary nodes, from November 2007 to September 2010. We use the vital dye in the first twenty patients, and the combined technique with vital dye and albumin labeled with technetium 99 in the other thirty patients. The site of injection for patients who use blue dye was the subdermal near to the tumor, and to the patients who use the technetium was the periareolar technique. The sentinel node biopsy was examined during the surgery. The sentinel node was cut through its long axis and then with fine cuts of 250 microns, with freezing technique. The axillary dissection was completed in the first seventeen patients, and in the remaining patients we performed total axillary dissection if the sentinel node was positive for metastasis. Results Sentinel nodes were identified in 49 of 50 patients (98%), procedures. The only case where we did not identify the sentinel node was a patient in the combined technique. The percentage of nodes identified in the patients with vital dye was one sentinel node, and in the patients who use technetium the percentage was two sentinel nodes. The false negative rate was 8% (4 patients), in three of them we found a micrometastasis in the final examination, in the other one we found a macrometastasis. This cases of false negative in the sentinel node biopsy occurred at the beginning of the study. Pathologists acquired a learning curve for sentinel node examination, and practiced subsequently fine cuts in the intraoperative examination of the sentinel node. Conclusion This experience indicates that intraoperative examination of sentinel node biopsy is crucial for staging of the axilla. The rate of identification of sentinel node is excellent and with the use of the technetium the technique is more accurate. The improvement in the learning curve about the intraoperative examination of the sentinel node biopsy has decreased our rates of false negatives. Disclosure All authors have declared no conflicts of interest.

s / International Journal of Surgery 10 (2012) S1–S52 S15 ABSTRACTS 1127: INTRA-OPERATIVE RE-EXCISION OF MARGINS IN BREASTCONSERVING SURGERY: HOW WELL ARE WE ABLE TO JUDGE TUMOUR PROXIMITY? Lorna Cook, Debasish Debnath, Zoe Lin, Raouf Daoud, Isabella Karat, Ian Laidlaw. Frimley Park Hospital, Frimley, UK Introduction: In breast-conserving surgery (BCS), specimen margin involvement with tumour often necessitates re-operation. For this reason, extra margins are often taken at the time of primary operation. The aim of this study was to determine how often such re-excisions are appropriate. Methods: The records of 100 consecutive patients undergoing BCS for cancer during 2011 were analysed. Data was collected on demographics, tumours characteristics, surgery performed and final histology. Results: All 100 patients were female, median age 56 years (range 33-83 years). 66% had intra-operative re-excision of margins. In 26/66 (40%), re-excision was the correct decision. 25 of the 34 patients who had no extramargins taken at all were managed appropriately with the remaining 9 patients having close/positive margins. Unnecessary re-excisions were performed in 40/66 patients. The correct intraoperative decision was therefore made in 51% of patients. Conclusion: The decision regarding intra-operative margin re-excision was appropriate in just over half of all cases and a second operation was avoided in 26%. However, in order to preserve as much uninvolved breast tissue as possible, further work should be done on methods to improve accuracy and to determine whether there are any patient, radiological or pathological predictors to guide intra-operative re-excision. 1181: FACTORS PREDICTING POSITIVE MARGIN STATUS IN BREAST CANCER PATIENTS UNDERGOING BREAST CONSERVING SURGERY Euan Harris , Andrew Lee . University of Dundee, Dundee, Tayside, UK; Abertawe Bro Morgannwg University Healthboard, Swansea, West

An assay to measure the ability to stimulate migration of fibroblasts into collagen gel was carried out on serum from treated and untreated breast cancer patients and from healthy controls. Migration stimulating activity was found in the serum of 10 (83%) of 12 untreated breast cancer patients immediately before surgical resection of the primary tumour and in 9 (75%) of them 4 days after resection; in 13 (93%) of 14 patients 1-13 years after tumour resection who had received adjuvant treatment; and in 2 (10%) of 20 healthy women matched for age. The migration stimulating activity in cancer patients' serum was indistinguishable from the migration stimulating factor produced in vitro by fetal and cancer patient skin fibroblasts in its behaviour in various biochemical fractionation procedures. The presence of this activity in the serum of treated breast cancer patients clearly distinguishes it from other oncofetal proteins, which all seem to be produced by tumours.

Tamoxifen has been used for the treatment of early and advanced breast cancer for over 20 years. Because of its clinical effectiveness [1] and low side-effect profile, it has become the treatment of first choice for patients with locally advanced and metastatic breast cancer. Phase III clinical trials indicate that it is as effective as older treatments, for example, oe- strogens [2], but has fewer side effects. In premenopausal women, treatment with tamoxifen is equivalent in effectiveness to oophorectomy [3].

Electrocardiograms, biochemical parameters, and drug histories were reviewed in 37 patients with anorexia nervosa. Prolongation of the Q-T interval was identified in 24%, sinus bradycardia in 41%, and low voltage in 11% of our study population. Hypocalcemia was identified in none of our patients, hypomagnesemia in one, and hypokalemia in nine. Hypokalemia was more frequent (67%) and marked in patients with Q-T prolongation than in those with normal Q-T intervals (11%). Bulimic tendencies were more frequent in anorexics with Q-T prolongation and were associated with hypokalemia. Q-T prolongation when present was usually mild. One patient had documented ventricular fibrillation associated with hypokalemia and the longest Q-T interval encountered in our group (G-Qc = 0.54 seconds). Patients with severe anorexia nervosa should be screened for hypokalemia and Q-T prolongation, particularly if bulimic tendencies are present. Although Q-T prolongation associated with weight loss due to dieting, starvation, and gastroplasty is not commonly associated with hypokalemia, such may not be the case with anorexia nervosa.

This study aimed to investigate the effect of tamoxifen on breast tumour levels of oestrogen and progesterone receptor (ER and PR) and proliferation as defined by the Ki67 antibody. A group of primary breast cancer patients was randomised to receive either tamoxifen (n = 59) or placebo (n = 44) treatment in the interval between clinic and surgery (median 21 days). Frozen sections of breast tumour biopsies obtained before and after treatment were stained immunocytochemically to obtain the percentage of nuclei containing ER and PR, and a Ki67 labelling index (LI). Tamoxifen-treated patients had a median Ki67 LI of 5.6% in the first biopsy falling to 3.0% in the second biopsy (P < 0.001 by Wilcoxon's matched pairs test), whereas placebo-treated patients had a median Ki67 LI of 5.4% in the first biopsy and 5.75% in the second (no significant difference). No significant differences were observed when the median %ER or %PR staining before and after treatment were compared. The Ki67 LI tended to increase with increasing histological grade and was greater in tumours that were ER - ve compared to those that were ER + ve (> 5% nuclei stained), median 7.8% and 4.3% respectively (P = 0.011 by Mann-Whitney U-test). However, the decline in tumour Ki67 LI following anti-oestrogen treatment failed to correlate with ER and PR status or to predict recurrence over a short follow-up period. To our knowledge, this is the first time that tamoxifen treatment has been shown to reduce the Ki67 LI in human breast tumours in vivo. These data indicate that staining with the Ki67 antibody may be useful in monitoring response to anti-oestrogen therapy.