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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).

PurposeTo investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy.Patients and MethodsThe IMPACT trial compared the preoperative use of tamoxifen with anastrozole alone or in combination in postmenopausal women (n = 330) with primary breast cancer. Biomarkers were measured in tumor biopsy specimens taken at baseline, and after 2 and 12 weeks of treatment.ResultsA decrease in the proliferation marker Ki67 occurred in the majority of patients: 52 (93%) of 56, 46 (85%) of 54, and 37 (84%) of 44 patients in the anastrozole, tamoxifen, and combination groups, respectively. There was a significantly greater suppression of Ki67 in the anastrozole-treated group than in the tamoxifen- or combination-treated groups, which is parallel to the greater efficacy seen for anastrozole over these two treatments in the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial. A positive relationship was noted between estrogen-receptor level and Ki67 suppression in all patients. Ki67 was reduced to a greater extent in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors. HER-2-negative tumors tended to show a greater reduction in Ki67 compared with HER-2-positive tumors, but the difference was only significant in the tamoxifen group after 2 weeks, and in the anastrozole group after 12 weeks.ConclusionThese results confirm the value of Ki67 as a molecular marker, and provide information regarding the relationships between treatment-induced changes in Ki67 and other important biomarkers. Studies such as this should help integrate agents targeted at growth factor signaling with endocrine agents in breast cancer.

ABC Access, Booking and Choice (MA Programme) AC Association of Coloproctology BAUS British Association of Urological Surgeons (www.baus.org.uk) BASO British Association of Surgical Oncologists (www.baso.org) BE Barium Enema BGS British Society of Gastrology (www.icr.ac.uk/research) BGS British Gynaecology Society (www.bspoga.ukgateway.uk) BSP Breast Screening Programme BX Biopsy CA 1. Calcium 2. Cancer 3. Carcinoma CAT Cancer Action Team C and D Capacity and Demand CHART Continuous Hyperfractionated Accelerated Radiation therapy CHI/CHAI Commission for Health Improvement (www.healthcarecommission.org.uk) Commission for Healthcare Audit and Inspection CSC-IP Cancer Services Collaborative-Improvement Partnership CT Computerised tomography (Radiology), a type of body scan

In both women and men, breast lumps are the most common presentation of breast cancer. The following cases illustrate the pathological entity of granulomatous mastitis, which can present simulating breast cancer – including the first description of this condition in a male. These cases demonstrate the difficulty in clinical diagnosis and emphasizes that although there may be clues from the history, clinical awareness that this condition can mimic breast cancer in all aspects of the triple assessment process should arouse suspicion. The importance of histological diagnosis by core or excision biopsy is stressed, as with accurate diagnosis of granulomatous mastitis there is a mandate to avoid unnecessary surgery.

Aims: To review our institution's practice of treatment of a mammographically detected population of ductal carcinoma in situ (DCIS) patients and to determine the outcome. Methods: Between April 1989 and March 1994, 304 women with median age 59 years (range 51–65) with DCIS detected on screening mammogram, were treated in the Newcastle General and Royal Victoria Infirmary Hospitals, Newcastle-upon-Tyne, UK. More than half of the women (n=176, 57.8%) decided to have mastectomy. Other treatment options were wide local excision (WLE) with radiotherapy (n=97, 32%) and WLE alone (n=31, 10.2%). All except five received adjuvant hormone treatment. Results: Predominant DCIS was comedo in 122 (42%), followed by cribriform in 87 (30%) and micropapillary in 44 (15%) cases. Grade I was found to be commonest grade (54%) followed by grade II (27%) and grade III (11%). With a median follow-up of 88 months, there were six (2%) recurrences, all of which were in women who were given breast conservation treatment, WLE with radiotherapy (n=1, 1%) and without radiotherapy (n=5, 16.6%). Mastectomy in this series was not associated with any recurrence at all. In three cases the recurrence was invasive, one of who also had distant metastasis. Conclusions: The findings of this study suggest that in women with DCIS suitable for breast conservation, WLE when combined with radiotherapy is associated with a very low recurrence rate.

This study prospectively examined tumour bed biopsies in 135 consecutive patients undergoing conservative surgery for breast carcinoma. All had wide resection of the primary tumour and histologically clear margins. Twelve patients (9%) had positive tumour bed biopsies. Two subgroups of patients had positive bed biopsies; those with ductal carcinoma in situ, and a second group with more aggressive disease characterized by lymph node involvement, vascular invasion and a higher grade and mitotic count. As the majority of recurrences from breast carcinoma occur in the region of the primary tumour, bed biopsy may aid in the identification of a group of patients with multifocal or aggressive disease who are at increased risk of local recurrence.

Gynaecomastia commonly affects pubertal boys. We report a rare case of bilateral ductal carcinoma in situ found incidentally after breast reduction surgery in a young man with neurofibromatosis.

Optimal margins for wide local excision (WLE) have not been clearly established. Larger margins lead to lower recurrence rates but at the expense of cosmetic appearance. NICE guidelines recommend a 2 mm margin for ductal carcinoma in-situ (DCIS), whilst the British Association of Surgical Oncology (BASO) recommend units develop local guidelines. There are presently no specific guidelines for invasive cancer. We surveyed members of the Association of Breast Surgeons (ABS) in order to establish current practice nationally. We hypothesised that larger units may accept narrower excision margins to the benefit of better cosmesis.A postal questionnaire was sent to all ABS members in October 2010. This consisted of questions about the current practice of the surgeon and their unit. 481 questionnaires were posted in total, all questionnaires returned by April 2011 were analysed.Questionnaire response rate was 60% (281). Surgeons operating on over 50 cancers per year accepted smaller margins than those operating on less than 50 (p0.02). Acceptable adequate anterior and radial margins ranged from 0 to 10 mm for DCIS and 0 to 5 mm for invasive cancer. A variety of approaches to re-excising anterior margins were reported.This survey suggests that substantial variations exist in current practice with regard to the approach to WLE. Operator workload appears to influence what is deemed to be an acceptable margin. There is a need for standardised national and international guidelines.

Aim—To determine whether the introduction of a standard reporting proforma has led to an improvement in the completeness of histopathology reports for breast cancer excision specimens. Methods—A standard reporting proforma was designed using the Royal College of Pathologists' minimum dataset for breast cancer histopathology reports and the national histopathology reporting form of the National Health Service (NHS) breast screening programme. This was introduced into our department in June 1999, with reports generated from the proforma replacing the standard text reports. The pathological information contained in 50 text reports issued before the introduction of the proforma and 50 reports generated using the proforma was compared with the minimum dataset and NHS breast screening programme guidelines. Results—A general improvement in documentation of individual pathological features was noted after introduction of the proforma. This was most significant in relation to documentation of features, such as microcalcification and ductal carcinoma in situ. In addition, important features such as tumour grade, tumour size, and hormone receptor status were documented more frequently in the proforma group. There was an overall increase in the number of reports regarded as complete after introduction of the proforma. Conclusions—The introduction of a standard proforma led to a significant improvement in the completeness of breast cancer histopathology reports in this centre, but continued vigilance is needed to ensure that standards continue to improve. Key Words: breast • proforma • histopathology • minimum dataset

Aims Sentinel lymph node biopsy (SLNB) is an important method of staging early breast cancer because of the inherent benefits it confers on patients in terms of arm function and quality of life. Its success depends on a high level of accuracy in detecting the sentinel node. This is achieved by a dual mapping technique that employs a radio-labelled nanocolloid and a vital blue dye. The vital dyes however carry the risk of anaphylaxis, and as more surgeons employ SLNB in their daily practice, a proportionate rise in the number of anaphylactic reactions can be expected. A comprehensive review of risks and benefits associated with using vital blues dyes has not been published and therefore a retrospective review was undertaken of the different levels of anaphylaxis associated with vital dyes as well as their benefits in SLNB. Methods An OVID MEDLINE search was performed of the English published literature using appropriate search terms to find published trial data and case series that focused on adverse reactions to vital blue dyes. Results The risk of severe anaphylaxis (grade 3) can be as low as 0.06%, and up to 0.4% for patients undergoing SLNB when data is analysed from large trials. Furthermore, adverse reactions associated with blue dyes are reversible with appropriate management. Conclusions Surgeons should continue to use vital dyes to ensure that SLNB remains a highly sensitive procedure.

Summary Objective To look at the national coverage, composition and discussion of breast cancer multi-disciplinary teams (MDTs) in England. Design and data source All breast units in England both symptomatic and screening were sent a questionnaire. Main outcome measures Attendance of core members at MDT meetings; Percentage of patients discussed with a treatment plan; Private patients discussed; Reconstructive surgery. Results The majority of core members of the breast MDT attend weekly meetings to discuss the multidisciplinary management of patients with breast cancer, although attendance by medical oncologists and reconstructive breast surgeons is limited. Three MDTs never had a radiologist present and 3 never had a pathologist present at the MDT meeting. Most breast MDTs have a meeting coordinator to collect case-notes, radiographs and pathology reports to facilitate the meeting. Seventy-nine out of 134 teams discuss every cancer patient and 118 also discuss private patients. Twenty-seven teams record the outcome of the MDT meeting electronically, 32 teams book surgery, 16 radiotherapy and 15 book chemotherapy direct from the MDT meeting.

The study of changes in proliferation as a marker of treatment benefit during presurgical endocrine treatment of breast cancer has become increasingly popular, particularly using the nuclear marker Ki67, and holds the potential for prioritizing new treatments for full clinical development. There are weakly significant relationships between Ki67 change and clinical response that differ according to data handling. In the neoadjuvant Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen trial, suppression of Ki67 at both 2 and 12 weeks was greater with the aromatase inhibitor anastrozole than with either tamoxifen or the combination of anastrozole and tamoxifen. We report here that absolute values of Ki67 after 2 weeks were also significantly lower with anastrozole than with tamoxifen and the combination. This indicates that it may be possible to make such comparisons using surgical samples only. We argue that these changes in proliferation and concurrent changes in apoptosis may be expected to be more predictive of adjuvant benefit from endocrine therapy than clinical response.

Neoadjuvant (preoperative) therapy for breast cancer may allow for the development of intermediate markers of treatment benefit, thereby circumventing the need for efficacy trials of adjuvant therapy, which require much larger patient numbers and longer follow-up. The aim of this study--as part of the Immediate Preoperative "Arimidex" (anastrozole), Tamoxifen, or Arimidex Combined with Tamoxifen (IMPACT) trial (n = 330)--was to test the hypotheses that changes in Ki-67 after 2 weeks and/or 12 weeks: (i) differed between treatments, (ii) predicted clinical tumor response, and/or (iii) may predict long-term outcome differences between treatments in adjuvant therapy.The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared these same agents in the adjuvant setting. Biomarkers were measured in biopsy specimens taken before and after 2 and 12 weeks of treatment.Suppression of the proliferation marker Ki-67 after 2 and 12 weeks was significantly greater with anastrozole than with tamoxifen (P = 0.004 and P0.001) but was similar between tamoxifen and the combination (P = 0.600 and P = 0.912). This result closely parallels that seen for the relative recurrence-free survival with the treatments after a median follow-up of 31 months in the ATAC trial in 9,366 patients. Against expectations, apoptosis was not increased in any of the treatment arms.The data indicate that short-term changes in proliferation in the neoadjuvant setting may be able to predict outcome during adjuvant use of the same treatments. If this can be confirmed, these findings could lead to a profound change in approaches to drug development in breast cancer. The data indicate that estrogen is not an important survival factor for human breast cancer cells.

Aim To determine the incidence of pre-malignant and malignant conditions in radial scars identified from screening mammograms in women taking part in the UK NHS breast cancer screening programme. Methods All women in our screening population from 1988 to 2002 with a radiological diagnosis of radial scar or complex sclerosing lesion confirmed on subsequent histopathology were included in this study. Patients were investigated with fine needle aspiration cytology then localisation biopsy ( n =46) or straight to localisation biopsy ( n =78). Patients where divided into two groups, one with pure RS/CSL with no associated epithelial features and the second with associated ADH, DCIS or invasive cancer. Results One hundred and twenty-four lesions were confirmed histologically as radial scar or complex sclerosing lesions. The median age was 58 years. Of the 124 patients, 82 were pure RS/CSL. Forty-two had associated epithelial lesions, 22 patients had ADH and 20 patients had either in situ or invasive carcinoma. Where FNA was performed ( n =46), mammograms had shown three lesions suspicious of cancer, which were not proven histologically. Mammograms picked up five malignancies out of the nine RS/CSL with associated cancers. Of these, FNA confirmed malignancy in only two patients. Where FNA was not done ( n =78), mammogram had read five pure RS/CSL as cancers. It picked up only four cancers in RS lesions with DCIS/Ca out of 11. Conclusion All screen-detected stellate lesions should be excised due to their association with pre-malignant and malignant conditions.

Several studies have found elevated levels of adrenal androgens in postmenopausal women and depressed levels in premenopausal women with breast cancer, suggesting a role for adrenal androgens in the aetiology of breast cancer. We have measured serum dehydroepiandrosterone sulphate and androstenedione in 81 women with primary operable breast cancer and 62 age-matched controls. Results showed that serum levels of both adrenal androgens fell significantly with age in women with breast cancer ( P =0.003). However, no relationship was observed between serum adrenal androgen levels and body mass index in either women with breast cancer or controls. Dehydroepiandrosterone sulphate levels were elevated in postmenopausal women with breast cancer compared to controls, and this was not due to preoperative stress. No differences were observed in androstenedione levels between premenopausal or postmenopausal women with breast cancer and controls, nor were dehydroepiandrostenedione sulphate levels significantly different between premenopausal women with breast cancer and controls. These results suggest that dehydroepiandrosterone sulphate has a role in the aetiology of postmenopausal breast cancer.

Abnormalities in p53 gene expression have been implicated in many inherited and sporadic forms of malignancies in humans. Immunohistochemical staining using monoclonal antibody D0-7 for the p53 protein expression was performed in 81 cases of pure DCIS, 14 benign breast lesions and 2 cases with normal breast tissue. Expression of p53 protein was detected in 15 (18.5%) cases of pure DCIS. Thirteen (25%) of the 52 comedo type DCIS showed p53 protein expression compared with 2 (6.9%) of the 29 non-comedo types (P0.02). p53 protein expression was also associated with high nuclear grade (P0.001) and high mitotic index (P0.05). The pattern of p53 protein staining was diffuse in one comedo type DCIS, regional in 6 comedo types, and focal in the remaining 8 cases (6 comedo type and 2 micropapillary type DCIS). The patient with comedo type DCIS showing diffuse staining has a family history of breast cancer in the first and second degree relatives (sister and maternal aunt). Clinical follow-up data was available in 52 cases. Follow-up period ranged from 9 to 55 months. Three patients, who were primarily treated by local excision, have had a documented local recurrence in the form of residual tumor within a short interval of 5 to 11 months. In all these three patients both the original and the recurrent tumors are negative for p53 protein expression. The difference in the local recurrence rate between p53 positive (0/15) and p53 negative (3/37) cased does not reach statistical significance (p0.05). We interpret that the local tumor recurrence in these three cases within a short period after primary excision is due to the presence of residual tumor at the excision site and is independent of the p53 gene alteration. It is concluded that p53 protein expression in DCIS is associated with comedo subtype, high nuclear grade, and high mitotic index, and is a promising new parameter to evaluate the cellular biology and prognosis of DCIS.

Background: The rate of mastectomy versus breast conserving surgery is an audit measure for breast units in the UK for both symptomatic and screen detected breast cancer patients.There are wide variations between units in the UK. Patients and Methods: 1009 women who had surgical treatment for breast cancer (580 screen detected,429 symptomatic)in our unit from Jan2004Dec2005 were included in this study.Data was obtained from multidisiplinary team meeting reports and our audit database. Results