Background Use of biological or synthetic mesh might improve outcomes of immediate implant-based breast reconstruction-breast reconstruction with implants or expanders at the time of mastectomy-but there is a lack of high-quality evidence to support the safety or effectiveness of the technique. We aimed to establish the short-term safety of immediate implant-based breast reconstruction performed with and without mesh, to inform the feasibility of undertaking a future randomised clinical trial comparing different breast reconstruction techniques. Methods In this prospective, multicentre cohort study, we consecutively recruited women aged 16 years or older who had any type of immediate implant-based breast reconstruction for malignancy or risk reduction, with any technique, at 81 participating breast and plastic surgical units in the UK. Data about patient demographics and operative, oncological, and complication details were collected before and after surgery. Outcomes of interest were implant loss (defined as unplanned removal of the expander or implant), infection requiring treatment with antibiotics or surgery, unplanned return to theatre, and unplanned re-admission to hospital for complications of reconstructive surgery, up to 3 months after reconstruction and assessed by clinical review or patient self-report. Follow-up is complete. The study is registered with the ISRCTN Registry, number ISRCTN37664281. Findings Between Feb 1, 2014, and June 30, 2016, 2108 patients had 2655 mastectomies with immediate implant-based breast reconstruction at 81 units across the UK. 1650 (78%) patients had planned single-stage reconstructions (including 12 patients who had a different technique per breast). 1376 (65%) patients had reconstruction with biological (1133 [54%]) or synthetic (243 [12%]) mesh, 181 (9%) had non-mesh submuscular or subfascial implants, 440 (21%) had dermal sling implants, 42 (2%) had pre-pectoral implants, and 79 (4%) had other or a combination of implants. 3-month outcome data were available for 2081 (99%) patients. Of these patients, 182 (9%, 95% CI 8-10) experienced implant loss, 372 (18%, 16-20) required re-admission to hospital, and 370 (18%, 16-20) required return to theatre for complications within 3 months of their initial surgery. 522 (25%, 95% CI 23-27) patients required treatment for an infection. The rates of all of these complications are higher than those in the National Quality Standards (< 5% for re-operation, re-admission, and implant loss, and < 10% for infection). Interpretation Complications after immediate implant-based breast reconstruction are higher than recommended by national standards. A randomised clinical trial is needed to establish the optimal approach to immediate implant-based breast reconstruction. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.

Introduction: The practice of breast surgery in the UK has evolved considerably in recent years, with fewer breast surgeons offering general surgery (GS) on-call. The aim of this paper was to evaluate the degree of specialisation required by employers and the preferences of current and future surgeons.

Background: Further to the successful adoption of the ERAS (Early Recovery After Surgery) pathways in specialities such as colorectal surgery, there is emerging evidence supporting its use in breast surgery including identification of components of ERAS applicable to oncoplastic breast surgery.

Background: This pilot study aimed to test the possibility of therapeutic benefit imparted by early intervention based on sequential tumour marker (TM) measurements during follow-up of primary breast cancer (PBC) patients.Methods: Patients with oestrogen receptor positive PBC with no clinical and/or radiological evidence of metastases were recruited and followed-up 3-monthly with clinical assessment and TM (CA15.3 and CEA) measurements. The clinical team was blinded to the TM results. Asymptomatic patients who developed raised TMs (based on pre-defined cut-offs) were randomised to either `treatment change' (either start or change of adjuvant endocrine agent to another agent) or `no change' (control). Patients who developed symptomatic metastases came off the study. The primary and secondary endpoints were intervals from randomisation to symptomatic metastases and to last follow-up/death respectively.Results: Eighty-five patients (median age - 54 years (30-72)) were recruited with a median follow-up of 81 months (1-124). Sixteen patients were randomised as described. There was no significant difference (treatment change versus no change) with regards to interval from randomisation to symptomatic metastases - 23 (2-62) and 22 (1-63) months respectively (p = 0.9), as well as interval from randomisation to last follow-up/death - 36 (7-63) and 37 (10-63) months respectively (p = 0.9).Conclusions: Despite long follow-up (up to 10+ years), this small study has thus far shown no significant difference in outcome. However, we have confirmed the feasibility of this study design but a larger study will be required to show if there is a benefit to this apporach. (C) 2014 Elservier Ltd. All right reserved.

639 Background: This study was initiated to pilot the concept of early therapeutic intervention based on sequential TM measurements in patients during follow-up for PBC. Methods: Patients with oestrogen receptor positive and moderate/poor prognostic PBC with no evidence of symptomatic metastases were invited to participate. Patients were followed up 3-monthly with clinical assessment and TM (CA15.3 and CEA) measurements. The clinical team were blinded to TM results. Patients who were asymptomatic and developed raised (based on pre-defined cut-offs) TMs were randomized to treatment change or control (no change). Patients who developed symptomatic metastases came off the study. The primary and secondary endpoints were intervals from randomization to symptomatic metastases and to last follow-up/death respectively. Results: 85 patients (median age = 54 years [30-72]) were recruited with a median follow-up of 81 months (1-124). 12 patients coming off the study because they developed symptoms without any TM rise. Sixteen patients were randomized as described. There was no difference between the treatment change and no change groups with regards to interval from randomization to symptomatic metastases: 23 (2-62) and 22 (1-63) months respectively (p = 0.9). There was also no significant difference between the two groups in terms of randomization to last follow-up/death: 36 (7-63) and 37 (10-63) months, respectively (p = 0.9). Conclusions: Despite long follow-up, this small study has thus far shown no significant difference in outcome. However, a significant proportion of patients with metastasis had asymptomatic rise in TMs prior to their diagnosis. We have confirmed the feasibility of this study design but a larger study will be required to show if there is a benefit to this approach. No significant financial relationships to disclose.

A pineal cyst is a relatively common benign condition of the pineal gland. The clinical management of patients with a pineal cyst remains controversial, especially when patients present with nonspecific symptoms.We performed a prospective study between 2000 and 2016. All patients with a pineal cyst >7 mm were included. Epidemiologic data, presenting symptoms, surgical results, and radiographic and clinical follow-up were documented.A total of 110 patients were enrolled in the present study. The most common presenting symptoms were tension headache (62.7%), vertigo (16.4%), migraine (12.7%), syncope (10.9%), nausea (8.2%), and diplopia (8.2%). Symptoms worsened during the follow-up period in 17 patients (15.5%), improved in 13 patients (11.8%), and remained stable in 81 patients (73.6%). The mean follow-up was 79.2 months. A pineal cyst increased in size during the follow-up in 6 patients (5.5%) and decreased in size in 9 patients (8.2%). Twenty-one patients underwent pineal cyst resection; 20 patients (95.2%) reported some improvement in their presenting symptoms, and 10 patients (47.6%) were symptom free after the surgery.We present the largest clinical series of patients with pineal cysts. Surgery, if indicated properly, is a legitimate treatment modality for symptomatic patients with satisfactory results. Relief of symptoms, even nonspecific ones, is achieved in the majority of cases. Simple growth of the cyst in the first decades of life is a part of the natural course and should not be considered as an indication for surgery.

1061 Background: We have previously presented first long-term human data (median time to progression [TTP] of 25.8 months) wherein treatment of breast cancer with fulvestrant (Faslodex) significantly decreased tumor expression of estrogen receptor (ER), progesterone receptor and proliferation marker, Ki67. We now present changes in HER2, phosphorylated HER2 (pHER2), epidermal growth factor receptor (EGFR), and phosphorylated mitogen activated phospho-kinase (pMAPK) in an attempt to begin to decipher the mechanism of resistance to fulvestrant. Methods: 32 ER+ postmenopausal women with measurable locally advanced (n=22) and metastatic breast cancer (n=10) had fulvestrant (250 mg. intramuscularly monthly) as first-line primary endocrine therapy. Immunohistochemical assays were performed on sequential core biopsies taken at diagnosis (before commencing fulvestrant, T1), 6 weeks (T2), 6 months (T3), and at progression (T4) of disease. Standard H scoring method was used for detection of immunoreactivity and nonparametric tests used for analysis. Results: P value (significance at p < 0.05) of changes at subsequent time points from pretreatment level on Wilcoxon analysis is shown in the Table. Kaplan-Meier analysis did not reveal any significant relation with TTP with any of the markers. Conclusions: This series with modest initial HER2/EGFR levels showed no significant increase at progression. This appears to differ from tamoxifen resistance in vitro and some tamoxifen-resistant patients. Interestingly, fulvestrant decreased pMAPK, which may contribute to response at 6 months through (decrease in) ligand-independent MAPK/ER cross talk, while lack of significant pMAPK fall at T4 suggests some pMAPK recovery may occur at relapse versus T3. Thus, MAPK needs to be investigated further for its role in development of fulvestrant resistance. Residual availability of ER and GFRs at progression also raises possibility of treatment with further anti- GFR agents either alone or in combination with anti-ER agents. Median H score at T1 (range) T1-T2 T1-T3 T1-T4 HER2, 55 (1-190) NS NS NS pHER2, 60 (4-280) NS NS NS EGFR, 57 (6-165) NS NS NS pMAPK,150 (15-300) NS p=0.032 NS Abbreviation: NS, nonsignificant. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca

641 Background: A transient initial rise (i.e. spike) in CA15.3 has been reported during treatment with anti-cancer therapies such as tamoxifen and chemotherapy. The spike may result from the partial agonistic and cytotoxic effects of these agents, respectively. Here, we report the clinical relevance of a transient initial rise in CA15.3 in patients treated with fulvestrant, an estrogen receptor (ER) antagonist with no agonist effects. Methods: Serial measurements of CA15.3 were made at regular intervals to monitor response in patients receiving fulvestrant 250 mg/month for the treatment of ABC. Marker profile at baseline, after 1, 3, 6, 9, and 12 months of treatment and at the time of progression was correlated with clinical benefit (CB) (complete response [CR]/partial response [PR]/stable disease ≥6 months) as per UICC criteria. Results: Sixty-seven patients (41 with metastatic breast cancer [MBC]; 26 with locally advanced primary breast cancer [LAPC]) with a median age of 72.9 years were treated with fulvestrant. CB was observed in 64.2% (n=43) with objective response (OR) in 19.4% (n=13). Median duration of clinical benefit (DoCB) was 26.6+ months. CA15.3 data at month 1 were available for 33 patients with CB. Eleven patients with CB (33.3%) had a rise in CA15.3 at month 1. Comparative responses in patients with and without spike phenomenon are shown in the Table . Five MBC patients with a spike in CA15.3 had an OR (CR=1; PR=4) compared with none of the MBC patients without a spike. Conclusions: Spike phenomenon is observed in more patients with MBC than patients with LAPC, which may reflect the overall tumor load in MBC patients. Higher OR rates were observed in MBC patients with spike phenomenon, but shorter DoCB. There was no apparent difference in ER status between patients with or without spike. Fulvestrant should not be stopped during the initial 1–2 months of treatment solely on the basis of a rising tumor marker, as a spike is observed in one-third of ABC patients who achieve CB with fulvestrant. [Table: see text] [Table: see text]

Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy, and to tamoxifen in particular, have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors, notably the epidermal growth factor receptor (EGFR) and HER2. Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor (ER) signalling. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade forms the basis for the use of EGFR specific tyrosine kinase inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer, where gefitinib has been studied more extensively to date. Here, we present an overview of the current development of gefitinib in clinical breast cancer. This includes results from our clinical breast cancer trial 1839IL/0057 that demonstrate the efficacy of gefitinib within ER-positive, tamoxifen-resistant patients with locally advanced/metastatic disease, where parallel decreases in EGFR signal transduction and the Ki67 (MIB1) proliferation marker can be detected as predicted from model system studies. We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay/prevent onset of anti-hormone resistance.

Breast cancer models of acquired tamoxifen resistance, oestrogen receptor (ER)+ /ER- de novo resistance and gene transfer studies cumulatively demonstrate the increased importance of growth factor receptor signalling, notably the epidermal growth factor receptor (EGFR)/HER2, in tamoxifen resistance. Our recent in vitro studies also suggest that EGFR signalling productively cross-talks with insulin-like growth factor receptor (IGF-1R) and, where present, activates ER on key AF-1 serine residues to facilitate acquired tamoxifen-resistant growth. This paper presents our immunohistochemical evidence that EGFR/HER2 signalling (i.e. transforming growth factor (TGF)alpha, EGFR and HER2 expression; phosphorylation of EGFR, HER2 and ERK1/2 MAP kinase) is also prominent in clinical de novo resistant and modestly increased in acquired tamoxifen-resistant states, suggesting that anti-EGFR/HER2 strategies may prove valuable treatments. Primary breast cancer samples employed were obtained for (1) patients subsequently treated with tamoxifen for advanced disease where endocrine response and survival data were available and (2) ER+ elderly patients during tamoxifen response and relapse. We also present our clinical immunohistochemical findings that IGF-1R expression, its phosphorylation on tyrosine 1316, and also phosphorylation on serine 118 of ER are not only prominent in ER+ tamoxifen-responsive disease, but are also detectable in ER+ de novo and acquired tamoxifen-resistant breast cancer, where there is evidence of EGFR/ER cross-talk. Our data suggest that agents to deplete effectively ER or IGF-1R signalling may be of value in treating ER+ de novo/acquired tamoxifen resistance in addition to tamoxifen-responsive disease in vivo. IGF-1R inhibitors may also prove valuable in ER- patients, since considerable IGF-1R signalling activity was apparent within approximately 50% of such tumours.

Aims: To compare the metastatic pattern at presentation and the prognosis with metastases of 48 patients with carcinomas with tubular features (45 tubular mixed and three pure tubular) and 302 patients with tumours of ductal of no special type (DNST). Materials and methods: We carried out a retrospective study from a prospectively maintained database of all patients who developed metastatic disease from carcinoma of the breast in Nottingham, U.K., since 1997. We recorded site of first presentation with metastatic disease, radiological features, histological features and characteristics of the primary tumour. Results: The group of patients with tubular features were older at metastatic presentation (63.9 years vs 59.6 years; P=0.012), had a longer disease-free interval (87 months vs 34 months; P<0.001) and a longer survival with metastases (P<0.002). This group were less likely to have liver metastases (23% vs 41%; P=0.028), in particular multiple liver metastases (50% vs 71%; P=0.015) than the patients with DNST. Other factors known to be associated with prolonged survival, such as low histological grade of the primary invasive tumour and positive oestrogen receptor (ER) status, were more common in the group of patients with tumours with tubular features (Grade 1: 33% vs 3%; Grade 2: 42% vs 25%; Grade 3: 25% vs 72%; P<0.001), (ER positivity 76% vs 52%; P=0.009). When patients with grade 2 tumours were compared, the age at metastatic presentation, disease-free interval and the presence of multiple liver metastases were still significantly different between the two groups. Conclusion: Patients with metastatic breast carcinoma with tubular features have a longer survival with metastases than patients with metastatic DNST carcinoma. This improved survival can be explained by better well-recognised prognostic features, such as metastatic site pattern, histological grade, ER status and disease-free interval.

Aims: Brain metastases from breast cancer are an uncommon initial presentation of metastatic breast cancer, but brain metastases commonly occur later in women's metastatic illness. The aims of this study were to document the type, frequency, and temporal occurrence of brain metastases from breast cancer as well as the survival of women with such metastases, and to attempt to identify a subgroup of women at high risk of brain metastases who may benefit from pre-emptive medical intervention.Materials and methods: The radiological reports of all women presenting with metastases aged under 70 years who had subsequently died were examined. The type, frequency, temporal occurrence and survival with brain metastases were documented. Correlations were sought between the frequency of brain metastases and age at metastatic presentation, tumour grade, histological type and oestrogen receptor (ER) status.Results: Of 219 patients who had died with metastatic disease and who were under 70 years of age at metastatic presentation, 49 (22%) developed brain metastases. The development of brain metastases was related to young age (P = 0.0002), with 43% of women under 40 years developing brain metastases. Brain metastases were more common in women whose tumours were ER negative (38%) compared with women with ER-positive disease (14%) (P = 0.0003). By combining age and ER status, it is possible to identify a group of women (age under 50 years and ER negative) with a 53% risk of developing brain metastases. This group included many women who had chemotherapy for visceral metastases, and 68% had either stable disease or disease response at other sites at the time of brain metastases presentation.Conclusion: It is possible to identify a subgroup of women with metastatic breast cancer at high risk of brain metastases who may benefit from pre-emptive medical intervention, such as screening or prophylactic treatment.